Patients with newly diagnosed, unresectable, metastatic and measurable ASPS will also be eligible if they show clinical evidence of disease progression (including history and increasing physical symptoms); on-study documentation will include a physician’s rationale that supports evidence of clinical disease progression (i.e., increasing tumor pain)Xx_NEWLINE_xXMetastatic and/or unresectable (cT4b) diseaseXx_NEWLINE_xXProgression of disease after 1 or 2 prior regimens in the metastatic settingXx_NEWLINE_xXThe patient has metastatic disease or locally recurrent, unresectable diseaseXx_NEWLINE_xXDefinitive clinical or radiologic evidence of metastatic disease; required imaging studies must have been performed within 90 days prior to randomizationXx_NEWLINE_xXPatients must have had =< 1 prior cytotoxic regimen for metastatic disease (unless enrolling in the Progressive Brain Metastases Cohort); note that endocrine and immunotherapies do not count as cytotoxic regimensXx_NEWLINE_xXClinical or radiographic evidence of metastatic disease; metastatic workup is not required, but is recommended for patients with clinical stage III disease; Note: isolated ipsilateral supraclavicular node involvement is permittedXx_NEWLINE_xXPatients must have melanoma that is metastatic and clearly progressive on prior therapyXx_NEWLINE_xXDefinitive clinical or radiologic evidence of metastatic diseaseXx_NEWLINE_xXNo evidence of residual involved lymph node disease or metastatic disease at the time of registration based on clinician assessment of imaging; the treating physician will determine if incidental lesions on imaging require workup to exclude metastatic disease; if based on review of images, the treating physician determines the patient to be stage III, then the patient is eligibleXx_NEWLINE_xXPatients must not have metastatic disease (i.e., must be M0); patients must not have locally recurrent diseaseXx_NEWLINE_xXExtent of disease:\r\n* Patients with non-metastatic and metastatic disease are eligible\r\n* Initially unresectable patients, with or without metastatic disease, are eligible as long as there is a commitment at enrollment to resect the primary tumorXx_NEWLINE_xXDefinitive clinical or radiologic evidence of metastatic diseaseXx_NEWLINE_xXDiagnosis of metastatic adenocarcinoma of colon or rectum without previous chemotherapy or any other systemic therapy for metastatic colorectal cancerXx_NEWLINE_xXPatients must have measurable disease at baseline and 3 or fewer discrete, extracranial metastatic disease sites that are technically amenable to stereotactic body radiation therapy (SBRT) or resection (at least one disease site must be amenable to radiation); some examples of what constitutes specific radiation treatment sites defining distinct metastatic disease sites are as follows: a) A lesion in each adrenal gland represents 2 of 3 sites of metastatic disease allowed to be treated on protocol; b) Similarly to NRG study RTOG 0631, disease in 2 contiguous vertebral bodies (with up to 6 cm of paraspinal extension) can represent one site of disease in the spine; non-contiguous lesions in vertebral bodies separated by one vertebral body free of disease should be viewed as 2 sites of treatment; and c) Two lesions in such close proximity to one another that treatment with one isocenter is more accurate and safer in the liver, lungs, or other similar anatomic locations should be viewed as one site of metastatic disease treatment.Xx_NEWLINE_xXFor de novo stage IV NSCLC patients (patients with metastatic disease at first presentation), primary disease must be treatable with local therapy in the form of SBRT or hypofractionated radiation. If the primary disease is found in the peripheral or central lung parenchyma without nodal disease, for instance, SBRT may be employed at the discretion of the treating institution. If primary disease is more advanced with involvement of the mediastinum (T4 tumor, N1-N3 disease, etc.), these volumes should be technically treatable with hypofractionated radiation; surgery should only be used for metastatic tumors that can be completely resected by lobectomy, segmentectomy, or wide wedge resection.Xx_NEWLINE_xXPatients with more than 3 discrete locations of extra-cranial metastatic disease after first-line systemic therapy requiring more than 3 radiation/surgery plans to cover these distinct metastatic disease entities.Xx_NEWLINE_xXPatients who have gross residual disease or distant metastatic diseaseXx_NEWLINE_xXPrior palliative radiation treatment for metastatic disease to be treated on the protocol (including radiopharmaceuticals)Xx_NEWLINE_xXDefinitive clinical or radiologic evidence of metastatic disease; no nodal involvement or evidence of metastatic disease allowed as defined by screening of the pelvisXx_NEWLINE_xXPatients must have advanced or metastatic MCC defined as evidence of distant metastasis(es) on imaging\r\n* Patients with locoregionally confined disease are not eligibleXx_NEWLINE_xXDefinitive evidence of metastatic meningiomaXx_NEWLINE_xXPatient must be eligible for treatment with nivolumab; patients previously treated with nivolumab, pembrolizumab or atezolizumab and who have progressed are eligible; patients with targetable with EGFR or ALK mutations are eligible after disease recurrence or progression after at least one targeted therapy for advanced or metastatic diseaseXx_NEWLINE_xXKnown definitive clinical or radiologic evidence of metastatic diseaseXx_NEWLINE_xXPatients must not be at short term risk for life threatening complications (such as airway compromise or bleeding from locoregional or metastatic disease,).Xx_NEWLINE_xXPatient must have unresectable diseaseXx_NEWLINE_xXMetastatic disease that is not amenable to curative surgery or radiationXx_NEWLINE_xXPatients who have received prior ipilimumab treatment for metastatic melanoma are not eligible.Xx_NEWLINE_xXPresence of distant metastatic diseaseXx_NEWLINE_xXPatients must have received irinotecan therapy in the metastatic setting; there are no limitation on number of prior therapies in the metastatic settingXx_NEWLINE_xXHave histologically confirmed unresectable or metastatic nonsquamous NSCLC and having received no prior systemic therapy for metastatic disease.Xx_NEWLINE_xXHave a history of an invasive metastatic disease, except for the following:Xx_NEWLINE_xXIndividuals with a history of invasive metastatic disease are eligible if they have been disease free for at least 2 years and are deemed by the Investigator to be at low risk for recurrence of that metastatic disease;Xx_NEWLINE_xXPresence of metastatic disease (stage IV NSCLC) is not allowed; subjects must be evaluated with a CT or PET scan prior to registration for protocol therapy to exclude metastatic diseaseXx_NEWLINE_xXHas cSCC that is either metastatic defined as disseminated disease, and/or unresectable disease that is not curable by surgery, radiation, or systemic therapy.Xx_NEWLINE_xXHas metastatic disease defined as disseminated disease distant to the initial/primary site of diagnosis, and/or must have locally recurrent disease that has been previously treated (with either surgery, radiotherapy, or systemic therapy), and is not amenable to either curative surgery, radiotherapy, or concurrent chemoradiotherapy treatment.Xx_NEWLINE_xXPatients with distant metastatic diseaseXx_NEWLINE_xXPatients must have at least ONE of the following: 1) Recurrent/progressive disease at any time prior to study enrollment, 2) Refractory disease, 3) Persistent diseaseXx_NEWLINE_xXPatients must have an accessible metastatic lesion for pretreatment core biopsy.Xx_NEWLINE_xXThe patient must have multiple sites of metastatic disease with at least one lesion amenable to treatment with stereotactic radiation therapy (SBRT) in the lung or liver and at least one lesion not being irradiated and meeting RECIST 1.1.Xx_NEWLINE_xXPatients who have received prior immunotherapy for unresectable or metastatic diseaseXx_NEWLINE_xXPatients may have progressive systemic diseaseXx_NEWLINE_xXSAFETY RUN-IN: Disease stage: unresectable metastatic diseaseXx_NEWLINE_xXSAFETY RUN-IN: Patients received up to 2 prior regimens for their disease in the metastatic settingXx_NEWLINE_xXRANDOMIZED PHASE II CLINICAL TRIAL: Patients received up to 2 prior regimens for their metastatic diseaseXx_NEWLINE_xXKnown spinal cord compromise or instrumentation due to metastatic disease. Radiation therapy for metastatic disease is allowed.Xx_NEWLINE_xXDisease status:Xx_NEWLINE_xXPatients with evidence of metastatic disease involvement in viscera or boneXx_NEWLINE_xXHave evidence of a distant metastatic diseaseXx_NEWLINE_xXPatients may have had up to 3 prior regimens for metastatic diseaseXx_NEWLINE_xXMetastatic CRPCXx_NEWLINE_xXPrior treatment with nab-P for the treatment of metastatic disease.Xx_NEWLINE_xXKnown metastatic diseaseXx_NEWLINE_xXPathologically (histologically or cytologically) proven diagnosis of solid malignancy\r\n* NOTE: fludeoxyglucose F 18 (FDG)-positron emission tomography (PET) scans are required for full staging of metastatic disease prior to enrollment; if subject has had an FDG-PET/computed tomography (CT) scan within the last 8 weeks, it will not need to be repeated\r\n* NOTE: pathological confirmation is not required for all disease sites as long as the sites of metastatic disease are radiographically and clinically consistent with metastatic disease from a known (biopsy proven) primary\r\n* NOTE: biopsy does not have to be performed at the time of enrollment for patients with recurrent disease as long as biopsy was performed at time of initial diagnosisXx_NEWLINE_xXPatients are stage IV (M1) or recurrent with any combination of T and N with oligometastatic disease as defined by 5 or fewer total sites of metastatic disease \r\n* NOTE: number of metastatic sites based on most recent imaging studies in order to determine number of oligometastatic sites; for example, if patient initially had 10 sites of metastatic disease, was treated with chemotherapy resulting in complete response of 5 lesions and stable disease of 5 lesions, and no new lesions based on repeat imaging, the patient would be eligible for treatment on protocolXx_NEWLINE_xXOther\r\n* Diffuse metastatic spread confined to one organ system is ineligible; examples of this include leptomeningeal spread in the CNS and peritoneal carcinomatosis. \r\n* Metastatic disease sites must be treatable with stereotactic radiosurgery (at discretion of treating physician); patients with oligometastatic sites not amenable to SRS treatment, either through size or locations, are ineligible for this trialXx_NEWLINE_xXMetastatic disease sites must be treatable with SRS (at discretion of treating physician)Xx_NEWLINE_xXExamples of patients ineligible for trial\r\n* T1N1M1 NSCLC with 1 CNS lesion, 1 bone lesion, 1 adrenal lesion and a cervical lymph node (4 sites of metastatic disease)\r\n* T2N1M1 Gastric cancer with 6 liver lesions (more than 5 sites of metastatic disease)Xx_NEWLINE_xXPatients with unresectable disease are eligibleXx_NEWLINE_xXProgressive, radioactive iodine-refractory, loco-regional recurrent or metastatic disease.Xx_NEWLINE_xXEvidence or high suspicion of metastatic disease at enrollmentXx_NEWLINE_xXUnresectable or metastatic GISTXx_NEWLINE_xXDefinitive clinical or radiologic evidence of metastatic disease.Xx_NEWLINE_xXexperienced disease progression during or after prior first-line regimen for metastatic diseaseXx_NEWLINE_xXProgressed on or intolerant of at least 2 prior cancer therapy regimens administered for metastatic disease.Xx_NEWLINE_xXParticipant has received more than one prior chemotherapy regimen for metastatic disease.Xx_NEWLINE_xXDisease statusXx_NEWLINE_xXNo evidence of extrahepatic metastatic diseaseXx_NEWLINE_xXMetastatic disease impinging on the spinal cord or threatening spinal cord compression; patients that have had previous treatment of disease with impinging on the cord with either surgery or radiotherapy with clinical or radiographic evidence of response or stability are eligibleXx_NEWLINE_xXPathologically confirmed squamous cell carcinoma of the head and neck with evidence of metastatic disease or locally recurrent disease considered incurable by local therapies; patients without pathologic or cytologic evidence of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluationXx_NEWLINE_xXMetastatic disease impinging on the spinal cord or threatening spinal cord compressionXx_NEWLINE_xXParticipants must have histologically or cytologically confirmed invasive breast cancer, with metastatic disease; participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluationXx_NEWLINE_xXDefinitive clinical or radiologic evidence of metastatic disease, as documented by the treating institutionXx_NEWLINE_xXMetastatic non-small cell lung cancer (NSCLC), metastatic urothelial carcinoma or microsatellite instability high metastatic colorectal cancer (except for patients enrolling based on elevated TMB); For patients enrolling based on elevated TMB, patients with metastatic NSCLC, metastatic urothelial carcinoma or metastatic colorectal cancer will be allowed to enrollXx_NEWLINE_xXAny patient with metastatic disease.Xx_NEWLINE_xXPathologically proven, radiologic or clinical evidence of distant metastatic disease (this includes all disease below the clavicles, as well as disease metastatic to the bone, brain, or in the spinal canal)Xx_NEWLINE_xXPatients with spinal diseaseXx_NEWLINE_xXPatient does not have metastatic diseaseXx_NEWLINE_xXPatients may have received adjuvant chemotherapy and up to two prior chemotherapy for metastatic or locally recurrent disease; no prior nab-paclitaxel or mifepristone therapy for metastatic disease will be allowedXx_NEWLINE_xXHas not received prior systemic treatment for metastatic NSCLC.Xx_NEWLINE_xXBefore the first dose of study drug: a) Has received prior systemic cytotoxic chemotherapy for metastatic disease; b) Has received other targeted or biological antineoplastic therapy (e.g., erlotinib, crizotinib, cetuximab) for metastatic disease; c) Has had major surgery (<3 weeks prior to first dose).Xx_NEWLINE_xXPatient has evidence of metastatic diseaseXx_NEWLINE_xXEvidence of measurable, locally recurrent or metastatic disease based on imaging studies within 28 days before the first dose of study drug.Xx_NEWLINE_xXHas received at least 1, but no more than 2, prior lines of systemic therapy for locally recurrent and/or metastatic disease.Xx_NEWLINE_xXNo metastatic disease as per NCCN guidelines (www.nccn.org) - Bone scan indicated to r/o metastatic disease if clinical T1 and PSA > 20 or T2 and PSA > 10Xx_NEWLINE_xXThe presence of extra capsular, seminal vesicle invasion or metastatic disease.Xx_NEWLINE_xXMetastatic melanoma eligible for {or currently oXx_NEWLINE_xXConfirmed metastatic diseaseXx_NEWLINE_xXDisease Status: Patients must have ONE of the following:Xx_NEWLINE_xXPatients must have at least one of the following for a diagnosis/disease status:\r\n* Unresectable disease\r\n* Metastatic disease\r\n* Medically unfit for surgical resection but with an expected survival of > 3 months, Eastern Cooperative Oncology Group (ECOG) < 2 and New York Heart Association (NYHA) status =< II\r\n* Disease where no conventional therapy leads to a survival benefit > 6 months in the respective cohort and line of therapy for which the patient is otherwise eligible\r\n* Actionable alterations determined by FoundationOneXx_NEWLINE_xXPHASE I: No limit on the number of prior systemic therapies for metastatic diseaseXx_NEWLINE_xXPHASE IB: =< 2 lines of prior systemic therapy for metastatic disease (if patients have metastatic disease)Xx_NEWLINE_xXKnown distant metastatic disease (e.g. pulmonary or hepatic metastases)\r\n* Subjects with malignant lymphadenopathy in the abdomen or pelvis considered appropriate for radical cystectomy and lymphadnectomy with the goal of complete resection of all malignant disease are allowedXx_NEWLINE_xXCancer that is recurrent, metastatic, or unresectable and for which no effective or curative measures exist.Xx_NEWLINE_xXPatients with distant metastatic disease or otherwise not confined to the ipsilateral hemithoraxXx_NEWLINE_xXPatients must have evidence of disease progression prior to enrollmentXx_NEWLINE_xXInitial diagnosis of metastatic disease must have occurred ?8 weeks prior to entry in the study.Xx_NEWLINE_xXAdvanced stage III, IV (N2C, N3) or surgically unresectable disease or disease that cannot be fully resected, obvious radiologic extracapsular spread (ECS), supraclavicular or matted metastatic disease, > 3 cervical nodes; (these patients will be placed on the quarterback trial due to advanced