No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration Participants must have histologically or cytologically confirmed breast cancer, with diagnosed or suspected metastatic, inoperable locally advanced breast cancer, or inoperable locally recurrent breast cancer for which standard curative or palliative measures do not exist or are no longer effective Locally advanced or metastatic HER2-positive breast cancer that has relapsed or is refractory to established therapies Prior chemotherapy or any other investigational agents for the treatment of locally advanced or metastatic pancreatic cancer Progressive metastatic or locally advanced or metastatic breast cancer. Relapsed, locally-advanced or metastatic colorectal or pancreatic cancer, squamous NSCLC, or SCCHN patients who are not candidates for standard therapy. Any breast cancer patient with metastatic or locally recurrent unresectable breast cancer currently progressive, after at least two prior lines of therapy in the advanced setting; patients with HER2+ disease must have failed two or more different anti-HER2 agents Pathologically confirmed diagnosis of breast cancer with radiographic evidence of incurable, unresectable, locally advanced or metastatic disease (LA/MBC) Patients must have locally advanced or metastatic urothelial cancer that is not amenable to surgical treatment Sign of locally advanced disease or metastatic bladder cancer Diagnosed with (a) locally advanced or metastatic (stage III-IV) breast cancer or (b) advanced prostate cancer Biopsy proven locally advanced or metastatic prostate cancer. Locally advanced/non-operable or metastatic breast cancer that has not been previously treated in the metastatic setting with systemic therapy (i.e. first line treatment) Histologic proof of metastatic or locally advanced, unresectable breast cancer Received >2 prior systemic anti-cancer drug regimen for locally advanced disease Non-hepatocellular carcinoma subjects must have received at least 1 prior standard of care systemic anti-cancer therapy for their locally advanced or metastatic disease. Metastatic or locally advanced breast cancer for which endocrine therapy is an appropriate treatment option Locally advanced or metastatic breast cancer Metastatic breast cancer: limited to the subset of patients with intact breast, locally advanced tumor and involved ipsilateral supraclavicular nodes Locally advanced or metastatic breast cancer Histologically or cytologically confirmed breast cancer that is either locally advanced or metastatic. Locally advanced breast cancer must not be amenable to surgical resection or radiation with curative intent. Locally advanced, relapsed, and/or metastatic cancer Phase I (Cohorts E and F): Post-menopausal females with locally advanced or metastatic hormone receptor-positive breast cancer that has progressed or failed to respond to at least one prior endocrine therapy in the adjuvant or metastatic setting Phase II: Post-menopausal female participants with locally advanced or metastatic HER2-negative, hormone receptor-positive breast cancer Have not previously received therapy for the treatment of unresectable locally-advanced breast cancer or metastatic breast cancer Previous chemotherapy for locally advanced or metastatic gastric cancer. Adult women (? 18 years of age) with metastatic or locally advanced breast cancer Progression while on, or within one month of end of letrozole or anastrozole treatment for locally advanced or metastatic breast cancer. Other anticancer therapy for locally advanced or metastatic breast cancer except for prior hormonal therapy. Locally advanced unresectable pancreatic cancer by National Comprehensive Cancer Network (NCCN) criteria Patients may have received up to one prior line of chemotherapy for metastatic or unresectable locally advanced breast cancer Prior treatment with any systemic anti-cancer therapy for locally advanced/metastatic NSCLC. Patients whose esophageal or GEJ cancer has become metastatic or unresectable locally advanced within 6 months of completing definitive therapy for localized or locally advanced cancer can be considered as having received one line of therapy for advanced cancer Willing and able to consent for biopsy of locally-advanced or metastatic breast cancer prior to treatment Metastatic or locally advanced unresectable breast cancer (includes metastatic or locally advanced unresectable breast cancer which is diagnosed while on adjuvant letrozole or exemestane) Subjects must have metastatic or locally advanced, unresectable cancer; cancer must be “active” (i.e. demonstrable by physical examination, blood tests, or radiographical procedures) Patients must not have received any prior systemic therapy for metastatic or locally advanced colorectal cancer (CRC); prior VEGF inhibitors are not allowed Patients with clinical evidence of locally advanced, nodal, or metastatic bladder cancer Patients whose tumors are defined as locally advanced cancer or metastatic cancer are not eligible Patients may have received up to one prior line of chemotherapy for metastatic or unresectable locally advanced breast cancer Participants with HER2-positive and hormone receptor-positive advanced metastatic or locally advanced breast cancer Previous systemic non-hormonal anticancer therapy in the metastatic or locally advanced breast cancer setting Locally advanced/unresectable or metastatic breast cancer Patients must have locally advanced or metastatic urothelial cancer that is not amenable to surgical treatment Patients must show signs of progression during or =< 4 months after being treated with a first line therapy for their metastatic or locally advanced inoperable cancer Diagnosis of locally advanced or metastatic