state of disease and poor prognostic features)Xx_NEWLINE_xXPatients must have histologically or cytologically confirmed papillary RCC\r\n* Patients with bilateral multifocal disease can have tumors localized to the kidney or have metastatic disease\r\n* Patients with sporadic papillary RCC (but without multifocal disease) should have advanced disease that is considered unresectableXx_NEWLINE_xXEvidence of metastatic diseaseXx_NEWLINE_xXPART II: Alk PO4 =< 3 x ULN (except for patients with documented metastatic disease to bone and/or liver)Xx_NEWLINE_xXPatients must have a diagnosis of metastatic melanoma which is measurable either clinically or radiologicallyXx_NEWLINE_xXPatients with a history metastatic melanoma involving the brain will be excluded if they have active disease or have had active disease within the prior six months that was not controlled with surgery or radiotherapyXx_NEWLINE_xXPatients must have previously received at least one systemic standard care (or effective salvage chemotherapy regimens) for metastatic or unresectable disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurredXx_NEWLINE_xXPatients must have completed or had disease progression on at least one prior line of disease-appropriate therapy for metastatic disease, or not be a candidate for therapy of proven efficacy for their disease due to an underlying physical conditionXx_NEWLINE_xXPatients may not have metastatic disease, unless aged 2-10 with embryonal histologyXx_NEWLINE_xXPatients must have radiologic evidence of disease progressionXx_NEWLINE_xXPatients with metastatic disease, including leptomeningeal or subarachnoid disseminated disease.Xx_NEWLINE_xXHas evidence of metastatic disease at time of diagnosis.Xx_NEWLINE_xXCohort A: unresectable or metastatic melanomaXx_NEWLINE_xXCohort B: metastatic NSCLCXx_NEWLINE_xXHas at least 2 identified sites of metastatic disease by imaging.Xx_NEWLINE_xXHas distant metastatic disease on imaging or staging laparoscopy at the time of study entryXx_NEWLINE_xXMetastatic melanoma, gastrointestinal, or genitourinary cancer with at least one lesion that is resectable; only patients with metastatic gastrointestinal cancer will be eligible for enrollment on the phase I portion of the study; patients with metastatic melanoma, gastrointestinal, or genitourinary cancer will be eligible for enrollment on the phase II portion of the studyXx_NEWLINE_xXDisease status as defined as.Xx_NEWLINE_xXDiagnosis of metastatic diseaseXx_NEWLINE_xXPresence of metastatic diseaseXx_NEWLINE_xXRecurrent/metastatic disease, fulfilling at least one of the criteria defined below:\r\n* Incurable disease as assessed by surgical or radiation oncology\r\n* Metastatic (M1) disease\r\n* Persistent or progressive disease following curative-intent radiation, and not a candidate for surgical salvage due to incurability or morbidity; patients who decline radical surgery are eligibleXx_NEWLINE_xXEvidence of disease progression at the time of enrollmentXx_NEWLINE_xXIf Her2 positive, must have received and have progressed or are intolerant to treatment with trastuzumab for metastatic or recurrent diseaseXx_NEWLINE_xXRecurrent and/or metastatic unresectable colorectal cancer with hepatic metastasesXx_NEWLINE_xXTotal volume of metastatic disease more than 30 cm^3 excluding lesion to be resectedXx_NEWLINE_xXPresence of distant metastatic diseaseXx_NEWLINE_xXPatients (both male and female) with advanced/metastatic GI cancers eligible for capecitabine monotherapy, including metastatic colorectal cancer, metastatic gastric and esophageal cancers, and unresectable or metastatic pancreatic cancer and cholangiocarcinoma, including gall bladder carcinoma, concurrent trastuzumab is allowed for HER2 positive gastric/esophageal cancerXx_NEWLINE_xXPathologic confirmation of respective malignancies; biopsy of metastatic disease is preferred but not mandatoryXx_NEWLINE_xXPatient has used capecitabine in a past regimen for metastatic diseaseXx_NEWLINE_xXKnown metastatic diseaseXx_NEWLINE_xXMetastatic diseaseXx_NEWLINE_xXPrior radiation treatment for metastatic diseaseXx_NEWLINE_xXPresence of metastatic disease that can be biopsied by any methodology applicableXx_NEWLINE_xXHas current or a history of any distant metastatic disease (including brain); an isolated or oligo-metastatic regional recurrence may be allowed if all other criteria are met, curative attempt is being pursued and if PI approval is grantedXx_NEWLINE_xXEvidence of metastatic diseaseXx_NEWLINE_xXProgression of diseaseXx_NEWLINE_xXDistant metastatic disease of peritoneum: \r\n* Positive peritoneal cytology.\r\n* Carcinomatosis on diagnostic laparoscopy or laparotomy.Xx_NEWLINE_xXFor patients with metastatic disease:Xx_NEWLINE_xXHas known metastatic disease as determined by conventional staging studies.Xx_NEWLINE_xXKnown Gilbert’s diseaseXx_NEWLINE_xXParticipants must have histologically or cytologically confirmed invasive breast cancer, with metastatic disease; participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluationXx_NEWLINE_xXHistological or cytological confirmation of locally recurrent or metastatic rectal adenocarcinoma\r\n* Note: Patients with locally recurrent/persistent disease within the pelvis after primary therapy (chemotherapy, surgery, and/or radiotherapy) are eligible\r\n* Note: Patients who have had prior pelvic radiotherapy with a total dose of =< 54 Gy are eligible\r\n* Note: Patients with or without metastatic disease (excluding untreated central nervous system [CNS] metastasis), with primary pelvic disease or pelvic recurrence are eligible\r\n* Note: Patients with pelvic disease that is potentially resectable or unresectable are eligibleXx_NEWLINE_xXNo evidence of metastatic disease as determined by imaging procedures.Xx_NEWLINE_xXPatients must not have received prior pembrolizumab or other anti-PD1/PDL1 therapies for their metastatic diseaseXx_NEWLINE_xXHistologically confirmed breast cancer (infiltrating ductal or lobular breast carcinoma) with evidence of measurable metastatic disease; metastatic disease must be biopsy proven\r\n* Since histologic type, lymphatic permeation, blood vessel invasion, and degree of anaplasia may be prognostic variables, appropriate slides of the primary lesion will be requested for future review; HER2, estrogen, and progesterone receptor positivity will be recordedXx_NEWLINE_xXPatients with known Gilbert’s diseaseXx_NEWLINE_xXHas pathologically confirmed metastatic pancreatic adenocarcinoma that has progressed after, at least, a first line of standard systemic chemotherapy for the metastatic disease, OR participants with pathologically confirmed metastatic adenocarcinoma of the colon or rectum who have progressed to at least 2 lines of standard systemic chemotherapy for the metastatic disease, OR participants with pathologically confirmed locally advanced or metastatic sqEC that has progressed after at least a first line of standard systemic therapy for metastatic disease. First-line participants can be enrolled if a platinum doublet is contraindicated or refused by the participants, OR pathologically confirmed locally advanced or metastatic sqNSCLC that has progressed after at least 2 lines of standard systemic therapy for metastatic disease.Xx_NEWLINE_xXPatients with either a confirmed diagnosis of (1) metastatic colorectal cancer in liver based on histopathology of either a prior resection of primary lesion or a biopsied liver metastatic lesion; (2) advanced HCC (BCLC-stage C) with a characteristic 3 or 4-phase CT or dynamic contrast enhanced MRI finding showing arterial uptake followed by \washout\ of contrast in the venous-delayed phases per American Association for the Study of Liver Disease (AASLD) criteria; (3) metastatic gastric cancer; (4) metastatic NSCLC without EGFR or ALK mutation.Xx_NEWLINE_xXPatients with distant metastatic disease (prostate adjacent adenopathy is not an exclusion)Xx_NEWLINE_xXUp to 3 prior chemotherapy regimens or metastatic diseaseXx_NEWLINE_xXPatients must have had at least one line of therapy in the metastatic settingXx_NEWLINE_xXDISEASE SPECIFIC EXPANSION COHORTS: Prostate cancers patients enrolled on this study must have:\r\n* Metastatic or advanced (incurable and unresectable) castration resistant metastatic cancer\r\n* Received at least one additional line of anti-androgen therapy with abiraterone or enzalutamide\r\n* Measurable disease is not required for enrollmentXx_NEWLINE_xXSubjects must have a histologic diagnosis of urothelial carcinoma with radiologic, histologic or cytologic evidence of metastatic diseaseXx_NEWLINE_xXBoth metastatic and inoperable primary-only patients are eligibleXx_NEWLINE_xXBoth patients with stage IV and patients with recurrent disease after progression must have had at least 1 line of standard systemic therapy in the advanced/metastatic setting; a. patients with HER2-positive disease must have had at least 2 lines of anti-HER2 therapy, including Perjeta and Kadcyla in the metastatic setting; b. prior eribulin treatment is allowedXx_NEWLINE_xXhave metastatic disease evaluable on imaging studies;Xx_NEWLINE_xXRadiographic evidence of metastatic diseaseXx_NEWLINE_xXKnown metastatic diseaseXx_NEWLINE_xXPatients must have metastatic or unresectable disease, including those with HER2+ diseaseXx_NEWLINE_xXPrevious treatment with cytotoxic chemotherapy therapy in the recurrent/metastatic setting; previous treatment with non-cytotoxic agents in the recurrent/metastatic setting is permittedXx_NEWLINE_xXPatients with extra-abdominal metastatic diseaseXx_NEWLINE_xXMore than 3 previous lines of therapy in the metastatic setting.Xx_NEWLINE_xXAny metastatic diseaseXx_NEWLINE_xXPatients with metastatic disease are allowed, if indication to remove primary tumorXx_NEWLINE_xXAll patients must have progressed on at least one line of cytotoxic therapy for metastatic diseaseXx_NEWLINE_xXPatients must have evidence of progressive diseaseXx_NEWLINE_xXHave recurrent or refractory/unresectable disease for which there is no known curative therapy\r\n* Wild type-GIST: patients with recurrent or progressive disease will be eligible; newly diagnosed patients with resectable localized disease will not be eligible; newly diagnosed patients with metastatic disease and newly diagnosed patients with residual tumor following surgical debulking will be eligible\r\n* PHEO/PGL: patients with recurrent or progressive disease will be eligible; newly diagnosed patients with PHEO/PGL that is metastatic at diagnosis and/or unresectable will be eligible; patients with PHEO/PGL with localized (non-metastatic), resectable disease will not be eligible\r\n* Renal cell cancer associated with HLRCC: patients with localized, resectable HLRCC-associated renal cell cancer will not be eligible; patients with metastatic and/or unresectable HLRCC-associated renal cell cancer will be eligibleXx_NEWLINE_xXWidely metastatic disease (oligometastatic disease acceptable)Xx_NEWLINE_xXThe patient has three or less observable metastatic lesions. Metastatic lesions include distant M1 lymph node group; which will be counted as one site (M1 metastatic lymph nodes to include cervical, mediastinal, gastric, retroperitoneal lymph nodes will be counted as one lesion). Osseous metastases or visceral metastases will each count as one metastatic site. Each central nervous system (CNS) metastases will count as one metastatic site. Satellite lesions in the primary esophageal malignancy such as skipped esophageal primaries are not considered metastatic sites. Symptomatic metastatic sites can be treated locally prior to randomization or by palliative radiationXx_NEWLINE_xXMetastatic disease.Xx_NEWLINE_xXPatients may or may not have received prior therapy for their recurrent/metastatic disease\r\n* NOTE: There is no limit to the number of prior therapies for stage IV disease\r\n* NOTE: Patients should not be a candidate for curative surgical treatment or radiation (palliative radiotherapy is permitted)Xx_NEWLINE_xXPatients may have received one prior hormonal treatment for metastatic diseaseXx_NEWLINE_xXTreatment for metastatic bladder cancerXx_NEWLINE_xXMetastatic CRCXx_NEWLINE_xXEvidence of metastatic disease.Xx_NEWLINE_xXPatients must have at least one focus of metastatic disease that is amenable to pre- and on-treatment biopsies; ideally the biopsied lesion should not be one of the target measurable lesions, although this can be up to the discretion of the investigatorsXx_NEWLINE_xXClinically no evidence of local, regional, or metastatic disease at the time of study entryXx_NEWLINE_xXClinical or radiologic evidence of local or regional recurrence of disease or metastatic disease prior to or at the time of study entryXx_NEWLINE_xXMetastatic RCCXx_NEWLINE_xXPatients with metastatic disease, including leptomeningeal or subarachnoid disseminated diseaseXx_NEWLINE_xXFirst line treatment for metastatic pancreatic cancer.Xx_NEWLINE_xXNewly diagnosed androgen-sensitive metastatic disease; orXx_NEWLINE_xXMetastatic disease or local-regional disease that is considered not resectable for cureXx_NEWLINE_xXHas known metastatic disease; staging CT C/A/P or PET/CT will be mandatory no more than 45 days prior to enrollment to evaluate for the presence of metastatic diseaseXx_NEWLINE_xXHas metastatic diseaseXx_NEWLINE_xXEvidence of distant metastatic diseaseXx_NEWLINE_xXPatients with more than >= 3 metastatic lung lesions or any one lesion greater than 5 cm and/or extensive metastatic disease outside the chestXx_NEWLINE_xXPatient has had at least one prior systemic therapy for metastatic diseaseXx_NEWLINE_xXPatients with Gilbert's disease.Xx_NEWLINE_xXMetastatic (stage IV) triple negative breast cancer that has progressed after at least one prior chemotherapy regimen in the metastatic setting; non-measurable disease (i.e. bone metastases) is permittedXx_NEWLINE_xXLiver involvement by > 50% with metastatic disease determined by the investigatorXx_NEWLINE_xXPatients with distant metastatic disease (M1c) from the current head and neck cancer including brain metastasisXx_NEWLINE_xXSubjects must have a histologic diagnosis of clear cell renal cell carcinoma (pure or mixed) with radiologic or histologic or cytologic evidence of metastatic diseaseXx_NEWLINE_xXCross-sectional imaging evidence of progression of recurrent/metastatic diseaseXx_NEWLINE_xXPatients must have received 1 line of prior systemic therapy for metastatic or resectable disease (i.e. patients may have received adjuvant gemcitabine and then later gemcitabine/cisplatin for recurrent metastatic disease)Xx_NEWLINE_xXClinically node negative, no evidence of metastatic diseaseXx_NEWLINE_xXHas metastatic diseaseXx_NEWLINE_xXMetastatic kidney cancer; clear cell histology component from primary or metastatic lesionXx_NEWLINE_xXRadiographic evidence of metastatic diseaseXx_NEWLINE_xXDisease status must be 1 of the following:Xx_NEWLINE_xXEvidence of metastatic disease that is extensive enough to preclude consideration of subsequent definitive surgery for the primary tumorXx_NEWLINE_xXMetastaticXx_NEWLINE_xXHistologic diagnosis of metastatic uveal melanoma.Xx_NEWLINE_xXDocumented distant metastatic diseaseXx_NEWLINE_xXPatients must have local or metastatic recurrence of IBC after prior surgeryXx_NEWLINE_xXHave metastatic or unresectable sarcomaXx_NEWLINE_xXMetastatic diseaseXx_NEWLINE_xXHave a diagnosis of histologically confirmed metastatic colorectal cancer to the liver (no other sites of metastatic disease)\r\n* Histologic confirmation of a colorectal primary tumor is acceptable if accompanied by radiographic evidence of metastatic diseaseXx_NEWLINE_xXPrior resection of extra-hepatic metastatic disease allowed if completed more than 12 months previous to study enrollment and no new extra-hepatic disease has been foundXx_NEWLINE_xXPatients must not have known metastatic diseaseXx_NEWLINE_xXAny evidence of metastatic urothelial carcinomaXx_NEWLINE_xXFive or more metastatic brain lesionsXx_NEWLINE_xXPresence of metastatic disease or gross orbital involvementXx_NEWLINE_xXPatients must have progressive metastatic disease defined as new or progressive lesions on cross-sectional imagingXx_NEWLINE_xXPatients with metastatic disease will not be excludedXx_NEWLINE_xXPatients with metastatic diseaseXx_NEWLINE_xXMR imaging of the total spine (performed within 14 days of enrollment) demonstrates no evidence of spinal metastatic diseaseXx_NEWLINE_xXPatients must have previously received systemic standard care (or effective salvage chemotherapy regimens) for metastatic disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurredXx_NEWLINE_xXHave had disease progression, been refractory or intolerant to no more than 2 prior systemic regimens for locally advanced or metastatic pancreatic cancer. Participants who have received prior neoadjuvant therapy and who now have metastatic disease must have received 1 of the following for their metastatic disease: FOLFIRINOX, nanoparticle albumin-bound paclitaxel/gemcitabine, TS-1 (tegafur gimeracil oteracil potassium), irinotecan liposome injection/5-fluorouracil (5FU)/Leucovorin or single-agent gemcitabine prior to enrolment in this study.Xx_NEWLINE_xXThe subject has metastatic disease at the time of screeningXx_NEWLINE_xXNo metastatic disease (M0)Xx_NEWLINE_xXSelf-identified Black, African or African American women with proven diagnosis of advanced breast cancer (locoregionally recurrent or metastatic disease), either from the primary or a metastatic siteXx_NEWLINE_xXPatients must have received at least one prior therapy for metastatic disease to be eligibleXx_NEWLINE_xXPatients with histologically confirmed metastatic melanoma, metastatic non-small cell lung cancer, metastatic breast cancer, or metastatic pancreatic adenocarcinoma relapsed or refractory to therapy as outlined below or patients with these malignancies who have declined, are or have become unable to tolerate (e.g. progressive chemotherapy-associated peripheral neuropathy), or were not eligible for standard therapy\r\n* Metastatic melanoma patients at any line of therapy\r\n* Metastatic non-small cell lung cancer patients who have relapsed or are refractory to at least one line of systemic anti-cancer therapy for metastatic disease, including cytotoxic chemotherapy or targeted therapy\r\n* Metastatic breast cancer patients who have relapsed or are refractory to at least one line of systemic anti-cancer therapy for metastatic disease, such as cytotoxic chemotherapy, hormonal therapy, or targeted therapy\r\n* Metastatic pancreatic adenocarcinoma who have relapsed or are refractory to at least one line of systemic anti-cancer therapy for metastatic disease, such as cytotoxic chemotherapy or targeted therapyXx_NEWLINE_xXUnresectable or metastatic breast cancer; locally recurrent disease must not be amenable to any local treatment with curative intent; metastatic disease must be demonstrated either radiographically or histologicallyXx_NEWLINE_xXAt least one prior regimen for treatment of recurrent or metastatic disease\r\n* Note: Prior regimen for recurrent or metastatic disease is not required if the patient had disease progression or recurrence during or within the first 6 months following completion of adjuvant or neoadjuvant chemotherapyXx_NEWLINE_xXPatients must have received at least one prior therapy for metastatic melanomaXx_NEWLINE_xXPatients must have progressed during or after first-line treatment for metastatic disease with oxaliplatin and fluoropyrimidines based chemotherapy (with failure within six months) or not be a candidate for oxaliplatin (i.e. neuropathy)Xx_NEWLINE_xXMay have received at least 1 prior therapy for recurrent or metastatic disease, up to 2 prior systemic therapies.Xx_NEWLINE_xXDiagnosis of uveal melanoma with histological or cytological confirmed metastatic disease. Disease must be treatment naive or have progressed (radiologically or clinically) on most recent therapy.Xx_NEWLINE_xXSymptomatic metastatic disease with signs of rapid progression per investigator’s clinical judgmentXx_NEWLINE_xXPatients must have metastatic pancreatic ductal adenocarcinoma (PDA) or metastatic colorectal cancer (CRC) to be eligible; (PDA patients with an elevated tumor marker following a primary pancreatic surgery would be eligible)Xx_NEWLINE_xXPatient must have received =< 3 prior cytotoxic regimens in the metastatic settingXx_NEWLINE_xXPresence of metastatic disease on scansXx_NEWLINE_xXPatient has stage N1 or M1 (metastatic) diseaseXx_NEWLINE_xXAgree to participate in biopsy of metastatic lesion during the study at day 21Xx_NEWLINE_xXPatients on anticoagulation therapy which cannot be held for metastatic biopsiesXx_NEWLINE_xXPatients with documented HER2-positive metastatic disease based on most recent biopsyXx_NEWLINE_xXKnown metastatic diseaseXx_NEWLINE_xXMetastatic or unresectable disease documented on diagnostic imaging studiesXx_NEWLINE_xXMetastatic disease outside of the liverXx_NEWLINE_xXInclusion criteria Part 1: Safety run-in\n\n          -  Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation\n\n          -  Aspartate transaminase (AST) < 2.5× ULN and Alanine transaminase (ALT) < 2.5× ULN\n\n          -  ECOG performance status ? 1\n\n        Part 2: Biomarker cohort\n\n          -  Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation\n\n          -  At least two cutaneous or subcutaneous or nodal lesions for tumor sample collection\n\n          -  ECOG performance status ? 2\n\n        Part 3: Double-blind, randomized, placebo-controlled part\n\n          -  Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation\n\n          -  ECOG performance status ? 2\n\n        Exclusion Criteria:\n\n        Part 1: Safety run-in\n\n          -  Subjects with uveal or mucosal melanoma\n\n          -  Any history of CNS metastases\n\n          -  Prior systemic anti-cancer treatment for unresectable or metastatic melanoma\n\n          -  Prior loco-regional treatment for unresectable or metastatic melanoma in the last 6\n             month\n\n          -  Prior neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months\n\n          -  Radiation therapy within 4 weeks prior to start of study treatment\n\n          -  Active, known, suspected or a documented history of autoimmune disease\n\n        Parts 2 & 3: Biomarker cohort & double-blind, randomized, placebo-controlled part\n\n          -  Subjects with uveal or mucosal melanoma\n\n          -  Clinically active cerebral melanoma metastasis\n\n          -  Prior systemic anti-cancer treatment for unresectable or metastatic melanoma\n\n          -  Prior loco-regional treatment for unresectable or metastatic melanoma in the last 6\n             month\n\n          -  Prior neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months\n\n          -  Radiation therapy within 4 weeks prior to start of study treatment\n\n          -  Active, known, suspected or a documented history of autoimmune disease\n\n        Other protocol-defined Inclusion/Exclusion may apply.Xx_NEWLINE_xXKnown metastatic diseaseXx_NEWLINE_xXDiagnosis of widespread visceral and/or osseous metastatic disease based on clinical and radiographic evidence; (patients may continue on study if surgery shows a non-malignant process)Xx_NEWLINE_xXRapidly progressive symptomatic metastatic disease, as defined by the need for increased opioid analgesics within one month of registration for the treatment of pain attributed to a prostate cancer metastatic lesion; patients receiving opioids must receive approval from the principal investigator (PI) for eligibilityXx_NEWLINE_xXPHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nPatients must have at least one focus of metastatic disease that is amenable to pre- and on-treatment biopsyXx_NEWLINE_xXAny number of metastatic disease is allowed in the pilot phase of the trial\r\n* For the phase II, metastatic patients will be allowed only if all sites of metastasis has been treated either surgically or radio-surgically; (if limited sites of metastasis are present, all of which can be resected during the nephrectomy, then the patient can be eligible)Xx_NEWLINE_xXUntreated or metastatic pheochromocytomaXx_NEWLINE_xXPresence of metastatic diseaseXx_NEWLINE_xXSubjects with uncontrolled distantly metastatic disease per RECIST criteria (progressive disease) on imaging following chemotherapyXx_NEWLINE_xXKnown metastatic diseaseXx_NEWLINE_xXIs receiving concurrent anti-cancer therapy for metastatic diseaseXx_NEWLINE_xXPatients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective\r\n* Subject must have undergone at least 2 prior regimens for treatment of recurrent or metastatic diseaseXx_NEWLINE_xXPatients with known synchronous distant metastatic diseaseXx_NEWLINE_xXMulti-focal or metastatic diseaseXx_NEWLINE_xXMulti-focal or metastatic disease (Arm B)Xx_NEWLINE_xXEvidence of metastatic diseaseXx_NEWLINE_xXKnown metastatic diseaseXx_NEWLINE_xXProgressive diseaseXx_NEWLINE_xXNo evidence of metastatic disease based on imaging of the chest, abdomen and pelvisXx_NEWLINE_xXMetastatic disease on pretreatment imagingXx_NEWLINE_xXRadiographical documentation of metastatic disease with imaging up to 6 weeks prior to enrollmentXx_NEWLINE_xXDefinitive clinical or radiologic evidence of metastatic disease; imaging must have been performed no greater than 30 days prior to initiation of chemotherapyXx_NEWLINE_xXPatient does NOT have known intracranial metastatic neuroblastoma; skull based disease with soft tissue extension is allowedXx_NEWLINE_xXFor patients undergoing definitive CFRT, patients with distant metastatic disease are not eligibleXx_NEWLINE_xXFor patients undergoing SABR, both early stage primary lung cancer patients and those with limited metastatic disease to the lungs are eligible; however, patients with oligometastatic disease should have a controlled primary and no more than one other involved organ systemXx_NEWLINE_xXProgression or refractory disease to at least one regimen of therapy for metastatic disease in the breast and pancreatic cancer cohortsXx_NEWLINE_xXDocumented or pathologically-proven metastatic diseaseXx_NEWLINE_xXPatients must have histological confirmation of metastatic cancer with at least one metastatic or primary lesion in the liver, lung, or adrenal glandXx_NEWLINE_xXPatients must have had anti-HER2 based therapy for metastatic disease (which may include trastuzumab and pertuzumab either sequentially or in combination).Xx_NEWLINE_xXThere must be documentation that the patient has evidence of measurable metastatic breast cancer. Histologic confirmation of metastatic disease is not required.Xx_NEWLINE_xXDistant metastatic diseaseXx_NEWLINE_xXKnown metastatic diseaseXx_NEWLINE_xXMetastatic diseaseXx_NEWLINE_xXRecurrent/progressive disease at any timeXx_NEWLINE_xXPresence of distant metastatic (M1) diseaseXx_NEWLINE_xXPresence of distant metastatic diseaseXx_NEWLINE_xXMetastatic uveal melanomaXx_NEWLINE_xXpT1-pT3pNxMx patients in whom standard National Comprehensive Cancer Network (NCCN) or American Urology Association (AUA) guidelines would suggest are at low risk for pelvic lymph node or metastatic disease and who would not require confirmatory imaging for metastatic disease; this includes patients with Gleason 6 or 7 (T2 disease) and prostate-specific antigen (PSA) less than 20Xx_NEWLINE_xXThe patients have documented disease beyond the peritoneal surfaces, which prevent achieving complete cytoreduction as indicated by:\r\n* Evidence of distant hematogenous metastatic disease or distant nodal metastases\r\n* Evidence of parenchymal hepatic metastases\r\n* Evidence of clinical, biochemical or radiological biliary obstruction\r\n* Evidence of gross disease of the small bowel mesentery characterized by distortion, thickening or loss of mesenteric vascular clarity which limits ability to obtain complete cytoreductionXx_NEWLINE_xXPatients must have previously received first line standard therapy (or effective salvage chemotherapy regimens) for metastatic disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurredXx_NEWLINE_xXMetastatic colorectal cancer patients \r\n* Patient must have received a minimum of 1 systemic therapy in the metastatic settingXx_NEWLINE_xXMetastatic pancreatic cancerXx_NEWLINE_xXPatients with metastatic disease outside of the pelvisXx_NEWLINE_xXHistory, presence, or suspicion of metastatic diseaseXx_NEWLINE_xXEvidence of metastatic disease on imaging studies performed at the discretion of their physicianXx_NEWLINE_xXPatients must have had disease progression on or following their most recent treatment regimen or on presentation for the first time with metastatic diseaseXx_NEWLINE_xXNo evidence of distant metastatic diseaseXx_NEWLINE_xXMetastatic pheochromocytomaXx_NEWLINE_xXRecurrent or second primary, previously irradiated squamous cell carcinoma of the head and neck (SCCHN) without clinically measurably metastatic diseaseXx_NEWLINE_xXNo evidence of distant metastatic disease as documented by history and physical examination (radiographic staging only to be performed as indicated by symptoms or physical findings)Xx_NEWLINE_xXStep 1 subjects only: metastatic breast patients refractory to at least one standard therapy, with easily accessible metastatic deposits (cutaneous, subcutaneous, or superficial and/or palpable adenopathy/mass)Xx_NEWLINE_xXPresence of metastatic disease or gross (residual) orbital involvementXx_NEWLINE_xXPatients with metastatic diseaseXx_NEWLINE_xXEvidence of metastatic diseaseXx_NEWLINE_xXPatients must be deemed to have borderline resectable disease (adapted from National Comprehensive Cancer Network [NCCN] Practice Guidelines in Oncology - v.2.2010) with no radiologic evidence of distant metastatic disease prior to registration; specifically, patients must have at least one designation of borderline resectable and no designation of unresectable diseaseXx_NEWLINE_xXNo known local regional or distant metastatic diseaseXx_NEWLINE_xXMore than one prior chemotherapy line for metastatic diseaseXx_NEWLINE_xXUntreated primary uveal melanoma except in cases where metastatic disease is diagnosed at the time of primary diseaseXx_NEWLINE_xXMetastatic uveal melanoma patients with bone-only diseaseXx_NEWLINE_xXMetastatic diseaseXx_NEWLINE_xXHistologically-confirmed, mesothelin-expressing metastatic or advanced non-metastatic disease (tumour type specific inclusion criteria)Xx_NEWLINE_xXSubjects must have bi-dimensionally measurable disease, defined as at least one lesion that can be accurately measured in at least two planes\r\n* This disease must be located primarily in the supratentorial region\r\n* Patients with significant disease that is metastatic outside of the supratentorial region are ineligibleXx_NEWLINE_xXPresence of metastatic diseaseXx_NEWLINE_xXNo prior chemotherapy for metastatic diseaseXx_NEWLINE_xXNo evidence of metastatic diseaseXx_NEWLINE_xXSubjects with recurrent diseaseXx_NEWLINE_xXRelapsed diseaseXx_NEWLINE_xXPatients must not have any evidence of progressive disease at the time of study entryXx_NEWLINE_xXNo clinical or radiological evidence of metastatic disease or local progressionXx_NEWLINE_xXAny evidence of metastatic diseaseXx_NEWLINE_xXReceived no more than 3 prior lines of systemic therapy for metastatic disease.Xx_NEWLINE_xXPatients must have had at least 2 lines of anti-HER2 directed therapies either in the metastatic or early-stage disease settingXx_NEWLINE_xXHistological or cytological diagnosis of metastatic CRC excluding known microsatellite instable sub-types, metastatic SCCHN or metastatic NSCLC that have progressed or have become intolerant to standard therapy, and whose disease may allow management with other available therapiesXx_NEWLINE_xXM0 stage based on no evidence of metastatic disease by CT imaging.Xx_NEWLINE_xXPresence of metastatic disease is not allowed; subjects must be evaluated with imaging consisting of CT scan and PET scan prior to enrollment for protocol therapy to exclude metastatic diseaseXx_NEWLINE_xXPatients must have measurable metastatic disease amenable to biopsy; patients who decline to undergo a biopsy for this trial will be ineligibleXx_NEWLINE_xXMetastatic diseaseXx_NEWLINE_xXWilling to undergo biopsy of a metastatic lesion at the time of progressionXx_NEWLINE_xXRecurrent disease with an:Xx_NEWLINE_xXPatients who have metastatic or recurrent disease after previous surgery, radiation therapy, and/or chemotherapy are eligible. In Stage 1, no restriction is placed on the number of prior therapies. In Stage 2, patients may have 0 or 1 prior chemotherapy treatments for adjuvant or metastatic disease and no prior endocrine therapies.Xx_NEWLINE_xXPatients with Gilbert's disease or known CNS metastatic disease.Xx_NEWLINE_xXEvidence of metastatic diseaseXx_NEWLINE_xXMore than 3 metastatic tumorsXx_NEWLINE_xXPatients must have histological verification of diagnosis. Patients with M+ disease (defined as evidence of neuraxis dissemination) are not eligible. Cerebrospinal fluid (CSF) cytology is not required but may be obtained if clinically indicated prior to study enrollment. If cytology is positive, the patient would be considered to have metastatic disease and would, therefore, be ineligibleXx_NEWLINE_xXHistologically confirmed adenocarcinoma of the breast with locally recurrent, unresectable disease or metastatic disease confirmed as described below; eligible