liver cancer obtained by histology/cytology or by imaging Locally advanced or inflammatory breast cancer (stage IIIA to IIIC) Subjects with histologically confirmed advanced primary endometrial cancer (locally advanced and incurable endometrial cancer that has been treated with surgery and/or radiation or is ineligible for such treatment), or recurrent or metastatic endometrial cancer, and No more than four prior systemic therapies for locally advanced or metastatic cancer Locally advanced or inflammatory cervical or uterine cancer Prior systemic therapy for locally advanced or metastatic hepatocellular cancer Histological documentation of incurable, locally advanced, or metastatic non-squamous Metastatic or unresectable locally advanced/recurrent breast cancer Patients must have histologically confirmed breast cancer that is:\r\n* Metastatic; OR\r\n* Incurable and locally advanced, as determined by the treating physician Breast cancer that is locally advanced or metastatic Patients with confirmed HER-2 positive, metastatic or non-operable locally advanced breast or gastric cancer Previous systemic non-hormonal anti-cancer therapy in the metastatic or locally advanced breast cancer setting Postmenopausal women with HER2-, HR+ locally advanced or metastatic breast cancer Previous chemotherapy for locally advanced or metastatic breast cancer Histologic documentation of incurable, locally advanced or metastatic disease that has failed prior chemotherapy and for which no standard therapy exists, including the following: non-squamous NSCLC or non-mucinous and platinum-resistant ovarian cancer Patients must have progressed during or after at least one previous systemic, anti-cancer treatment for locally advanced or metastatic NSCLC. Locally advanced, recurrent, or metastatic, PIK3CA mutant, incurable solid tumor malignancy, including breast cancer Stages I and II, Arm B: Postmenopausal female participants with histologically documented locally advanced or metastatic PIK3CA-mutant HR+/HER2- breast cancer Postmenopausal female participants with locally advanced or metastatic PIK3CA-mutant HR+/HER2? breast cancer Stages I and II: Patient is at least 3 weeks post-diagnosis of an incurable (locally advanced or metastatic) solid malignancy PATIENTS: Diagnosis of advanced cancer (defined as locally advanced, metastatic recurrent, or incurable disease) Patients with advanced cancer (locally advanced, metastatic, recurrent and/or incurable cancer) Patients with diagnosis of advanced cancer, including recurrent, locally advanced, or metastatic cancer Diagnosis of advanced cancer (defined as locally advanced, metastatic, recurrent, or incurable disease) Locally advanced breast cancer patients treated with surgery and adjuvant radiation No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 year prior to registration Locally advanced breast cancer, defined as being clinically appropriate for neoadjuvant chemotherapy Advanced cancer diagnosis (locally advanced, recurrent or metastatic disease) Patients with a diagnosis of advanced cancer, including recurrent, locally advanced, or metastatic cancer Patients with the diagnosis of advanced cancer defined as locally advanced, recurrent or metastatic disease Diagnosis of advanced cancer, defined as locally advanced, recurrent or metastatic disease Locally advanced or metastatic head and neck cancer. Participants must have metastatic or locally advanced incurable anal cancer that has been histologically confirmed; patients with locally advanced anal cancer must have had cancer recurrence after chemoradiation and must be unresectable INCLUSION CRITERIA FOR SECOND-LINE THERAPY: Histologically confirmed metastatic adenocarcinoma of the pancreas INCLUSION CRITERIA FOR THIRD-LINE THERAPY: Histologically confirmed metastatic adenocarcinoma of the pancreas Patient has definitive histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas. Patients with islet cell or neuroendocrine neoplasms are excluded. Patients must have histologically or cytologically documented advanced or metastatic adenocarcinoma of the pancreas Participants with biopsy-proven adenocarcinoma of the pancreas that is determined to be potentially or borderline resectable by National Comprehensive Cancer Network (NCCN) criteria Histologically or cytologically proven adenocarcinoma of the pancreas Histologically or cytopathologically confirmed adenocarcinoma of the pancreas Histologic or cytologic diagnosis of adenocarcinoma of the pancreas Histologically confirmed adenocarcinoma of the pancreas or ampulla of Vater; at least the majority of the histopathologic specimen must be identified as adenocarcinoma as opposed to another histologic subtype; in patients with a diagnosis of recurrent disease (based on radiographic progression and/or rising CA19-9 levels) and a history of a biopsy-proven adenocarcinoma of the pancreas or the ampulla of Vater, repeat biopsy of the recurrence site is not required for participation of the trial Diagnosis of ductal adenocarcinoma of the pancreas (PDAC). Patients with histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas Histologically or cytologically confirmed pancreas adenocarcinoma receiving initial chemotherapy for metastatic disease and without evidence of disease progression on treatment For Part II (Arm C): Patients can have either locally advanced or metastatic pancreas adenocarcinoma; up to two prior treatment regimens are permissible (excluding a prior PARP inhibitor) for either localized or metastatic pancreas adenocarcinoma; prior combined chemotherapy and radiotherapy is permissible provided the patient has measurable disease outside the radiation port; prior therapy must have been completed at least 3 weeks prior to