patients include those with either:\r\n* De novo metastatic disease presenting without prior history of HER2-positive breast cancer:\r\n** Diagnosis should have been made from a biopsy of a metastatic disease site, but biopsy from the breast primary or involved regional lymph nodes is acceptable if biopsy of the metastatic sites was thought to carry excessive risk for the patient\r\n* Locally recurrent or metastatic disease following prior therapy for early breast cancer:\r\n** Diagnosis must have been made from the biopsy of the locally recurrent or metastatic disease\r\n** There must be an interval of >= 6 months between completion of neoadjuvant/adjuvant HER2-targeted therapy and documentation of locally recurrent or metastatic HER2-positive disease by biopsyXx_NEWLINE_xXPatients with metastatic disease limited to the CNSXx_NEWLINE_xXMetastatic diseaseXx_NEWLINE_xXPatients must have at least ONE of the following: 1) Recurrent/progressive disease at any time prior to study enrollment, 2) Refractory disease, 3) Persistent diseaseXx_NEWLINE_xXOther metastatic melanoma systemic disease allowedXx_NEWLINE_xXMetastatic RCCXx_NEWLINE_xXMetastatic disease or non-testicular primaryXx_NEWLINE_xXPart 1: have a diagnosis of metastatic melanoma and be scheduled to receive anti PD1 immunotherapyXx_NEWLINE_xXPatients with clinical evidence of metastatic disease.Xx_NEWLINE_xXMeasurable metastatic disease (by RECIST version [v] 1.1) in the peritoneal cavity or retroperitoneal lymph nodes; disease outside of the peritoneal cavity is allowed as long as metastatic sites are also present within the peritoneum/retroperitoneumXx_NEWLINE_xXEligible for neutron radiation treatment to 1-3 sites of metastatic disease (lesions do not have to be symptomatic)Xx_NEWLINE_xXPatients must have refractory, recurrent or metastatic disease, which is deemed to be inoperableXx_NEWLINE_xXMeasurable metastatic uveal melanomaXx_NEWLINE_xXHave received at least one prior therapy for metastatic diseaseXx_NEWLINE_xXPresence of distant metastatic disease or disease not amenable to radiation treatmentXx_NEWLINE_xXMetastatic pancreatic cancer based on imagingXx_NEWLINE_xXPhase I only: Histologic confirmation of pancreatic, colorectal, gastroesophageal or biliary adenocarcinoma, as follows:\r\n* Patients with metastatic disease from pancreatic cancer who received no more than 2 lines of prior therapy in the metastatic setting\r\n* Patients with metastatic disease from colorectal cancer who received no more than 3 lines of prior therapy in the metastatic setting\r\n* Patients with metastatic disease from gastroesophageal cancer who received no more than 1 line of prior therapy in the metastatic setting\r\n* Patients with metastatic disease from biliary tract cancer who received no more than 1 line of prior therapy in the metastatic setting\r\n* NOTE: No prior exposure to irinotecan in the metastatic setting will be allowed except in the phase I dose escalation portion and in colon cancer patients only; in pancreas cancer, exposure to irinotecan is only allowed in the neoadjuvant setting and no progressive disease < 3 months from last dose of irinotecanXx_NEWLINE_xXPhase Ib only: Histologic confirmation of pancreatic or gastroesophageal adenocarcinoma, as follows:\r\n* Patients with metastatic disease from pancreatic cancer who received no more than 1 line of prior therapy in the metastatic setting\r\n* Patients with metastatic disease from gastroesophageal cancer who received no more than 1 line of prior therapy in the metastatic setting\r\n* NOTE: No prior exposure to any irinotecan in the metastatic setting will be allowedXx_NEWLINE_xXPresence of metastatic diseaseXx_NEWLINE_xXPancreatic cancer cohort specific criteria:\r\n* Patients must have unresectable or metastatic pancreatic cancer\r\n* Patients must have failed at least one prior line of therapy for metastatic or unresectable disease or have recurred within 6 months of completing adjuvant chemotherapy\r\n* Patients with liver metastases must have < 50% involvement of the liverXx_NEWLINE_xXHistologic diagnosis of metastatic melanomaXx_NEWLINE_xXNo evidence of distant metastatic diseaseXx_NEWLINE_xXClinical or radiographic evidence of disease progressionXx_NEWLINE_xXPatients with evidence of extraneural diseaseXx_NEWLINE_xXDiagnosis of metastatic diseaseXx_NEWLINE_xXPatients with evidence of metastatic disease involvement in viscera or boneXx_NEWLINE_xXRadiographic evidence of metastatic diseaseXx_NEWLINE_xXPatients with metastatic diseaseXx_NEWLINE_xXDefinitive clinical or radiologic evidence of metastatic diseaseXx_NEWLINE_xXEvidence of distant metastatic disease (i.e. lung, liver, bone, brain, etc.)Xx_NEWLINE_xXHave localized pancreatic ductal adenocarcinoma (PDA)s at the time of original diagnosis without any definitive evidence of distant metastatic diseaseXx_NEWLINE_xXCohort 2 (MTD) only: metastatic adenocarcinoma of the pancreas; prior systemic treatment for metastatic disease is allowedXx_NEWLINE_xXNo evidence of metastatic disease by clinical and radiological stagingXx_NEWLINE_xXNo more than two prior therapies for metastatic diseaseXx_NEWLINE_xXPatients with metastatic disease beyond the neck and supraclavicular region will be excludedXx_NEWLINE_xXEvidence or suspicion of disease metastatic to sites remote from the supratentorial brainXx_NEWLINE_xXCOHORT II (MTD): metastatic adenocarcinoma of the pancreas and tumor amenable to biopsies; prior systemic treatment for metastatic disease is allowedXx_NEWLINE_xXThe subject must have progressive disease following at least one prior line of hormonal or chemotherapy for treatment of their metastatic diseaseXx_NEWLINE_xXFor metastatic disease to lung, primary tumor needs to be controlled (no evidence of progression on imaging for at least 2 months)Xx_NEWLINE_xXMetastatic disease by bone scanXx_NEWLINE_xXPatients must have no evidence of metastatic disease; metastatic disease:\r\n* Are lesions which are discontinuous from the primary tumor, are not regional lymph nodes and do not share a body cavity with the primary tumor; if there is any doubt whether lesions are metastatic, a biopsy of those lesions should be taken\r\n* Skeletal lesions in adjacent bones (trans-articular)\r\n* Contralateral pleural effusion and contralateral pleural nodules\r\n* Distant lymph node involvement\r\n* Patients with pulmonary nodules are considered to have metastatic disease if the patient has:\r\n** Solitary nodule > 0.5 cm or multiple nodules of > 0.3 cm unless biopsied and negative for Ewing's\r\n** Biopsies of solitary nodule =< 0.5 cm or multiple nodules =< 0.3 cm are not required but if performed and positive indicate metastatic diseaseXx_NEWLINE_xXHave stable metastatic pancreatic cancer after receiving 8-12 doses of FOLFIRINOX (measurable disease is not required)Xx_NEWLINE_xXPatients who have had prior chemotherapy for metastatic pancreatic cancer (other than FOLFIRINOX); prior radiation is allowed; chemotherapy for non-metastatic disease is allowedXx_NEWLINE_xXPatients must have histologic or cytologic verification of extra-ocular retinoblastoma; extra-ocular disease includes orbital disease, optic nerve involvement at the surgical margin, regional nodal disease, and/or overt distant metastatic disease (at sites such as bone, bone marrow, liver and/or the central nervous system); patients with trilateral retinoblastoma will also be included in this protocol\r\n* Patients with a CNS lesion consistent with trilateral or stage 4b disease may be enrolled without tissue confirmation if (1) unequivocal leptomeningeal disease is present on brain or spine magnetic resonance imaging (MRI) scan and/or (2) the primary tumor is at least 2 cm in diameter, predominantly solid, and demonstrates enhancement on the post-gadolinium images; however, even in such cases surgery should be given serious considerationXx_NEWLINE_xXPatients must have metastatic diseaseXx_NEWLINE_xXPatient has known nodal or distant metastatic disease; patients with nodal or metastatic disease require systemic chemotherapy; furthermore, they should be excluded from this clinical trial because of their poor overall prognosisXx_NEWLINE_xXPatients are allowed (but not required) to have up to two lines of prior chemotherapy regimens for metastatic diseaseXx_NEWLINE_xXPatients must have received at least 1 chemotherapy regimens in the setting of metastatic diseaseXx_NEWLINE_xXDefinitive clinical or radiologic evidence of metastatic disease or adenopathy below the claviclesXx_NEWLINE_xXPHASE II: Patients must NOT have received gemcitabine or nab-paclitaxel in a metastatic settingXx_NEWLINE_xXPatients must have pathologically or radiologically confirmed metastatic disease in the brainXx_NEWLINE_xXDisease status: stable disease or better at the time of enrollmentXx_NEWLINE_xXHave not been treated with gemcitabine in the metastatic settingXx_NEWLINE_xXChest x-ray negative for metastatic diseaseXx_NEWLINE_xXDefinitive clinical or radiologic evidence of metastatic disease; (chest imaging [mandatory for all patients] and other imaging [if required] must have been performed within 90 days prior to randomization)Xx_NEWLINE_xXPatients with metastatic disease must have received at least one line of standard of care (SOC) treatment for metastatic disease prior to enrollmentXx_NEWLINE_xXPatients with distant metastatic disease (stage IVC)Xx_NEWLINE_xXMeasurable metastatic ocular melanomaXx_NEWLINE_xXRadiological evidence of metastatic diseaseXx_NEWLINE_xXUnresectable diseaseXx_NEWLINE_xXPatients with evidence of metastatic disease outside of the pelvisXx_NEWLINE_xXPatients may be treatment-naive or may have been previously treated for metastatic diseaseXx_NEWLINE_xXEvidence of metastatic disease outside of the abdomenXx_NEWLINE_xXEvidence of metastatic disease outside of the abdomenXx_NEWLINE_xXFirst or second line chemotherapy treatment for metastatic diseaseXx_NEWLINE_xXPatients must have progressive diseaseXx_NEWLINE_xXPatients have locally recurrent or distant relapsed metastatic diseaseXx_NEWLINE_xXPhase I: Patients must have received at least one prior chemotherapy regimen for metastatic disease; patients with deleterious germ line mutations in breast cancer (BRCA)1 or BRCA2 are not required to have received prior chemotherapy for metastatic diseaseXx_NEWLINE_xXUp to four prior chemotherapy regimens and anti-HER2 agents in the metastatic setting allowed; patients must have progressed on trastuzumab based therapy and must have received ado-trastuzumab emtansine for metastatic breast cancerXx_NEWLINE_xXOne to ten brain metastatic lesionsXx_NEWLINE_xXPrevious radiosurgery to any currently progressive gross metastatic diseaseXx_NEWLINE_xXBe receiving first-line therapy for metastatic diseaseXx_NEWLINE_xXSubjects enrolled in phase II part of the protocol should not have metastatic disease; however, patients with oligometastatic disease that can be treated with localized treatment with definitive intent are eligibleXx_NEWLINE_xXPatients may have received chemotherapy as a component of their primary tumor treatment but not for recurrent or metastatic diseaseXx_NEWLINE_xXCurrent or previous evidence of muscle invasive (muscularis propria) or metastatic disease presented at the screening visit. Examples that increase the risk of metastatic disease are (but not limited to):Xx_NEWLINE_xXPatient with documented evidence of metastatic diseaseXx_NEWLINE_xXSubjects enrolled into the C3 Cohort must have not had treatment for their metastatic diseaseXx_NEWLINE_xXWidespread (metastatic) disease, or returned after previous treatment (recurrent)Xx_NEWLINE_xXPrevious treatment for metastatic or recurrent diseaseXx_NEWLINE_xXReceived prior trastuzumab or chemotherapy for metastatic breast cancer except if patient has CNS as only site of metastatic diseaseXx_NEWLINE_xXSubjects must have recurrent/metastatic disease and may have been previously treated in the recurrent/metastatic setting.Xx_NEWLINE_xXDisease progression after crizotinib only. No prior chemotherapy is allowed in the metastatic disease setting.Xx_NEWLINE_xXDisease progression after crizotinib and 1 or 2 prior regimens of chemotherapy in the metastatic disease setting.Xx_NEWLINE_xXInclusion Criteria for dose escalation and expansion phase:\n\n          -  Signed written informed consent\n\n          -  Male or female subjects aged greater than or equal to 18 years\n\n          -  Subjects must have histologically or cytologically proven metastatic or locally\n             advanced solid tumors, for which no standard therapy exists or standard therapy has\n             failed. Availability of tumor archival material or fresh biopsies is optional for\n             subjects in dose escalation\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at trial entry\n             and an estimated life expectancy of at least 3 months\n\n          -  Disease must be measurable with at least 1 uni-dimensional measurable lesion by RECIST\n             1.1, except for subjects with metastatic castrate-resistant prostate cancer (mCRPC) or\n             metastatic breast cancer (MBC) who may be enrolled with objective evidence of disease\n             without a measureable lesion\n\n          -  Adequate hematological, hepatic and renal function as defined in the protocol\n\n          -  Effective contraception for both male and female subjects if the risk of conception\n             exists\n\n          -  Other protocol defined inclusion criteria could apply\n\n        Inclusion Criteria for expansion phase:\n\n          -  Subjects must have relapsed, refractory, or progressive disease following last line of\n             treatment (with the exception of the gastric and gastroesophageal junction (GEJ)\n             cancer cohort, which does not require progression). Availability of tumor archival\n             material or fresh biopsies (excluding bone biopsies) is mandatory for eligibility in\n             the expansion cohorts. For subjects in the MBC cohort, the biopsy or surgical specimen\n             must have been collected within 90 days prior to the first investigational medicinal\n             product (IMP) administration. Specifically, the following will be required:\n\n          -  NSCLC post platinum doublet: Histologically or cytologically confirmed stage IIIB or\n             stage IV NSCLC that has progressed after 1 line of platinum-containing doublet\n             chemotherapy. Subjects should have received only 1 line of platinum-containing\n             treatment for metastatic disease (i.e., adjuvant treatment with a platinum-containing\n             regimen is not sufficient for eligibility because not received in the context of a\n             metastatic disease). Subjects in the NSCLC cohort will only be enrolled in USA\n\n          -  NSCLC first line: Stage IV (per 7th International Association for the Study of Lung\n             Cancer [IASLC] classification) or recurrent NSCLC that is histologically proven.\n             Subjects must not have received treatment for their metastatic or recurrent disease.\n             No activating epidermal growth factor receptor (EGFR) mutation nor ALK\n             translocation/re-arrangement\n\n          -  Gastric and GEJ cancer: Histologically confirmed, unresectable locally advanced or\n             metastatic adenocarcinoma of the gastric and gastro-esophageal junction, treated with\n             first-line chemotherapy combination with or without disease progression. Subjects\n             should have received no more than 1 line of treatment for metastatic disease. Subjects\n             should not have been treated with trastuzumab (but can be Human Epidermal growth\n             factor Receptor 2 [HER2] positive). Subjects who received any platinum containing\n             doublet or triplet as a neoadjuvant chemotherapy strategy, but are not ultimately\n             candidates for surgery will also be eligible, as long as they did not have progressive\n             disease after completion of the neoadjuvant chemotherapy. In addition, subjects with\n             gastric cancer can enter in the study if their white blood cell (WBC) and lymphocyte\n             count is as defined in the protocol\n\n          -  MBC: Subjects must have histologically confirmed locally advanced or MBC and have\n             tumor that is refractory to or progressive after standard of care therapy. Subjects\n             must have received no more than 3 prior lines of cytotoxic therapy for metastatic\n             disease. Subjects must have received a taxane and an anthracycline, unless\n             contra-indicated\n\n          -  Secondary expansion cohorts: Metastatic colorectal cancer (mCRC), Metastatic\n             castrate-resistant prostate cancer (mCRPC), melanoma, ovarian cancer, ACC,\n             mesothelioma, urothelial carcinoma and renal cell carcinoma as defined in the protocol\n\n          -  Efficacy expansion cohorts: Gastric and GEJ cancer (third line), ovarian cancer\n             (platinum Refractory + liposomal doxorubicin), urothelial carcinoma, and HNSCC as\n             defined in the protocol\n\n               -  Other protocol defined inclusion criteria for expansion phase could apply\n\n        Exclusion Criteria for dose escalation and expansion phase:\n\n          -  Concurrent treatment with a non-permitted drug\n\n          -  Prior therapy with specific antibody/drug targeting T cell co-regulatory proteins\n             (immune checkpoints)\n\n          -  Concurrent anticancer treatment, major surgery, or use of any investigational drug\n             within 28 days before the start of trial treatment; or concurrent systemic therapy\n             with immunosuppressive agents, use of hormonal agents within 7 days before the start\n             of trial treatment as defined in the protocol. Note: Subjects receiving bisphosphonate\n             or denosumab are eligible provided treatment was initiated at least 14 days before the\n             first dose of avelumab.\n\n          -  Previous malignant disease other than the target malignancy to be investigated in this\n             trial within the last 5 years with the exception of basal or squamous cell carcinoma\n             of the skin or cervical carcinoma in situ\n\n          -  Rapidly progressive disease (for example, tumor lysis syndrome)\n\n          -  Active or history of central nervous system metastases\n\n          -  Receipt of any organ transplantation including allogeneic stem-cell transplantation\n\n          -  Significant acute or chronic infections as defined in the protocol\n\n          -  Active or history of any autoimmune disease (subjects with diabetes Type 1, vitiligo,\n             psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are\n             eligible) or immunodeficiencies\n\n          -  Known severe hypersensitivity reactions to monoclonal antibodies, any history of\n             anaphylaxis, or uncontrolled asthma\n\n          -  Persisting toxicity related to prior therapy greater than Grade 1 NCI-CTCAE v4.0,\n             however sensory neuropathy less than or equal to Grade 2 is acceptable\n\n          -  Pregnancy or lactation period\n\n          -  Known alcohol or drug abuse\n\n          -  Clinically significant (that is, active) cardiovascular disease\n\n          -  All other significant diseases (for example, inflammatory bowel disease), which, in\n             the opinion of the investigator, might impair the subject's tolerance of trial\n             treatment\n\n          -  Any psychiatric condition that would prohibit the understanding or rendering of\n             informed consent\n\n          -  Legal incapacity or limited legal capacity\n\n          -  Non-oncology vaccine therapies for prevention of infection disease (for example,\n             seasonal flu vaccine, human papilloma virus vaccine) within 4 weeks of study drug\n             administration. Vaccination while on study is also prohibited except for\n             administration of the inactivated influenza vaccineXx_NEWLINE_xXStable systemic diseaseXx_NEWLINE_xXProgression of systemic disease at ScreeningXx_NEWLINE_xXPatients with synchronous disease at initial diagnosis must have metastatic (M1) disease (American Joint Committee on Cancer [AJCC] 7th edition T1-4N0-1M1)Xx_NEWLINE_xXHave received more than one prior systemic chemotherapy regimen for metastatic disease.Xx_NEWLINE_xXClinical and radiologic assessments that are negative for local or regional recurrence of disease or metastatic disease at the time of study entry, includingXx_NEWLINE_xXClinical or radiologic evidence of local or regional recurrence of disease or metastatic disease prior to or at the time of study entryXx_NEWLINE_xXPrior or present evidence of distant metastatic disease as assessed by radiographic imaging;Xx_NEWLINE_xXis unresectable or metastaticXx_NEWLINE_xXDisease progression during or within 6 months after treatment with one line of 5-Fluorouracil (5-FU)- or gemcitabine-based chemotherapy in the metastatic settingXx_NEWLINE_xXHistologically confirmed metastatic soft tissue sarcoma (i.e., non-GIST, non-adipocytic) that has progressed by RECIST following treatment with anthracycline chemotherapy. Patients may have received up to four lines of systemic therapy for metastatic disease and no more than two lines of combination treatment ( Phase 2 only)Xx_NEWLINE_xXSubjects with recurrent (unresectable) or metastatic CRC:Xx_NEWLINE_xXThere must be residual diseaseXx_NEWLINE_xXMetastatic disease documented by bone lesions on bone scan or by measurable soft tissue disease by CT/MRI. Patients whose disease spread is limited to regional pelvic lymph nodes are not eligibleXx_NEWLINE_xXEvidence of distant metastatic diseaseXx_NEWLINE_xXPatients with known HER-2 overexpressing MBC must have failed at least one prior trastuzumab-containing regimen for metastatic disease.Xx_NEWLINE_xXConfirmed recurrent or metastatic diseaseXx_NEWLINE_xXPatients must have had one and only one prior regimen of systemic therapy for metastatic disease unless the patient meets the criteria belowXx_NEWLINE_xXMetastatic disease or incurable locally recurrent diseaseXx_NEWLINE_xXPrior systemic therapy for metastatic or recurrent NSCLC.Xx_NEWLINE_xXHistory of metastatic disease at any time or presence of detectable metastases.Xx_NEWLINE_xXPatients with chemotherapy for metastatic disease (patients with 0-3 prior lines of chemotherapy for metastatic breast cancer [MBC])Xx_NEWLINE_xXNo prior or present evidence of metastatic disease;Xx_NEWLINE_xXNo prior cytotoxic chemotherapy to treat their metastatic diseaseXx_NEWLINE_xXReceived first-line combination therapy containing oxaliplatin and fluoropyrimidine with or without bevacizumab for metastatic disease with documented evidence of disease progression during or after treatment completionXx_NEWLINE_xXEvidence of distant metastatic disease (Masaoka stage IVB)Xx_NEWLINE_xXDefinitive clinical or radiological evidence of metastatic diseaseXx_NEWLINE_xXMore than 3 prior regimens for metastatic RCC.Xx_NEWLINE_xXFor dose escalation phase (Phase Ib) distant metastatic disease or unresectable disease and not a candidate for down staging to resection.Xx_NEWLINE_xXFor expansion phase (Phase II) distant metastatic disease only.Xx_NEWLINE_xXNo prior systemic chemotherapy for recurrent or metastatic diseaseXx_NEWLINE_xXMetastatic disease involving bone with metastatic disease previously confirmed by prior biopsy; or Metastatic disease involving bone previously confirmed on imaging (e.g. CT or MRI) with known (biopsied) primary disease (primary bone cancer is excluded)Xx_NEWLINE_xXPain must be from one painful metastatic lesion involving the bone that is amenable to cryoablation with CT (additional less painful metastatic sites may be present)Xx_NEWLINE_xXInclusion Criteria:\n\n          -  Must have cancer of the anal canal OR rectal cancer.\n\n          -  Must have metastatic disease or persistent/recurrent loco-regional disease\n\n          -  Prior Therapy: may have received <2 regimens for disease in the metastatic setting. At\n             least one line of therapy.\n\n          -  Be willing and able to provide written informed consent for the trial.\n\n          -  Be ?18 years of age on day of signing informed consent.\n\n          -  Have measurable disease based on RECIST 1.1\n\n          -  Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n\n          -  Demonstrate adequate organ function as defined in protocol.\n\n          -  Females cannot be pregnant or breastfeeding and must take two methods of birth controlXx_NEWLINE_xXKnown untreated or unstable CNS metastatic disease.Xx_NEWLINE_xXMore than 3 prior systemic anti-cancer therapies (e.g. cytotoxic agents, biologic agents) regimens for metastatic diseaseXx_NEWLINE_xXMetastatic disease, unresectable disease involving one or more sites including liver, lung, lymph nodes and peritoneum, with each nodule measuring =< 3 cm OR no more than two sites of disease (two nodules) > 4.5 cmXx_NEWLINE_xXPresence of metastatic disease that, in the opinion of investigators, would require palliative treatment within 4 weeks of enrollmentXx_NEWLINE_xXEvidence of metastatic disease or nodal disease outside the prostate on bone scan or cross-sectional imaging.Xx_NEWLINE_xXRandomized Phase 2 Dose Expansion - Individuals may have disease progression during treatment or within 12 months of completion of endocrine therapy (tamoxifen, and/or AI) in the adjuvant setting, or disease progression during treatment with endocrine therapy (tamoxifen, AI or CDK4/6 inhibitor plus AI) for advanced/metastatic disease. Individuals may have had unlimited prior hormonal therapy, but must be naive to fulvestrant in the metastatic setting. A total of 2 prior chemotherapies are allowed, however, only one for metastatic disease is permitted.Xx_NEWLINE_xXPrior systemic therapy for metastatic diseaseXx_NEWLINE_xXAny other malignant diseaseXx_NEWLINE_xXPrevious chemotherapy for recurrent or metastatic disease.Xx_NEWLINE_xXFor relapsed disease:Xx_NEWLINE_xXAdult Asian women with locoregionally recurrent or metastatic disease not amenable to curative therapyXx_NEWLINE_xXHave locoregionally recurrent disease not amenable to resection or radiation therapy with curative intent or metastatic diseaseXx_NEWLINE_xXA diagnosis of metastatic or unresectable sarcomaXx_NEWLINE_xXPatients must have had one or two prior regimens of systemic chemotherapy for metastatic or locally advanced, unresectable disease; (a maintenance regimen of 5-fluorouracil or capecitabine, with or without bevacizumab, should not be counted as a separate line of treatment); prior treatment with irinotecan is allowed; prior treatment for metastatic disease is not required for patients who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapyXx_NEWLINE_xXPatients may not be receiving concurrent chemotherapy for treatment of metastatic diseaseXx_NEWLINE_xXHistologic diagnosis of unresectable or metastatic melanoma; for unknown primary disease, diagnosis of metastatic disease by cytology fine-needle aspiration (FNA) is not acceptable; BRAF wild-type confirmed, and NRAS mutation assessedXx_NEWLINE_xXRCC subjects must have received ?1 prior line of therapy for metastatic disease (Part 1A)Xx_NEWLINE_xXSubjects must have experienced disease progression or recurrence during or after at least one systemic therapy for advanced or metastatic diseaseXx_NEWLINE_xXDocumented distant metastatic disease; NOTE: pelvic lymphadenopathy is NOT excludedXx_NEWLINE_xXEvidence of metastatic disease on cross sectional imaging or bone scanXx_NEWLINE_xXPatients must have at least stable disease (no overt progressive disease) at the time of study registrationXx_NEWLINE_xXAdult women with locoregionally recurrent or metastatic disease not amenable to curative therapy.Xx_NEWLINE_xXPatients must have progressive metastatic disease; progressive will be defined as new or progressive lesions on cross-sectional imagingXx_NEWLINE_xXPatients must have progressive metastatic disease; progressive disease will be defined as new or progressive lesions on cross-sectional imagingXx_NEWLINE_xXDocumented distant metastatic diseaseXx_NEWLINE_xXNo stage IV (metastatic) disease, however no specific staging studies are required in the absence of symptoms or physical exam findings that would suggest distant disease.Xx_NEWLINE_xXMETASTATIC SAFETY COHORTXx_NEWLINE_xXPrior therapy with more than one line of cytotoxic chemotherapy following diagnosis of advanced/metastatic disease, or disease which has progressed despite prior fulvestrant therapy.Xx_NEWLINE_xXThe patient must have received no more than 3 prior lines of therapy for metastatic disease.Xx_NEWLINE_xXThe patient must have received no more than 2 prior regimens with VEGF inhibitors and 1 prior regimen with checkpoint inhibitors for metastatic disease.Xx_NEWLINE_xXThe patient must have received no more than 2 prior lines of therapy for metastatic disease.Xx_NEWLINE_xXThe patient must have received at least 1 and no more than 2 prior lines of treatment in the metastatic setting.Xx_NEWLINE_xXHave histologically confirmed unresectable or metastatic melanoma having received no more than one prior systemic therapy for the metastatic disease (eg. ipilumamab and/or BRAF inhibitor); unresectable or metastatic smoking-associated NSCLC having received no more than one prior systemic therapy for the metastatic disease (eg standard of care chemotherapy, as appropriate); unresectable or metastatic transitional cell carcinoma of the bladder, urethra, ureter or renal pelvis having received no more than one prior systemic therapy for the metastatic disease.Xx_NEWLINE_xXDisease and disease status:Xx_NEWLINE_xXClinical or radiographic evidence of metastatic disease; metastatic workup is not required\r\n* Note: isolated ipsilateral supraclavicular node involvement is permittedXx_NEWLINE_xXPatients must have disease that is not amenable to potentially curative resection, and must not have metastatic diseaseXx_NEWLINE_xXResectable, borderline resectable or metastatic diseaseXx_NEWLINE_xXProgression after at least first-line systemic therapy for metastatic diseaseXx_NEWLINE_xXPatients must have recurrent and/or metastatic disease not amenable to potentially curative surgery or radiotherapyXx_NEWLINE_xXNo more than 4 prior chemotherapeutic regimens for metastatic diseaseXx_NEWLINE_xXProgressive metastatic disease defined by one of the following, occurring within 6 months of study entry:\r\n* At least a 20% increase in radiologically or clinically measurable disease\r\n* Appearance of any new lesion\r\n* Symptomatic disease (including worsening hormonal symptoms or symptoms related to tumor burden)Xx_NEWLINE_xXWidespread progressive disease, i.e., more than three sites of progressive disease (note that more than three sites of disease are permitted provided there are no more than three sites of progressive disease)Xx_NEWLINE_xXBiopsy proven breast carcinoma which is persistent and metastatic or recurrent and metastatic.Xx_NEWLINE_xXPatients must have failed at least one line of chemotherapy for metastatic disease.Xx_NEWLINE_xXDefinite evidence of metastatic diseaseXx_NEWLINE_xXAny distant metastatic diseaseXx_NEWLINE_xXHave histologically or cytologically diagnosed oligo-metastatic prostate cancer; oligo-metastatic disease is defined to reflect men with low volume disease; specifically, oligo-metastatic disease is defined as less than 5 extra-pelvic metastases; metastatic lesions may be lymph nodesXx_NEWLINE_xXCohort 2 patients must have had a complete resection of all sites of metastatic disease within 30 days prior to enrollment\r\n* Patients will only be eligible after they have undergone complete surgical resection of suspected metastatic disease that is histopathologically confirmed to be osteosarcoma prior to enrollment\r\n** Note: the definition of complete resections is: gross resection of all disease as per the operating surgeon; post-operative imaging is not required for confirmation of complete resection\r\n* Patients must undergo resection of any lung lesion meeting criteria for likely metastatic disease, defined as: \r\n** 3 or more lesions > 5 mm in diameter OR a single lesion > 1 cm\r\n* Patients with lung as the only site of resected metastatic disease must have refused participation in protocol AOST1421\r\n** Note: this applies if AOST1421 is open to enrollment at the enrolling institution on the day the patient consentsXx_NEWLINE_xXEvidence of metastatic diseaseXx_NEWLINE_xXKnown metastatic diseaseXx_NEWLINE_xXMetastatic diseaseXx_NEWLINE_xXMetastatic or recurrent CRCXx_NEWLINE_xXSystemic disease must be well-controlled or no evidence of disease (NED) in the opinion of the patient’s primary oncologistXx_NEWLINE_xXProgressive systemic diseaseXx_NEWLINE_xXMetastatic or unresectable disease documented on diagnostic imaging studiesXx_NEWLINE_xXPhysical, clinical, radiographic or pathologic evidence of satellite, in-transit, regional, or distant metastatic melanoma.Xx_NEWLINE_xXVisceral (eg, lung, liver) metastatic disease. Adenopathy is allowed;Xx_NEWLINE_xXHave histological or cytological evidence of colorectal adenocarcinoma with confirmation of metastatic disease either by pathologic or radiologic findings.Xx_NEWLINE_xXHave