starting study therapy Histologically-proven invasive adenocarcinoma of the pancreas Primary tumor may be located anywhere in the pancreas Have a newly diagnosed, biopsy-proven adenocarcinoma of the head, neck and uncinate of the pancreas, and is a candidate for a pancreaticoduodenectomy; if the biopsy is not sufficient for diagnosis, the patient can be considered to meet eligibility if the study team agrees that clinically the patient’s tumor is suspected to be adenocarcinoma Subjects must have histologically or cytologically confirmed adenocarcinoma of the pancreas Cytologic or histologic proof of adenocarcinoma of the pancreas; patients can have tumor which is locally advanced or borderline resectable; unequivocal metastases and islet cell tumors are not eligible Adenocarcinoma of the pancreas Histologically or cytologically proven adenocarcinoma of the pancreas (within the last 90 days) Pathologically confirmed adenocarcinoma of the pancreas Histologically and/or cytologically confirmed adenocarcinoma of the pancreas, clinical stage T1-4, N0-1, M0 Patients must have pathologically confirmed adenocarcinoma of the pancreas Subjects with biopsy-proven potentially resectable or borderline adenocarcinoma of the pancreas as determined by National Comprehensive Cancer Network (NCCN) criteria Histologically or cytologically confirmed adenocarcinoma of the pancreas Patients who have had prior chemotherapy or radiotherapy for the treatment of pancreas cancer Histologically proven adenocarcinoma of the pancreas Histologic or cytological diagnosis of recurrent or metastatic pancreas adenocarcinoma (PCA) who present for first line chemotherapy treatment Histologically or cytologically proven adenocarcinoma of the pancreas that has been resected with a close (< 2.5mm) or positive margin based on surgical and pathological findings Cancer of pancreas, colon or rectum Cohort 2 (MTD) only: metastatic adenocarcinoma of the pancreas; prior systemic treatment for metastatic disease is allowed COHORT II (MTD): metastatic adenocarcinoma of the pancreas and tumor amenable to biopsies; prior systemic treatment for metastatic disease is allowed Have histologically proven adenocarcinoma of the pancreas; patients with mixed histology will be excluded PHASE II: Patients must have histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas with no prior systemic therapy for metastatic disease Histologically or cytologically proven diagnosis of adenocarcinoma of the pancreas prior to registration Subject has a definitive histologically or cytologically confirmed locally advanced or metastatic adenocarcinoma of the pancreas. Subjects with islet cell neoplasms are excluded. Metastatic adenocarcinoma of the pancreas. Patients with islet cell neoplasms are not eligible. Patients must have histologic or cytologic evidence of adenocarcinoma of the pancreas, such as a core tissue biopsy or a surgical resection specimen. adenocarcinoma of the pancreas, Histologically confirmed adenocarcinoma of the pancreas that has been documented to be resectable by standardized radiographic criteria by a pancreatic surgeon Histological diagnosis of adenocarcinoma of the pancreas Histological documentation of primary adenocarcinoma of the pancreas Patients must have histologically or cytologically confirmed carcinoma of the pancreas; most cases will be adenocarcinoma; cases with “undifferentiated” or “poorly differentiated” carcinoma will also be eligible Histologically or cytologically confirmed locally advanced adenocarcinoma of the pancreas that is considered unresectable or borderline resectable based on institutional standardized criteria of unresectability or medical inoperability; patients with and without regional adenopathy are eligible Have histologically- or cytologically-proven adenocarcinoma of the pancreas; patients with mixed histology will be excluded Previously untreated, apparently resectable, adenocarcinoma of the pancreas at registration Pathologically confirmed adenocarcinoma of the pancreas; patients have resectable borderline resectable disease, or unresectable disease with no evidence of distant metastases or peritoneal disease; the maximum dimension of the tumor must be =< 10 cm Histologically or cytopathologically confirmed adenocarcinoma of the pancreas A histological diagnosis of adenocarcinoma of the pancreas confirmed by pathology. Histologic or cytologic diagnosis of adenocarcinoma of the pancreas. Resectable primary tumor of the head, body or tail of the pancreas defined as a visible mass in the pancreas and: Cytologic or histologic proof of adenocarcinoma of the pancreas is required prior to treatment; patients with Islet cell tumors are not eligible Prior systemic therapy for pancreas cancer Patients must have histologically or cytologically confirmed adenocarcinoma of the pancreas; patients who have not undergone biopsy but have highly suspected adenocarcinoma of the pancreas with borderline resectable features on imaging study may also be eligible for study and undergo the pretreatment biopsy as per protocol; the biopsy must confirm adenocarcinoma of the pancreas to continue on study; biopsy is required within 14 days of starting therapy Histologically or cytologically proven diagnosis of metastatic ductal adenocarcinoma of the pancreas. Histologically or cytologically confirmed adenocarcinoma of the pancreas. Advanced adenocarcinoma of the pancreas that is inoperable or metastatic. Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas. A histological diagnosis of adenocarcinoma of the pancreas confirmed by pathology. Histologically confirmed metastatic or advanced inoperable adenocarcinoma of the pancreas with immunohistochemistry (IHC) evidence of guanylyl cyclase C (GCC) expression indicated by an H-score of 10 or greater. Treatment with 1 or more prior chemotherapies for advanced or metastatic adenocarcinoma of the pancreas. Histologically or cytologically confirmed adenocarcinoma of the pancreas. Advanced adenocarcinoma of the pancreas that is inoperable or metastatic. The presence of a mass in the pancreas, OR Histologically or cytologically confirmed adenocarcinoma of the pancreas Patient has histologically or cytologically confirmed localized adenocarcinoma of the pancreas including tumors in the pancreatic head, uncinate process, neck, body and tail that are potentially resectable by pancreatico-duodenectomy (Kausch-Whipple procedure); patients with islet cell or other neuroendocrine neoplasms are excluded Patient has histologically or cytologically confirmed borderline resectable adenocarcinoma of the pancreas; patients with islet cell or other neuroendocrine neoplasms are excluded Histologically or cytopathologically confirmed adenocarcinoma of the pancreas Histologically documented Stage IV ductal adenocarcinoma of the pancreas Prior adjuvant therapy for the treatment of ductal adenocarcinoma of the pancreas Histologically documented Stage IV ductal adenocarcinoma of the pancreas Prior adjuvant therapy for the treatment of ductal adenocarcinoma of the pancreas Subjects with a neuroendocrine tumor of the pancreas, an acinar tumor of the pancreas or a pancreatic tumor with mixed histologies. Histologically or cytologically proven adenocarcinoma of the pancreas; if the patient has mixed tumor with predominant adenocarcinoma pathology, they can be enrolled Have histologically proven malignant adenocarcinoma of the pancreas; measurable disease is not required, mixed histology is not allowed; subjects must have metastatic disease Received prior GVAX pancreas vaccine or CRS-207 Have histologically proven malignant adenocarcinoma of the pancreas; measurable disease is not required. (Subjects with mixed histology will be included if the predominant component is adenocarcinoma. Subjects must have metastatic disease.) The subject has a resectable tumor or cyst arising from the pancreatic exocrine gland (pancreatic ductal adenocarcinoma, intraductal papillary mucinous neoplasm of the pancreas, or mucinous cystic neoplasm of the pancreas) and is undergoing surgical resection of the neoplasm Phase Ib: Histologically or cytologically confirmed adenocarcinoma of the pancreas, colon or rectum which disease is advanced (defined as not surgically curable) or metastatic in whom combination treatment using fluorouracil, oxaliplatin and irinotecan is a rational option Prior chemotherapy or radiation therapy of any kind for treatment of pancreas adenocarcinoma Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas Histologically or cytologically confirmed adenocarcinoma of the pancreas that has not been previously treated in the metastatic setting Patients who require any type of pancreas resection other than a distal pancreatectomy All patients with metastatic pancreas cancer will be eligible Patients who have tumors other than metastatic pancreas cancer Previous partial or complete resection of the pancreas for adenocarcinoma Histologically confirmed adenocarcinoma of the pancreas Presence of suspicious lesion of the pancreas consistent with pancreatic adenocarcinoma; cytological confirmation is not required Patients with primary or metastatic tumors in the lungs, liver, or pancreas No prior therapy for pancreas cancer is allowed* Subject has a locally advanced unresectable or metastatic, relapsed and/or refractory, non-hematological malignancy for which treatment with an approved agent that is considered standard of care in the indication either does not exist or has proven ineffective. Histologic documentation of locally advanced, recurrent, or metastatic incurable malignancy that has progressed after at least one available standard therapy; or for which standard therapy has proven ineffective, intolerable, or considered inappropriate; or for which a clinical trial of an investigational agent is a recognized standard of care Histological documentation of locally advanced, recurrent or metastatic solid malignancy that has progressed after standard therapy appropriate for the specific tumor type, or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate. Subjects should not have received more than 5 prior lines of therapy for advanced disease including both standards of care and investigational therapies. Subjects whose cancers harbor molecular alterations for which targeted therapy is standard of care should have received health authority approved appropriate targeted therapy for their tumor types before enrollment. Histologic documentation of locally advanced, recurrent or metastatic solid malignancy that has progressed and standard therapy has been ineffective or intolerable. Phase 1b subjects must also have experienced disease progression after treatment with an anti PD-1 or PDL-1 agent. Locally advanced, recurrent, or metastatic incurable malignancy that has progressed after at least one available standard therapy; or for whom standard therapy has proven to be ineffective or intolerable, or is considered inappropriate; or for whom a clinical trial of an investigational agent is a recognized standard of care; or for whom a clinical trial of an investigational agent is considered an acceptable treatment option Histologic documentation of locally advanced, recurrent or metastatic incurable solid malignancy that has progressed after all available standard therapy or for which standard therapy has proven to be ineffective or intolerable, or is considered inappropriate Histologic documentation of locally advanced, recurrent, or