had no prior systemic therapy for advanced or metastatic disease. Prior adjuvant therapy should have been completed at least 9 months from documentation of metastatic disease. Prior palliative radiotherapy allowed if toxicities resolved to grade 1 or baseline.Xx_NEWLINE_xXPhase Ib dose escalation cohort study: subjects with histologically assessed metastatic clear cell RCC (defined as more than 50% clear cell component) after failure of at least one systemic therapy for metastatic disease (including, but not limited to prior therapy with interleukin 2, interferon, bevacizumab, VEGF TKI, and mTOR) for metastatic disease. NOTE: A biopsy to prove metastatic disease is not required.Xx_NEWLINE_xXPhase II study: subjects with treatment-naïve histologically assessed metastatic clear cell RCC (defined as more than 50% clear cell component) and who are candidates for standard first-line therapy. NOTE: A biopsy to prove metastatic disease is not required.Xx_NEWLINE_xXPresence of metastatic disease (stage IV NSCLC) is not allowed. Subjects must be evaluated with a PET scan within 28 days prior to registration for protocol therapy to exclude metastatic diseaseXx_NEWLINE_xXHistologically confirmed recurrent or metastatic SCCHN; tumor progression or recurrence during or after treatment with only 1 systemic palliative regimen for recurrent or metastatic disease that must have contained a platinum agent; Patients who have only received chemo-radiation with curative intent for treatment of their locally advanced disease or recurrent disease are not eligible. Patients who received concurrent chemo-radiation as part of treatment of their recurrent disease are also not eligible.Xx_NEWLINE_xXReceived more than 1 regimen for recurrent or metastatic diseaseXx_NEWLINE_xXPatients must have been treated with at least one prior systemic treatment for incurable advanced or metastatic SCCA of the anal canal; prior treatment for metastatic disease is not required for patients who develop new metastatic lesions during or within 6 months of completion of chemoradiation for limited-stage disease; patients who receive chemotherapy for incurable advanced or metastatic SCCA of the anal canal must wait a minimum >= 28 days (6 weeks for nitrosoureas or mitomycin C) after the date of completion of chemotherapy prior to initiating treatment with nivolumab on this study; patients who undergo radiotherapy to a site of tumor must wait a minimum >= 3 months from the date of completion of radiotherapy prior to initiating treatment with nivolumab on this studyXx_NEWLINE_xXHave metastatic diseaseXx_NEWLINE_xXHas a metastatic deposit that can be biopsiedXx_NEWLINE_xXDefinitive clinical or radiologic evidence of metastatic disease.Xx_NEWLINE_xXTreatment with bevacizumab in at least one prior line of therapy for metastatic diseaseXx_NEWLINE_xXMetastatic diseaseXx_NEWLINE_xXRecurrent/metastatic disease, fulfilling at least one of the criteria defined below:\r\n* Incurable disease as assessed by surgical or radiation oncology\r\n* Metastatic (M1) disease\r\n* Persistent or progressive disease following curative-intent radiation, and not a candidate for surgical salvage due to incurability or morbidity; patients who decline radical surgery are eligibleXx_NEWLINE_xXUse of a systemic treatment regimen for metastatic disease within 28 days preceding the first dose of AEB071 and BYL719Xx_NEWLINE_xXPreviously treated with 3 or more systemic regimens given for recurrent and/or metastatic diseaseXx_NEWLINE_xXHave metastatic diseaseXx_NEWLINE_xXHave received and failed only 1 prior chemotherapy regimen for metastatic pancreatic cancer\r\n* Must have received and failed only 1 prior regimen administered for pancreatic cancer in the metastatic setting; failure includes development of metastases on or within 3 months of adjuvant chemotherapy treatment or development of metastases on or within 3 months of treatment for locally advanced disease or radiographic disease progression on or within 3 months of treatments for metastatic disease; documented intolerance (grade 3 or 4 toxicity or hospitalization leading to discontinuation) of treatment for metastatic disease will also be considered a failure\r\n* Radiosensitizing doses of chemotherapy are not considered systemic chemotherapyXx_NEWLINE_xXPresence of metastatic or recurrent diseaseXx_NEWLINE_xXHave recurrent or metastatic solid tumorsXx_NEWLINE_xXDocumented radiological disease progression during the most recent treatment regimen for metastatic diseaseXx_NEWLINE_xXMost recent treatment regimen for metastatic disease must include Trastuzumab and chemotherapy.Xx_NEWLINE_xXLast treatment for metastatic disease including Trastuzumab in combination with pertuzumabXx_NEWLINE_xXReceived more than 1 systematic palliative regimen for recurrent or metastatic diseaseXx_NEWLINE_xXPatients with metastatic pancreatic adenocarcinoma not treated with chemotherapy for metastatic diseaseXx_NEWLINE_xXSubject may have received ?2 prior regimens for the treatment of their metastatic disease.Xx_NEWLINE_xXFor patients with metastatic melanoma not of uveal origin, v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation determination using a Clinical Laboratory Improvement Amendments (CLIA)-approved testing method on metastatic tumor tissue\r\n* NOTE: patients with metastatic melanoma of uveal origin do not need to have formal BRAF testing due to low probability of a BRAF V600 mutation in their metastatic tumorXx_NEWLINE_xXPatients with metastatic cancerXx_NEWLINE_xXPatient must have received at least one, and no more than two prior systemic therapies for metastatic cancerXx_NEWLINE_xXPatients with distant metastatic disease (M1c) will not be eligible for this studyXx_NEWLINE_xXDocumentation of metastatic diseaseXx_NEWLINE_xX1-3 sites of metastatic disease able to be targeted by SABRXx_NEWLINE_xXrelapsed with radiologic evidence of progression more than 1 year from completion of adjuvant endocrine therapy and then subsequently relapsed with radiologic evidence of progression after receiving treatment with either an antiestrogen or an aromatase inhibitor as first-line endocrine therapy for metastatic disease. Participants may not have received more than 1 line of endocrine therapy or any prior chemotherapy for metastatic diseaseXx_NEWLINE_xXpresented de novo with metastatic disease and then relapsed with radiologic evidence of progression after receiving treatment with either an antiestrogen or an aromatase inhibitor as first line endocrine therapy for metastatic disease. Participants may not have received more than 1 line of endocrine therapy or any prior chemotherapy for metastatic diseaseXx_NEWLINE_xXPatients must have recurrent and/or metastatic disease not amenable to potentially curative surgery or radiotherapyXx_NEWLINE_xXAny distant metastatic disease visualized on preoperative imaging:\r\n* Solid organ metastases\r\n* Clear radiologic evidence of carcinomatosisXx_NEWLINE_xXHave hormone-sensitive metastatic disease (M1) as evidenced by soft tissue and/or bony metastasesXx_NEWLINE_xXPrior chemotherapy for metastatic diseaseXx_NEWLINE_xXEvidence of metastatic diseaseXx_NEWLINE_xXMetastatic diseaseXx_NEWLINE_xXPHASE II: Patients with evidence of metastatic disease involvement in viscera or boneXx_NEWLINE_xXHistopathologic documentation of melanoma concurrent with the diagnosis of metastatic diseaseXx_NEWLINE_xXCOHORT B: Visceral metastatic diseaseXx_NEWLINE_xXNo prior chemotherapy for metastatic diseaseXx_NEWLINE_xXPrior systemic chemotherapy for metastatic diseaseXx_NEWLINE_xXEvidence of metastatic disease (stage M1)Xx_NEWLINE_xXImaging confirmation of metastatic diseaseXx_NEWLINE_xXPatients must not have evidence of metastatic tumor or other cancerXx_NEWLINE_xXCTCAE v4.0 grade 3 or 4 anorexia or nausea related to metastatic disease.Xx_NEWLINE_xXPatient presents with Stage 4 pulmonary metastatic disease with metastatic disease previously confirmed by prior biopsy; or Patient presents with Stage 4 pulmonary metastatic disease previously confirmed on imaging (e.g. computerized tomography or CT) with histology proven primary cancer.Xx_NEWLINE_xXPatient has uncontrollable primary or metastatic disease outside of the lung.Xx_NEWLINE_xXPatients may have received 1-3 prior systemic therapies in the metastatic setting.Xx_NEWLINE_xXNo stage IV (metastatic) disease, however no specific staging studies are required in the absence of symptoms or physical exam findings that would suggest distant disease.Xx_NEWLINE_xXMay have previously received lapatinib as part of a regimen in the perioperative or metastatic setting with evidence of progression of disease; washout period for lapatinib of 14 daysXx_NEWLINE_xXPatients have progressive metastatic disease with predominantly bone metastasis with 1 or more lesions and at least 1 bone lesion has pathological confirmation, have not been treated or have been treated with any prior therapies (including bisphosphonate treatment and/or radiation therapy); patients can have soft tissue involvement (lymph node and skin) and/or metastatic lesions at major organ sites (i.e. lung, liver, etc)Xx_NEWLINE_xXPatients with metastatic sites that requires chemotherapyXx_NEWLINE_xXGroup B:\r\n* Newly diagnosed patient with histologically proven Ewing sarcoma family of tumor involving the bone or soft tissue and at least one of the following:\r\n** Metastatic disease (must be biopsy proven)\r\n** Pelvic primary\r\n** Age >= 14 years at the time of diagnosis\r\n*** Patients with more than one pulmonary lesion > 1cm may be considered as having evidence of metastatic disease without biopsy, as long as there is no other clear medical reason for these lesions; these cases should be discussed with the principal investigator (PI) and if there is any doubt, a biopsy should be obtained\r\n* Newly diagnosed patients with intra-abdominal, unresectable or metastatic desmoplastic small round cell tumor; metastatic site must be biopsy provenXx_NEWLINE_xXRadiographic evidence of metastatic disease; evaluable non-target lesions and/or bone only metastasis are permittedXx_NEWLINE_xXFor the dose-finding phase, patients may have stable disease OR progression of disease on the most recent treatment; for the expansion phase, patients must also have stable disease OR progression of disease on the most recent treatment; progression of disease is defined as new or worsening disease on objective imaging; progression or disease includes recurrence diagnosed while on adjuvant letrozole or exemestaneXx_NEWLINE_xXPatients with rapidly progressive or extensive symptomatic visceral metastatic diseaseXx_NEWLINE_xXHistological or cytological documentation of solid tumors for whom single agent irinotecan is recommended; biopsy of primary tumor alone is adequate if the patient has clear evidence of metastatic disease and/or elevated carcinoembryonic antigen (CEA) and the treating physician does not feel biopsy of metastatic disease is clinically warrantedXx_NEWLINE_xXNo evidence of disease by standard morphology; minimal residual disease or molecular evidence of disease will not excludeXx_NEWLINE_xXLocoregionally recurrent or metastatic disease that has not previously been treated with systemic therapy of recurrent or metastatic diseaseXx_NEWLINE_xXPrior treatment with any chemotherapy for metastatic disease from pancreatic cancerXx_NEWLINE_xXPatients with metastatic uveal melanomaXx_NEWLINE_xXEvidence of metastatic disease with measurable lesion(s) as defined by RECIST guideline version 1.1 to permit tumor response evaluation; subjects with unresected primary tumors may be enrolled as long as evidence of measurable metastatic disease is also presentXx_NEWLINE_xXDocumented, progressive disease/tumor growth, which may include after exposure to a platinating agent (e.g. cisplatin or carboplatin) or another cytotoxic chemotherapy or radiation in a prior line of therapy, or documented intolerance to such an agent; prior line of therapy may include induction chemotherapy or chemoradiotherapy, in addition to treatment for recurrent/metastatic disease; de novo metastatic disease is also allowed as long as progressive disease/evidence of tumor growth is documentedXx_NEWLINE_xXPatients with metastatic disease involving viscera or bones are ineligible; patients with extensive nodal involvement alone classified as stage IV disease, are eligibleXx_NEWLINE_xXRadiographic evidence of metastatic disease, detectable by bone scan, CT scan, or MRI. At least one site of metastatic disease must be amenable to needle biopsy.Xx_NEWLINE_xXPatients with metastatic or advanced-stage malignant tumor. Patients may have received up to 2 prior lines of chemotherapy for their metastatic diseaseXx_NEWLINE_xXParticipants must not have metastatic disease; pre-operative chest CT scan is required within 10 weeks prior to registration; patients with overt evidence of lung metastatic disease are excluded from the study; however, because of the sensitivity/specificity of the chest CT, small incidental lesions without a histologic diagnosis may not be a basis for study exclusionXx_NEWLINE_xXSTEP 2 ENROLLMENT AND RANDOMIZATION: less than or equal to three metastatic lesions and no evidence of disease progression based on RECIST criteria; note that patients that had > 3 metastatic lesions in Step 1 may be eligible for enrollment in Step 2 if the number of metastatic sites is reduced to three or lessXx_NEWLINE_xXPatients must have metastatic disease of the esophagus, gastroesophageal junction or stomach; patients with locally recurrent disease who are not deemed eligible for radiation are also permitted\r\n* Histological, cytologic or radiographic documentation of metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, gastroesophageal junction or stomach; radiologic, endoscopic, histologic or cytologic evidence of locally recurrent disease is also permittedXx_NEWLINE_xXPatients must be untreated with chemotherapy for metastatic or locally recurrent disease; prior radiation therapy is permittedXx_NEWLINE_xXSymptomatic metastatic disease, as defined by the need for opioid analgesics for the treatment of pain attributed to a prostate cancer metastatic lesion; patients receiving opioids must receive approval from the principal investigator (PI) for eligibilityXx_NEWLINE_xXPatient must not have known distant metastatic disease at presentationXx_NEWLINE_xXEvidence of distant metastatic disease.Xx_NEWLINE_xXSpinal metastatic lesion being treated must be =< 6cm in greatest dimensionXx_NEWLINE_xXAt least one prior treatment for metastatic diseaseXx_NEWLINE_xXMetastatic disease for stratum B onlyXx_NEWLINE_xXAny metastatic diseaseXx_NEWLINE_xXPatients with clinical, radiological/laboratory, or pathological evidence of distant metastatic diseaseXx_NEWLINE_xXPhase Ia: Patients may have de novo metastatic disease, or documented progression despite any number of prior therapies; patients must have no curative or other effective therapeutic options availableXx_NEWLINE_xXPatients must have metastatic or unresectable diseaseXx_NEWLINE_xXPatients with prior surgical resection who develop radiological or clinical evidence of metastatic cancer do not require separate histological or cytological confirmation of metastatic disease unless an interval of > 5 years has elapsed between the primary surgery and the development of metastatic disease; clinicians should consider biopsy of lesions to establish diagnosis of metastatic disease if there is substantial clinical ambiguity regarding the nature or source of apparent metastasesXx_NEWLINE_xXPatients with a history of colorectal cancer treated by surgical resection who develop radiological or clinical evidence of metastatic cancer do not require separate histological or cytological confirmation of metastatic disease unless:\r\n* Either an interval of > 5 years has elapsed between the primary surgery and the development of metastatic disease, OR\r\n* The primary cancer was stage I\r\nClinicians should consider biopsy of lesions to establish the diagnosis of metastatic colorectal cancer in each case if there is substantial clinical ambiguity regarding the nature or source of apparent metastasesXx_NEWLINE_xXMetastatic Pancreatic CancerXx_NEWLINE_xXPatients must have histologically or cytologically confirmed invasive breast cancer, with metastatic disease; patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis by physical exam or radiologic studyXx_NEWLINE_xXMeasurable metastatic melanoma with available autologous TILXx_NEWLINE_xXPatient has known metastatic diseaseXx_NEWLINE_xXUveal melanoma with biopsy proven metastatic diseaseXx_NEWLINE_xXDocumented distant metastatic disease; but pelvic lymphoadenopathy is NOT excludedXx_NEWLINE_xXMore than three prior lines of cytotoxic chemotherapy for metastatic diseaseXx_NEWLINE_xXWomen with metastatic disease outside of pelvisXx_NEWLINE_xXNo evidence of extranodal metastatic diseaseXx_NEWLINE_xXI 02. Metastatic disease.Xx_NEWLINE_xXPatients should have at least one organ system involved with distant metastatic disease; if only a single metastatic lesion is present, biopsy is mandatoryXx_NEWLINE_xXPatients with newly diagnosed stage IV NSCLC with an untreated primary must have no more than 3 active extracranial metastatic lesions other than the primary site and regional lymph nodes\r\n* Patients with metastatic disease treated by local therapy at the time of registration but untreated thoracic disease will be includedXx_NEWLINE_xXOTHER METASTATIC SITES:Xx_NEWLINE_xXDefinitive clinical or radiologic evidence of metastatic disease; indeterminant lung nodules less than 8 mm are acceptableXx_NEWLINE_xXPatients must have recurrent and/or metastatic disease not amenable to potentially curative surgery or radiotherapyXx_NEWLINE_xXExpansion Cohort 6: Subjects with metastatic CRPC (adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features) who have radiographically progressed in soft tissue on or after enzalutamide and/or abiraterone acetate for metastatic disease.Xx_NEWLINE_xXPatients with metastatic diseaseXx_NEWLINE_xXResectable primary tumor with no evidence of metastatic disease by imaging. Imaging must be performed within 45 days of Day 1 of study.Xx_NEWLINE_xXHave received prior treatment for metastatic disease with oxaliplatin-based regimen and either:\r\n* Had disease progression OR\r\n* Had stable disease OR\r\n* Discontinued oxaliplatin due to neuropathyXx_NEWLINE_xXPatients who have received more than one chemotherapy regimen for metastatic diseaseXx_NEWLINE_xXCT or MRI evidence of metastatic disease to the boneXx_NEWLINE_xXPresence of extra-cranial metastatic diseaseXx_NEWLINE_xXPrior palliative chemotherapy for metastatic or recurrent diseaseXx_NEWLINE_xXPrior biological therapy for metastatic or recurrent disease within 3 weeks prior to randomizationXx_NEWLINE_xXPatients who have metastatic disease, if the metastatic sites are amendable for local therapy (i.e. radiation and/or surgery), and are candidates for breast surgery will be eligibleXx_NEWLINE_xXAt least 2 biopsiable easily accessible cutaneous and subcutaneous lesions in patients in the metastatic disease cohortXx_NEWLINE_xX1 to 3 bone metastatic sites (metastatic lesions in the same bone that are within 3 cm of each other are considered as one site)Xx_NEWLINE_xXAt least 1 prior antineoplastic chemotherapy treatment regimen for metastatic disease and at least 1 prior treatment with a trastuzumab-containing regimen for at least 6 weeks, for metastatic disease or subject relapsing under adjuvant treatment (part 2 only).Xx_NEWLINE_xXMore than 2 prior antineoplastic treatment regimens (excluding hormonotherapy) for metastatic disease. Subjects who relapsed under adjuvant treatment shouldn't have received more than one line of chemotherapy for metastatic disease (part 2 only).Xx_NEWLINE_xXDisease-freeXx_NEWLINE_xXPatients with evidence of disease are only eligible if the disease is stable (or persistent) in comparison to the status prior to transplantationXx_NEWLINE_xXPatients must have at least ONE of the following: 1) Recurrent/progressive disease at any time prior to study enrollment, 2) Refractory disease, 3) Persistent diseaseXx_NEWLINE_xXConcurrent metastatic solid tumorsXx_NEWLINE_xXNo prior systemic therapy for metastatic disease.Xx_NEWLINE_xXDefinitive clinical or radiologic evidence of metastatic disease; pN3 disease is not allowed (positive common iliac node)Xx_NEWLINE_xXSevere (CTCAE v 4.03 grade 3 or higher) concurrent hepatic impairment, renal impairment, heart disease, hematological disease, respiratory disease, or metabolic diseaseXx_NEWLINE_xXProgressive metastatic (M1) disease on androgen deprivation therapyXx_NEWLINE_xXPatients with metastatic diseaseXx_NEWLINE_xXPatients may undergo an optional biopsy of the metastatic disease at baseline and after 2 cycles of BIBF-1120Xx_NEWLINE_xXHave received at least one any prior treatment for local recurrence or metastatic disease and have relapsedXx_NEWLINE_xXPatients with only locally or regionally confined disease without evidence of metastatic diseaseXx_NEWLINE_xXEvidence of disease progression at study entry.Xx_NEWLINE_xXNo evidence of metastatic diseaseXx_NEWLINE_xXMetastatic brain or meningeal tumorsXx_NEWLINE_xXEvidence or suspicion of disease metastatic to sites remote from supratentorial brainXx_NEWLINE_xXPatients with metastatic disease i.e. leptomeninges, multi-focal lesions in the CNSXx_NEWLINE_xXMetastatic diseaseXx_NEWLINE_xXCNS metastatic diseaseXx_NEWLINE_xXHave extra-hepatic metastatic disease. Suspicious lesions should be rigorously evaluated with other imaging techniques and/or biopsy to exclude extra-hepatic metastatic disease prior to submitting for central radiology review.Xx_NEWLINE_xXUnilobar diseaseXx_NEWLINE_xXPatient treated with more than one prior chemotherapy regimen for recurrent/metastatic diseaseXx_NEWLINE_xXPatients with known metastatic disease are excludedXx_NEWLINE_xXPathologically (histologically or cytologically) confirmed metastatic disease with a new tumor involving or abutting bone that has the clinical and imaging features of metastatic disease\r\n* If the nature of the metastatic disease has been previously documented, index tumor to be treated does not require further documentation (i.e., biopsy)Xx_NEWLINE_xXPain must be from one or two painful metastatic sites in the bone (additional less painful metastatic sites may be present)\r\n* Pain from the reported one or two metastatic sites must correlate with an identifiable tumor on CT, magnetic resonance imaging (MRI), or ultrasound (US) imaging\r\n* Metastatic tumors must be amenable to cryoablation with CT or MRIXx_NEWLINE_xXEligible subjects are required to have > or = to 1 line of multi-agent chemotherapy either neoadjuvantly or adjuvantly. Subjects may have had 0-2 lines of therapy for metastatic disease.Xx_NEWLINE_xXHistopathological documentation of MCC concurrent with the diagnosis of metastatic diseaseXx_NEWLINE_xXFor Phase Ib, there is no restriction on the number of prior therapies for recurrent or metastatic diseaseXx_NEWLINE_xXFor Phase II, patients may have received a maximum of 1 prior line of therapy for recurrent or metastatic diseaseXx_NEWLINE_xXRecurrent disease with an:Xx_NEWLINE_xXPatients may not have received more than 2 prior systemic treatment regimens for distant metastatic disease. The following prior therapy is permitted in either the adjuvant or metastatic disease setting, provided treatment is discontinued at least 4 weeks prior to initiating study treatment:Xx_NEWLINE_xXUnresectable or metastatic diseaseXx_NEWLINE_xXFor non-urothelial cancer patients, no more than 1 prior line of combination systemic chemotherapy for metastatic disease is allowedXx_NEWLINE_xXHistologic or cytologic confirmation of head and neck malignancy without clinical or radiographic evidence of metastatic diseaseXx_NEWLINE_xXMetastatic cancer with evaluable diseaseXx_NEWLINE_xXPatients must have previously received at least one systemic standard care (or effective salvage chemotherapy regimens) for metastatic disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurredXx_NEWLINE_xXPrior chemotherapy for metastatic or locally recurrent disease Exceptions:Xx_NEWLINE_xXPrior immunotherapy for metastatic or locally recurrent diseaseXx_NEWLINE_xXPatients in the phase I portion must have:\r\n* Histologically confirmed diagnosis of metastatic, genitourinary solid tumor\r\n* Metastatic disease defined as new or progressive lesions on cross-sectional imaging; patients must have at least:\r\n** One evaluable site of disease \r\n** Or, appearance of one new bone lesionXx_NEWLINE_xXHistory of renal disease or current evidence of renal diseaseXx_NEWLINE_xXSubjects with negative metastatic involvement (M0).Xx_NEWLINE_xXMetastatic or recurrent disease that is deemed partially resectable or unresectable based on preoperative imagingXx_NEWLINE_xXMetastatic disease outside the confines of the abdomen and pelvis (such as lung, bone, brain)Xx_NEWLINE_xXRadiographic evidence of diseaseXx_NEWLINE_xXEither complete disappearance of all lesions, or persistence of metastatic disease (stable disease) without unequivocal progression or the occurrence of new lesionsXx_NEWLINE_xXPatients with surgically resected metastatic disease at high risk of relapse are also eligible.Xx_NEWLINE_xXPatients must have completed or had disease progression on at least one prior line of disease-appropriate therapy for metastatic disease, or not be candidates for therapy of proven efficacy for their disease.Xx_NEWLINE_xXClinical or radiologic evidence of distant metastatic disease other than small volume (<1.5 cm) nodes, this should be tested within 12 months from enrollment;Xx_NEWLINE_xXTreatment with erlotinib prior to developing metastatic diseaseXx_NEWLINE_xXMetastatic disease.Xx_NEWLINE_xXThe diagnosis of metastatic disease will be fulfilled by one of two criteria: previous pathological diagnosis of cancer with suspicion of metastatic disease on imaging, and clinical diagnosis of metastatic disease; if there is not pathological diagnosis, a specimen will be sent to pathology at the time of the surgery to confirm malignancyXx_NEWLINE_xXPain not localized to the region of metastatic disease; this may include:\r\n* Diffuse non-focal back pain\r\n* RadiculopathyXx_NEWLINE_xXImpending or actual pathological fracture of the humerus, secondary to metastatic bone disease.Xx_NEWLINE_xXDocumented presence of at least one metastatic lesion of the humerus.Xx_NEWLINE_xXA diagnosis of a metastatic or unresectable sarcomaXx_NEWLINE_xXMeasurable metastatic disease with a target lesion that has increased in size by 20% in maximal dimension either during or within six months after treatment with chemotherapy using a gemcitabine containing regimenXx_NEWLINE_xXPatients must have one focus of metastatic disease in the liver that is amenable to SBRT in the opinion of radiation oncologyXx_NEWLINE_xXKnown N2 nodal disease or distant metastatic diseaseXx_NEWLINE_xXWidespread progressive disease, i.e., more than 3 sites of progressive disease (more than 3 sites of disease are permitted provided there are no more than 3 sites of progressive disease)Xx_NEWLINE_xXParticipants with evidence of non-hepatic metastatic diseaseXx_NEWLINE_xXSubjects with recurrent diseaseXx_NEWLINE_xXMust have unresectable metastatic disease, and have tumor(s) present that is (are) evaluable by the RECIST, v1.1; may have spinal-associated metastases but must have concluded dexamethasone therapy and be evaluated by the Investigator to have stable CNS disease.Xx_NEWLINE_xXPatients must have completed or had disease progression on at least one prior line of disease-appropriate therapy for metastatic disease, or not be candidates for therapy of proven efficacy for their diseaseXx_NEWLINE_xXFailed treatment with one regimen containing at least a platinum/fluoropyrimidine doublet for unresectable or metastatic disease.Treatment failure is defined as progression of disease (clinical or radiologic) during first line treatment for unresectable or metastatic disease or ? 6 months after last dose of first line treatment.Xx_NEWLINE_xXNo evidence of known metastatic disease (M0 or Mx allowed)Xx_NEWLINE_xXPatients must have unresectable or metastatic diseaseXx_NEWLINE_xXPatients with bilateral diseaseXx_NEWLINE_xXBiopsy-confirmed Merkel cell carcinoma with metastatic or loco-regional disease.Xx_NEWLINE_xXPrior systemic therapy for metastatic disease.Xx_NEWLINE_xXPre-existing cancers and/or metastatic disease to the adrenal glandsXx_NEWLINE_xXHistologic diagnosis of unresectable or metastatic melanoma; for unknown primary disease, diagnosis of metastatic disease by cytology fine needle aspiration (FNA) is not acceptableXx_NEWLINE_xXPrior treatment with more than two regimens of systemic cytotoxic chemotherapy for locally recurrent or metastatic diseaseXx_NEWLINE_xXDocumented evidence of distant metastasis or locoregional recurrence per required assessments within 28 days prior to starting study therapy. Note: Histologic confirmation of metastatic disease is not required.Xx_NEWLINE_xXFailed available therapy known to confer clinical benefit but no more than 4 prior lines of chemotherapy for metastatic disease.Xx_NEWLINE_xXPatients who have failed at least 1 systemic chemotherapy regimen for metastatic disease, but not more than 2 regimensXx_NEWLINE_xXPatients must have demonstrated metastatic disease and not received > 2 lines of chemotherapy for metastatic disease (N/A for phase II)Xx_NEWLINE_xXPatients must have newly diagnosed metastatic disease; note this may include non-measurable chest wall recurrenceXx_NEWLINE_xXFor participants who present with de novo metastatic disease, no prior systemic chemotherapy is allowedXx_NEWLINE_xXPatients must have received at least one prior anticancer regimen for metastatic disease unless there is no other therapy available and evidence of progressive disease on study entry. Patients with stable disease will be included if there has been failure to respond to another drug(s) within the previous 3 monthsXx_NEWLINE_xXMetastatic prostate carcinoma and at least one of the following:Xx_NEWLINE_xXprogressive disease while receiving an AI for metastatic diseaseXx_NEWLINE_xXMay have received ?1 prior systemic chemotherapy regimen for metastatic disease.Xx_NEWLINE_xXParticipants must have received prior systemic chemotherapy treatment for metastatic urothelial carcinoma. NOTE: Up to 2 prior systemic chemotherapeutic regimens given in the metastatic disease setting for urothelial carcinoma are allowed.Xx_NEWLINE_xXAdenocarcinoma of the stomach or gastroesophageal junction with inoperable, metastatic disease, not amenable to curative therapyXx_NEWLINE_xXPresence of metastatic disease to the boneXx_NEWLINE_xXPresence of distant metastatic disease; patients will undergo radiographic evaluation to exclude the possibility of distant metastatic disease; for patients who have undergone pre- or postoperative biopsies that definitively diagnose ICC, the diagnostic studies may be modified at the discretion of the MSKCC principal investigator; clinical or radiographic evidence of metastatic disease to regional lymph nodes will be allowed, provided it is amenable to resectionXx_NEWLINE_xXRecurrent disease, refractory disease, or progressive disease after having received at least one standard therapy for their disease. Note: Subjects with metastatic (and surgically unresectable) melanoma can be enrolled for first-line treatment; Melanoma subjects with CNS involvement may be enrolled.Xx_NEWLINE_xXPatients with newly diagnosed, unresectable, metastatic, and measurable ASPS who show clinical evidence of disease progression (including history and increasing physical symptoms) will also be eligible; on-study documentation will include a physician’s rationale that supports evidence of clinical disease progression (i.e., increasing tumor pain)Xx_NEWLINE_xXPatients with no prior therapy are eligible, provided they have metastatic disease that is not curable by surgeryXx_NEWLINE_xXCompletely resected hepatic metastases without current evidence of other metastatic diseaseXx_NEWLINE_xXPatients must have recurrent and/or metastatic disease that is progressive and not amenable to surgery or curative radiotherapy occurring within 6 months of study entry, as evidenced by: at least a 20% increase in radiographically or clinically measurable disease, appearance of any new lesions, or deterioration in clinical statusXx_NEWLINE_xXMust have metastatic, progressive, castrate-resistant prostate cancer (CRPC) with radiographic evidence of disease that has continued to progress radiographically or biochemically (rising prostate-specific antigen [PSA] levels on successive measurements) despite adequate androgen-deprivation therapy; if patients had been on flutamide, disease progression is documented 4 weeks or more after withdrawal; for patients on bicalutamide or nilutamide disease progression is documented 6 or more weeks after withdrawal; flutamide, nilutamide and bicalutamide disease progression requirements only apply to patients who have been on these drugs for at least the prior 6 monthsXx_NEWLINE_xXPatients participating in the study must have metastatic (m)CRPCXx_NEWLINE_xXPatients with one of the following diagnoses by histological diagnoses and by head and