metastatic incurable solid malignancy that has progressed after available standard therapy; or for which standard therapy is ineffective, intolerable, or considered inappropriate; or for which a clinical trial of an investigational agent is recognized standard of care Histologically or cytologically documented, locally advanced or metastatic solid tumour, excluding lymphoma, for which standard therapy does not exist or has proven ineffective or intolerable. Progression following at least one standard therapy; or standard therapy considered ineffective, intolerable, or inappropriate; or use of an investigational agent recognized as a standard of care Histologically or cytologically documented advanced or metastatic solid tumors for which established therapy either does not exist or has proven ineffective or intolerable Diagnosis of one of the following advanced solid tumors for which standard therapy either does not exist or has proven ineffective, intolerable or inacceptable for the participant: NMC;TNBC; NSCLC; or CRPC Standard therapies are considered intolerable Histologically or cytologically documented, locally advanced or metastatic solid tumors for which standard therapy either does not exist or has proven ineffective or intolerable Histologically or cytologically documented advanced or metastatic solid tumors for which established therapy either does not exist or has proven ineffective or intolerable Locally advanced or metastatic solid KRAS-mutant tumors, for which standard therapies do not exist, have proven ineffective or intolerable or are considered inappropriate Participants with histologic documentation of locally advanced, recurrent, or metastatic incurable malignancy that has progressed after at least one available standard therapy; or for whom standard therapy has proven to be ineffective or intolerable, or is considered inappropriate; or for whom a clinical trial of an investigational agent is a recognized standard of care Histologically or cytologically documented, locally advanced or metastatic solid tumors or lymphoma for which standard therapy either does not exist or has proven ineffective or intolerable Tumor for which prior treatment has proven to be ineffective or intolerable or for which no standard therapy exists Histologically or cytologically documented, locally advanced or metastatic solid tumors for which standard therapy either does not exist or has proven ineffective or intolerable Metastatic disease or locally advanced disease that is not resectable. Locally advanced/unresectable or metastatic disease Re-registration: locally advanced/unresectable or metastatic disease Patients must have a locally advanced and unresectable or metastatic gastroenteropancreatic neuroendocrine carcinoma that is either known or suspected to be of gastrointestinal (GI) origin; primary tumors arising from the lung, gynecologic organs or prostate are not permitted Locally advanced or metastatic disease; locally advanced disease is defined as disease not amenable to local therapy such as surgery and/or radiation Patients must have either metastatic (stage IVC) or locally advanced unresectable disease (stage IVB) No prior chemotherapy or targeted systemic therapy for inoperable locally advanced or metastatic TNBC Chemoradiation and/or surgery should be considered prior to study entry for those patients with locally advanced disease if those therapies are considered to be in the best interest of the patient. Must have failed at least 1 prior treatment regimen for locally advanced or metastatic disease or be intolerant to treatment or refuse standard treatment In the dose escalation phase, the trial will be open for patients with stage IV or locally advanced unresectable gastrointestinal adenocarcinomas (gastric, cholangiocarcinoma, pancreatic, colorectal) who have failed at least one prior therapy; subjects must have received, and then progressed or been intolerant to, at least 1 standard treatment regimen in the advanced or metastatic setting In the dose expansion phase, Arm A will be open for 25 patients with pancreatic adenocarcinoma; patients must have histologic diagnosis and either locally advanced unresectable or metastatic disease and have not received prior irinotecan; patients must have received at least one prior line of standard treatment for locally advanced or metastatic disease In dose expansion phase, Arm B will be open for 25 patients with colorectal adenocarcinoma; patients must have histologic diagnosis and metastatic disease and have not received prior irinotecan; patients must have received at least one prior line of standard treatment for locally advanced or metastatic disease Disease that is unresectable, locally advanced, or metastatic (not amendable to curative therapy) Metastatic or locally advanced angiosarcoma, treated with at least one prior systemic therapy where no standard of care curable therapy is available OR metastatic or locally advanced malignant and progressive epithelioid hemangioendothelioma (EHE)\r\n* A maximum of 5 EHE patients will be accrued on this study Histologically or cytologically confirmed locally advanced unresectable or metastatic adenocarcinoma of gastric or gastroesophageal junction; (for the 1L Cohort: no prior systemic therapy for the locally advanced or metastatic disease; for the 2L Cohort: disease progression during or following a first-line platinum-containing or fluoropyrimidine-containing chemotherapy regimen); RASMUT/BRAFMUT NSCLC: Subject must have a locally confirmed diagnosis of RAS (NRAS, KRAS, HRAS) or BRAF mutated non-small cell malignancies of the lung. Subject must have received at least 1 prior approved regimen for locally advanced or metastatic disease followed by documented progressive disease. SCCHN: Subject must have a locally confirmed diagnosis of SCCHN. Subject must have received at least 1 prior approved agent for advanced or metastatic disease followed by documented progressive disease. Locally advanced unresectable or metastatic disease that has progressed since last treatment. Locally advanced, unresectable or metastatic disease Metastatic disease or locally advanced, unresectable disease Locally advanced or metastatic NSCLC Patient with histological proven metastatic GIST or non-operable locally advanced GIST Refractory or intolerant to at least one prior standard therapy(ies) for metastatic or locally advanced disease. Patients must have locally advanced, metastatic or refractory leiomyosarcoma or dedifferentiated liposarcoma Patients must have metastatic disease or locally advanced unresectable disease Disease must be locally advanced and unresectable or metastatic; disease which may be resected but with an associated level of morbidity deemed unacceptable by the treating clinician is considered eligible Locally advanced unresectable or metastatic stage 4 (i.e. T4 or N3 or M1) penile squamous cell carcinoma (PSCC) The patient must have advanced disease, defined as cancer that is either metastatic, OR locally advanced and unresectable (and for which additional radiation therapy or other locoregional therapies are not considered feasible). Patients with metastatic (lymph node or distant metastasis, i.e. N+ or M1) or locally advanced unresectable PSCC Patients with metastatic (lymph node or distant metastasis, i.e. N+ or M1) or locally advanced unresectable (T4b) TCC Patient has only locally advanced disease. Advanced 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) Patients must have pathologically?confirmed, non-metastatic locally/regionally advanced squamous cell carcinoma of the head and neck, stage III/IV, referred for definitive chemo?RT, and meet one of the following criteria:\r\n* Primary tumor (T4) with or without metastatic lymph nodes; tumor or nodes are: unresectable, resection is considered by the treating surgeon or patient to result in unacceptable functional or oncological results, patient refuses surgery, or surgery is not possible due to co-morbidities\r\n* Human papillomavirus (HPV)(?) or p16(-) locally/regionally advanced (T3?4 or N2?3) oropharyngeal cancer\r\n* HPV(+) or p16(+) locally/regionally advanced (T4 or N3) oropharyngeal cancer\r\n* T3 or T4 laryngeal or hypopharyngeal cancer that is locally advanced, bulky (> 40 cc), unresectable, or patient declines surgery\r\n* Stage III/IV oral cavity or paranasal sinus cancers in patients who refuse surgery or are unfit for surgery\r\n* Locally/regionally advanced (stage T3?4 and/or N3) nasopharyngeal cancer which is EBV (-) (Epstein?Barr virus) Locally advanced or metastatic disease\r\n* Patients with locally advanced or metastatic disease must have disease deemed not amenable to surgical and/or locoregional therapies or patients who have progressed following surgical and/or locoregional therapies\r\n* Measurable disease, as defined as lesions that can accurately be measured in at least one dimension according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at least 1 cm with contrast enhanced dynamic imaging (magnetic resonance imaging or computed tomography) Locally advanced/unresectable or metastatic disease. Patients must have had disease progression on or following their most recent treatment regimen or on presentation for the first time with locally advanced unresectable or metastatic disease Patients with inflammatory breast cancer, widespread locally advanced unresectable disease involving the chest wall/nodal basins in which a curative surgical resection cannot be performed, or those in whom de novo metastatic disease is suspected or confirmed Locally advanced or metastatic solid tumors that have exhausted standard of care therapy Patients should have had either progression during or after at least two HER2-targeting treatment regimens for locally advanced or metastatic disease or progression during or after (ado-)trastuzumab emtansine treatment for locally advanced or metastatic disease; Locally advanced, unresectable disease, as defined by NCCN criteria Stage IV or locally advanced unresectable cancers for which no alternative therapies with proven survival advantage are available Patients with recurrent unresectable locally advanced or metastatic urothelial carcinoma (also known as [aka] transitional cell carcinoma) previously NOT treated with systemic chemotherapy for current stage of disease\r\n* Low-dose chemotherapy (e.g., low-dose cisplatin, cisplatin plus fluorouracil (5-FU), mitomycin plus 5-FU, or cisplatin plus paclitaxel) given concurrently with radiation to the primary tumor site is not considered systemic chemotherapy; in that clinical setting, chemotherapy is given with the purpose of sensitizing the tumor to local radiation; it is not administered at doses with any systemic efficacy\r\n* Surgery is not considered first-line therapy following diagnosis of advanced/metastatic disease\r\n* If unresectable locally advanced urothelial cancer, could have been previously radiated, but must have Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 measurable, untreated progression of disease component Stage IV disease or locally advanced/unresectable tumors Locally advanced/unresectable disease as determined by site attending urologic oncologist or metastatic disease Previously treated, pathologically confirmed, locally advanced or metastatic solid tumors with measurable disease; Must have histologically or cytologically documented rare tumor as defined per protocol that is metastatic or locally advanced and unresectable. Patients