spine magnetic resonance imaging (MRI):\r\n* Classic histology metastatic medulloblastoma\r\n* Desmoplastic histology metastatic medulloblastoma\r\n* High-risk supratentorial, non-metastatic, PNET\r\n* Metastatic PNETXx_NEWLINE_xXRadiographic evidence of diseaseXx_NEWLINE_xXSurgically unresectable or metastatic disease.Xx_NEWLINE_xXMore than 2 prior cytotoxic chemotherapy regimens for recurrent or metastatic diseaseXx_NEWLINE_xXEvidence of disease progression, as determined by the investigatorXx_NEWLINE_xXMetastatic disease on baseline staging scansXx_NEWLINE_xXThe patient has another metastatic cancer disease.Xx_NEWLINE_xXPatients must have metastatic malignant melanoma or metastatic renal cell cancer (American Joint Committee on Cancer [AJCC] stage IV [M1] or equivalent disease); metastatic renal cell cancer patients must either have refused treatment with, have been unable to tolerate or have experienced progressive disease after treatment with sorafenib or sunitinib, and temsirolimusXx_NEWLINE_xXNo more than two prior chemotherapy regimens for metastatic diseaseXx_NEWLINE_xXAt least one line of endocrine therapy in the metastatic settingXx_NEWLINE_xXPatients with known primary or metastatic CNS disease, are eligible for participation in cohort B, but not in cohort AXx_NEWLINE_xXPatients with known primary or metastatic CNS disease (cohort B), are not eligible if they have a mini mental state exam score < 15 or evidence of leptomeningeal diseaseXx_NEWLINE_xXPatients with metastatic disease who are eligible for first line FOLFOX chemotherapy. Adjuvant or neoadjuvant given at least 12 months prior for non-metastatic disease is permitted.Xx_NEWLINE_xXPatients who had received Oxaliplatin within 12 months prior to diagnosis of metastatic disease.Xx_NEWLINE_xXThe participant has metastatic disease at the time of study entryXx_NEWLINE_xXPresence of metastatic disease in other locations in addition to the lung.Xx_NEWLINE_xXMetastatic disease outside of liverXx_NEWLINE_xXHas distant metastatic disease on imaging or staging laparoscopy at the time of study entryXx_NEWLINE_xXRadiographic evidence measurable of residual or metastatic disease after surgeryXx_NEWLINE_xXNo prior chemotherapy for metastatic diseaseXx_NEWLINE_xXNo evidence of distant metastatic diseaseXx_NEWLINE_xXPatients with evidence of distant metastatic diseaseXx_NEWLINE_xXEvidence of metastatic disease on imaging studiesXx_NEWLINE_xXEvidence or suspected recurrent or metastatic disease; prior brain irradiation is not allowedXx_NEWLINE_xXDefinitive clinical or radiologic evidence of metastatic disease; if applicableXx_NEWLINE_xXMetastatic cancerXx_NEWLINE_xXPatients with metastatic diseaseXx_NEWLINE_xXNo evidence of diseaseXx_NEWLINE_xXPatients with advanced prostate cancer suitable for systemic treatment defined as: having metastatic disease, a biochemical relapse after primary therapy, or patients in whom primary therapy is not appropriate or feasible; patients without metastatic disease will need evaluation for local therapy and deemed inappropriate or have refused this treatment optionXx_NEWLINE_xXPrior treatment with >1 chemotherapy regimen for metastatic diseaseXx_NEWLINE_xXHave metastatic cancerXx_NEWLINE_xXPatients with metastatic disease (BREAST ONLY)Xx_NEWLINE_xXPatients with metastatic diseaseXx_NEWLINE_xXPresence of metastatic diseaseXx_NEWLINE_xXPatients with widespread metastatic disease (> 3 distant metastases); patients with oligometastatic disease (=< 3 distant metastases) are allowed only if they are receiving definitive (curative) radiation therapy (RT) with or without chemotherapyXx_NEWLINE_xXEligible patients must be considered disease-free or have stable diseaseXx_NEWLINE_xXDiagnosis of pathologically confirmed metastatic pancreatic, hepatobiliary, esophageal, or lung cancer, either newly metastatic or metastatic at presentation (M1+) and enrollment within 6 weeks of diagnosis; measurable disease need not be presentXx_NEWLINE_xXClinical evidence of metastatic diseaseXx_NEWLINE_xXFree of macro-metastatic diseaseXx_NEWLINE_xXHave no current evidence of diseaseXx_NEWLINE_xXMetastatic solid tumorsXx_NEWLINE_xXSurvivors must not have evidence of recurrent or metastatic diseaseXx_NEWLINE_xXAny spinal cord compromise or instrumentation due to metastatic disease; radiation therapy for metastatic disease is allowedXx_NEWLINE_xXRENAL CANCER: Metastatic disease, in the opinion of the treating providerXx_NEWLINE_xXRENAL CANCER: Starting any systemic therapy for metastatic diseaseXx_NEWLINE_xXSystemic disease burden with metastatic tumor to the brainXx_NEWLINE_xXPresence of metastatic diseaseXx_NEWLINE_xXPresence of metastatic diseaseXx_NEWLINE_xXPatients seen in the SCC with a diagnosis of cancer with or without evidence of metastatic diseaseXx_NEWLINE_xXNo known evidence of diseaseXx_NEWLINE_xXRadiologic evidence of distant diseaseXx_NEWLINE_xXHave no evidence of recurrence or metastatic diseaseXx_NEWLINE_xXPatients with no active disease; (as defined as no detectable disease)Xx_NEWLINE_xXEvidence of active progression of disease or recurrenceXx_NEWLINE_xXRecurrent diseaseXx_NEWLINE_xXPatients with evidence of muscle-invasion or metastatic disease will be excludedXx_NEWLINE_xXPatients who have known metastatic disease or other bulk disease in the thoracic or cervical regionsXx_NEWLINE_xXEvidence of active malignant diseaseXx_NEWLINE_xXPatients with evidence of distant metastatic PDACXx_NEWLINE_xXMetastatic disease of any kindXx_NEWLINE_xXHistologically or cytologically confirmed locally mEC or metastatic adenocarcinoma of the GEJ Siewert Classification Type I in participants who have not received prior systemic therapy for primary and metastatic disease or chemoradiation therapy for primary diseaseXx_NEWLINE_xXStaging to rule out metastatic disease is recommended for subjects with clinical stage III diseaseXx_NEWLINE_xXSubject with metastatic diseaseXx_NEWLINE_xXParticipants with known metastatic disease should be excluded from this clinical trialXx_NEWLINE_xXDistant metastatic disease at the time of enrollmentXx_NEWLINE_xXKnown metastatic diseaseXx_NEWLINE_xXEvidence of or treatment for metastatic diseaseXx_NEWLINE_xXPatient must not have evidence of progressive diseaseXx_NEWLINE_xXInformed of metastatic disease within the previous 8 weeksXx_NEWLINE_xXNo prior therapy for metastatic diseaseXx_NEWLINE_xXPresence of metastatic diseaseXx_NEWLINE_xXEvidence of relapsed diseaseXx_NEWLINE_xXPatients with clinical evidence of gross diseaseXx_NEWLINE_xXMetastatic bone disease with metastatic disease previously confirmed by prior biopsy; or Metastatic bone disease previously confirmed on imaging [e.g. computed tomography (CT) or magnetic resonance imaging (MRI)] with known (biopsied) primary disease (primary bone cancer is excluded)Xx_NEWLINE_xXPain must be from one or two painful metastatic sites in the bone that is amenable to cryoablation with CT or MRI (additional less painful metastatic sites may be present)Xx_NEWLINE_xXGross nodal or metastatic disease at presentation (>= N1, M1)Xx_NEWLINE_xXAll patients with metastatic pancreas cancer will be eligibleXx_NEWLINE_xXThere is no limit to the amount of prior therapy for metastatic diseaseXx_NEWLINE_xXPatients who have tumors other than metastatic pancreas cancerXx_NEWLINE_xXPulmonary disease, renal dysfunction, hepatic disease, cardiac disease, neurologic disease;Xx_NEWLINE_xXNo evidence of residual disease on scanXx_NEWLINE_xXHistory of known sarcoid diseaseXx_NEWLINE_xXPrior cancers allowed if no evidence of diseaseXx_NEWLINE_xXEvidence of progressive disease at the time of study enrollmentXx_NEWLINE_xXPatients with metastatic diseaseXx_NEWLINE_xXMetastatic diseaseXx_NEWLINE_xXKnown distant metastatic diseaseXx_NEWLINE_xXParticipants with biopsy proven metastatic disease (M1)Xx_NEWLINE_xXClinical or radiographic evidence of metastatic diseaseXx_NEWLINE_xXSynovial sarcoma that has been treated with standard chemotherapy containing ifosfamide and/or doxorubicin and remains: unresectable or metastatic or progressive/persistent or recurrent diseaseXx_NEWLINE_xXAbsence of metastatic disease as documented by radiographic scansXx_NEWLINE_xXEvidence of disease progression or metastatic disease during or following definitive local therapy documented in the 10- to 12-week post-definitive local therapy scansXx_NEWLINE_xXClinical evidence of metastatic (T4b, any N; any T, N2-3; M1) diseaseXx_NEWLINE_xXClinical or radiological evidence of metastatic diseaseXx_NEWLINE_xXDocumented disease recurrence or disease progression of: (a) locally advanced disease that is not considered curable by surgery and/or radiation; or (b) metastatic disease.Xx_NEWLINE_xXPrior treatment with a taxane in the metastatic settingXx_NEWLINE_xXHistory of known sarcoid diseaseXx_NEWLINE_xXNo evidence of diseaseXx_NEWLINE_xXPatients with metastatic diseaseXx_NEWLINE_xXPatient must NOT have received prior endocrine therapy for metastatic disease (i.e., must be first-line endocrine therapy for metastatic disease)Xx_NEWLINE_xXInitiation of new therapy for recurrent and/or progressive metastatic disease since radiographic documentation of recurrence/progression.Xx_NEWLINE_xXMetastatic diseaseXx_NEWLINE_xXMetastatic disease outside of pelvis on any imaging or biopsyXx_NEWLINE_xXGroup 1 patients: Presence of a suspicious metastatic lesion or suspicious for recurrent disease in the head and neck regionXx_NEWLINE_xXMore than one metastatic cancer active in the last 5 yearsXx_NEWLINE_xXPatients have no clinical evidence of distant metastatic diseaseXx_NEWLINE_xXScheduled to undergo radioimmunotherapy (RIT) for metastatic diseaseXx_NEWLINE_xXUnresectable or metastatic SCCHN.Xx_NEWLINE_xXPlan to start a new systemic therapy for metastatic diseaseXx_NEWLINE_xXScheduled for extirpative surgery or biopsy of suspected metastatic lesionXx_NEWLINE_xXMultifocal metastatic disease in either castrate sensitive or castrate resistant patientsXx_NEWLINE_xXHave regional or distant metastatic diseaseXx_NEWLINE_xXFor patients with metastatic renal tumors to be enrolled, a histologic diagnosis of renal cell carcinoma must exist and any burden of disease >= 1 cm by CT or MRI is acceptable; the metastatic sites may be kidney, intra-abdominal (such as liver), brain, bone, or lymph nodes; lung lesions are NOT eligible because of the motion artifact caused by respirationXx_NEWLINE_xXClinically distant metastatic disease, either M1a/M1b/M1cXx_NEWLINE_xXKnown metastatic thyroid cancerXx_NEWLINE_xXAny disease typeXx_NEWLINE_xXPatient can remain on androgen deprivation therapy if on the same regimen prior to documentation of progressive metastatic diseaseXx_NEWLINE_xXInitiation of new therapy for progressive metastatic disease since radiographic documentation of progressionXx_NEWLINE_xXPatients with known metastatic diseaseXx_NEWLINE_xXPatients with nodal disease or distant metastatic diseaseXx_NEWLINE_xXPatients with any metastatic diseaseXx_NEWLINE_xXParticipants with known clinical or radiographic evidence of metastatic CNS diseaseXx_NEWLINE_xXPatients with known metastatic diseaseXx_NEWLINE_xXPatient may have distant metastatic disease provided the estimated survival is at least 1 yearXx_NEWLINE_xXParticipants must be women who have histological confirmation of metastatic invasive breast cancer that has metastasized outside the region of the primary tumor and axilla; biopsy must be obtained prior to initiation of chemotherapy; it should be performed within 28 days prior to enrollment (patients with a biopsy of recurrent disease that is HER2-positive and have not received HER2-directed therapy since the biopsy can exceed the 28-day window up to 6 months); patients must have metastatic disease in lung, liver, soft-tissue or bone to qualify for the study (more than one site is permissible)Xx_NEWLINE_xXNo metastatic sites >= 20 mmXx_NEWLINE_xXZero or one prior chemotherapy regimens for metastatic diseaseXx_NEWLINE_xXPatients must already be known to have metastatic, incurable cancerXx_NEWLINE_xXRadiographic evidence of metastatic diseaseXx_NEWLINE_xXPatients with metastatic diseaseXx_NEWLINE_xXPatients with a history of CRC without clear evidence of metastatic disease who have completed their acute cancer-specific treatmentXx_NEWLINE_xXFor salvage setting patients: Metastatic Disease at PSA riseXx_NEWLINE_xXThe patient has known distant metastatic diseaseXx_NEWLINE_xXIs unresectable or metastaticXx_NEWLINE_xXHave confirmed metastatic diseaseXx_NEWLINE_xXPatient: Does not have metastatic diseaseXx_NEWLINE_xXDoes not have metastatic diseaseXx_NEWLINE_xXExclude any patient who has a history of metastatic cancerXx_NEWLINE_xXNo evidence of metastatic diseaseXx_NEWLINE_xXHas no evidence of diseaseXx_NEWLINE_xXDiagnosis of unresectable or metastatic melanomaXx_NEWLINE_xXPhase 3: Previous treatment with 3 or more systemic regimens given for recurrent and/or metastatic diseaseXx_NEWLINE_xXInclusion Criteria:\n\n        Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB\n        to IV per American Joint Committee on Cancer [AJCC]), or confirmed diagnosis of\n        non-resectable advanced metastatic colorectal cancer (mCRC), or any other indication upon\n        agreement with the Sponsor, whose disease has progressed despite previous antineoplastic\n        therapy or for whom no further effective standard therapy is available\n\n          -  Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation\n\n          -  Evidence of measurable disease as determined by RECIST v1.1\n\n          -  World Health Organization (WHO) Performance Status ? 2\n\n          -  Negative serum pregnancy test within 72 hours prior to the first study dose in all\n             women of childbearing potential\n\n        Exclusion Criteria:\n\n        Progressive disease following prior treatment with RAF-inhibitors in combination with\n        MEK-inhibitors\n\n          -  Symptomatic or untreated leptomeningeal disease\n\n          -  Symptomatic brain metastases. Patients are not permitted to receive enzyme inducing\n             anti-epileptic drugs\n\n          -  Known acute or chronic pancreatitis\n\n          -  History or current evidence of retinal disease, retinal vein occlusion or\n             ophthalmopathy\n\n          -  Clinically significant cardiac disease\n\n          -  Patients with abnormal laboratory values at Screening/baseline\n\n          -  Impairment of gastrointestinal (GI) function or GI disease that may significantly\n             alter the absorption of oral LGX818/MEK162\n\n          -  Previous or concurrent malignancy\n\n          -  Pregnant or nursing (lactating) women\n\n          -  For addition of LEE011 in the triple combination, congenital long QT syndrome or\n             family history of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade ? 3,\n             brain metastases at baseline, abnormal coagulation results PT/INR >1.5 x ULN or aPTT\n             >1.5 x ULN.\n\n        Other protocol-defined inclusion/exclusion criteria may applyXx_NEWLINE_xXThey have progressed on at least one previous line of endocrine therapy (ET) for\n                  their metastatic disease (but are not currently progressing on fulvestrant), OR;Xx_NEWLINE_xXPatient is about to start a new line of ET for their metastatic diseaseXx_NEWLINE_xXTime of disease progression.Xx_NEWLINE_xXPatients have either metastatic or non-metastatic lung cancer as defined in history and physicalXx_NEWLINE_xXOne, 2, or 3 prior lines of chemotherapy for metastatic disease and with progression of disease on last treatment regimen.Xx_NEWLINE_xXHistologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive by an FDA-approved assay performed centrally. Patients must be ALK positive by local test prior to submitting tissue to the central lab. Randomization will occur after ALK positive confirmation is received from the central lab. Patients may have received up to 1 prior chemotherapy regimen for metastatic disease, which may also include maintenance therapy. Note that patients that have received adjuvant or neoadjuvant chemotherapy and developed metastatic disease within 6 months from the end of that therapy would be considered to have received 1 prior regimen for metastatic disease.Xx_NEWLINE_xXLife-threatening metastatic visceral disease (defined as extensive hepatic involvement or symptomatic pulmonary lymphangitic spread).Xx_NEWLINE_xXPatients with distant metastatic disease (cM1) or a life expectancy of less than 5 yearsXx_NEWLINE_xXFor phase II only: Patients who received more than 2 prior systemic regimens for recurrent and/or metastatic disease (no restriction in the phase Ib part of the trial).Xx_NEWLINE_xX