with locally advanced cutaneous squamous cell carcinoma that are technically resectable but in whom surgery is expected to lead to substantial function impairment or disfigurement are eligible Evidence of locally advanced or metastatic disease; Stage III unresectable locally advanced pancreatic carcinoma Pathologically confirmed adenocarcinoma of the pancreas; patients with either initially diagnosed or recurrent locally advanced disease; the maximum dimension of the treatment target must be =<10 cm; locally advanced disease defined as: T 1-2N+MO or T3-4 NxMo, or borderline resectable and unresectable adenocarcinoma without distant metastatic disease or resectable T3-4 NxMo disease or M1 with controlled distant disease Subjects must have unresectable, recurrent, locally advanced, or metastatic neuroendocrine tumor including\r\n* Cohort A; unresectable, recurrent, locally advanced, or metastatic pheochromocytoma-paraganglioma (PC-PG) who have failed or are refractory to available therapies; sample size (N)=12\r\n* Cohort B will include only patients with unresectable, locally advanced or metastatic tumors who have failed or are refractory to available therapy; other neuroendocrine cancer varieties as characterized by expression of neuroendocrine markers on tumor tissue including CD56, synaptophysin, chromogranin and/or presence of a detectable serum or urine biomarker (3-methoxytyramine, normetanepherine, metanepherines, homovanillic acid [HVA], vanillylmandelic acid [VMA], and dopamine), varieties will include neuroblastoma, Ewing sarcoma, neuroectodermal tumor, clear call sarcoma, myoepithelial tumor, primitive neuroectodermal tumor [PNET], desmoplastic small round cell tumor, round cell sarcoma, and unresectable, metastatic or locally advanced , well-differentiated neuroendocrine tumors who have relapsed or are refractory to at least 2 systemic therapies (e.g. lanreotide, sunitinib, or everlimus); patients with small cell carcinomas will not be included in this clinical trial; N=12 Locally advanced disease that is not resectable or metastatic disease. Locally advanced unresectable or metastatic disease with no standard curative therapy available Patients with borderline resectable, locally advanced or metastatic disease Metastatic or unresectable locally advanced For Part I (Arms A, B): Patients can have either locally advanced or metastatic pancreas adenocarcinoma for which no prior therapy has been administered for either locally advanced or metastatic disease; prior adjuvant therapy is permissible if gemcitabine or a fluoropyrimidine was administered with or without radiation and if disease recurrence has been documented at least 6 months after completion of adjuvant therapy That is relapsed or refractory after treatment with an approved therapy(ies), defined as metastatic or non-resectable, locally advanced disease that has previously been treated with and progressed following approved therapy(ies) (Cohort 2) Subjects who were previously treated with carboplatin and paclitaxel for locally advanced and/or metastatic disease and who received the last dose of the drug(s) ? 12 months prior to the first dose of the study treatment may be enrolled Subjects who were not previously treated with carboplatin and paclitaxel for locally advanced and/or metastatic disease and for whom, in the opinion of the Investigator, this chemotherapy regimen is appropriate may be enrolled Subjects who were not previously treated with paclitaxel for locally advanced and/or metastatic disease and for whom, in the opinion of the Investigator, this chemotherapy regimen is appropriate may be enrolled Patients eligible for this study should have locally and/or regionally advanced melanoma that is considered potentially surgically resectable and with biopsiable tumor at baseline Locally advanced or metastatic CRC Disease progression after prior therapy in locally advanced or metastatic setting In the phase Ib portion, must have locally advanced or metastatic GIST and have progressed on imatinib Stage IV or locally advanced cancers for which no alternative therapies with proven survival advantage are available Have an unresectable, locally advanced pancreatic cancer (AJCC stage III). (Excluded: resectable and borderline resectable patients are ineligible per NCCN criteria) Presence of locally advanced, inoperable or metastatic disease Previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease. Previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease. Previously treated with one or more regimen of systemic therapy for locally advanced or metastatic disease. Previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease. Subject has radiologically confirmed locally advanced unresectable or metastatic disease within 28 days prior to the first dose of study treatment. Locally advanced (T4b, any N; or any T, N 2?3) or metastatic disease (any T, any N and M1). Locally advanced bladder cancer must be unresectable i.e. invading the pelvic or abdominal wall (stage T4b) or presenting with bulky nodal disease (N2-3). Retroperitoneal/hilar adenopathy concerning for locally advanced disease Locally advanced (including unresectable or borderline resectable) pancreatic cancer based on computed tomography (CT) imaging, as determined by the principal investigator (PI) Locally advanced/unresectable (as determined by local surgeon) OR metastatic disease Locally advanced (T4b, any N; any T, N2-3) or metastatic (M1) disease as determined by the treating investigator Have locally advanced (unresectable) or metastatic small bowel adenocarcinoma PSTAT3 SCREENING: Participants must have histologically or cytologically confirmed invasive breast cancer (testing of either the primary tumor or in the metastatic setting), with either metastatic disease or unresectable locally advanced disease (including inflammatory breast cancer); patients without pathologic or cytologic confirmation of metastatic disease (or unresectable locally advanced disease) should have unequivocal evidence of metastasis (or unresectable locally advanced disease) by physical examination or radiologic study Participants must have histologically or cytologically confirmed invasive breast cancer with either metastatic disease or unresectable locally advanced disease; patients without pathologic or cytologic confirmation of metastatic disease (or unresectable locally advanced disease) should have unequivocal evidence of metastasis (or unresectable locally advanced disease) by physical examination or radiologic study No evidence of locally advanced or metastatic disease Must have locally advanced or distant metastatic disease that is not surgically curable Locally advanced or metastatic malignancy Metastatic or locally advanced disease Subjects with histological confirmation of locally advanced unresectable or metastatic MSI high CRC. Use of taxanes as adjuvant therapy or to treat locally advanced disease is permitted, if given more than 6 months prior to C1D-2 unresectable locally advanced recurrent BC or metastatic BC For dose escalation, locally advanced and/or metastatic gastrointestinal (GI) solid tumor in participants who have progressed on a standard therapy, are intolerant to SOC, and/or are non-amenable to SOC and other solid tumors expressing CEA. Only locally advanced and/or metastatic colorectal cancer participants should be included in the scheduled comparison expansion nab-Paclitaxel and Nivolumab: Subjects must have received 1 prior systemic chemotherapy regimen for locally advanced or metastatic disease. Subject must have locally advanced or metastatic solid tumor; Phase 2 only: Previous treatment with >3 chemotherapy regimens for locally advanced or metastatic disease VLA009A: Locally advanced and/or metastatic disease for which curative surgery and/or radiation therapy is not possible and judged not to be a candidate for the current standard of care treatment. VLA009B: locally advanced and/or metastatic disease and judged to be a candidate for pembrolizumab to be used in combination with CVA21. Subjects with recurrent, locally advanced unresectable or metastatic adenocarcinoma of the pancreas who have progressed after primary therapy with FOLFIRINOX or FOLFIRINOX-like regimen or were intolerant of it. Prior treatment for BC in the: adjuvant; unresectable locally advanced; or metastatic settings; which must include both, a taxane and trastuzumab (alone or in combination with another agent) Progression must have occurred during or after most recent treatment for locally advanced/metastatic BC or within 6 months after completing adjuvant therapy Prior systemic therapy and chemoradiotherapy for treatment of resectable, borderline resectable or locally advanced unresectable disease is allowed and does not count toward prior therapy for metastatic disease Patients who received systemic therapy with gemcitabine/nab-paclitaxel for resectable or borderline/locally advanced unresectable disease and progressed with metastatic disease within 3 months of the past dose of systemic therapy are eligible Receipt of prior systemic anti-cancer therapy for unresectable, locally advanced or metastatic melanoma Previously received more than 1 regimen of systemic anticancer therapy for locally advanced or metastatic disease. Metastatic disease or locally advanced, unresectable disease. Inclusion Criteria - Cohort Expansion Phase:\n\n - Histologically-proven, unresectable, locally advanced or metastatic melanoma or NSCLC\n\n - Melanoma: Advanced or metastatic melanoma patients may be systemic therapy naïve\n or may have received systemic treatment for unresectable locally advanced or\n metastatic disease. A patient who previously received systemic therapy must have\n had progression on a checkpoint inhibitor (e.g., anti-PD-L1, anti-PD-1,\n anti-CTLA-4) as the most recent prior therapy.\n\n - NSCLC: NSCLC that has progressed during or following 1 or more prior systemic\n therapies for unresectable locally advanced or metastatic disease. Patients who\n are intolerant of, or have refused treatment with standard first line cancer\n therapy, will be allowed to enroll. Patients must not have had more than 5 prior\n systemic regimens (excluding experimental therapies) for unresectable locally\n advanced or metastatic disease.\n\n - B7-H3 expression is not required for eligibility in this study; however, tumor\n expression of B7-H3 will be evaluated for all patients.\n\n - Measurable disease per RECIST 1.1 criteria\n\n - ECOG performance status 0 or 1\n\n - Acceptable laboratory parameters and adequate organ reserve.\n\n Exclusion Criteria - Cohort Expansion Phase:\n\n - Patients with a history of symptomatic central nervous system metastases, unless\n treated and asymptomatic\n\n - Patients with history of autoimmune disease with certain exceptions\n\n - History of allogeneic bone marrow, stem cell, or solid organ transplant\n\n - Treatment with systemic cancer therapy or investigational therapy within 4 weeks;\n radiation within 2 weeks; trauma or major surgery within 4 weeks\n\n - History of clinically-significant cardiovascular disease; gastrointestinal\n perforation; gastrointestinal bleeding, acute pancreatitis or diverticulitis within 4\n weeks;\n\n - Active viral, bacterial, or systemic fungal infection requiring parenteral treatment\n within 7 days; positive for human immunodeficiency virus or AIDS, hepatitis B or C.\n\n - Known hypersensitivity to recombinant proteins, polysorbate 80, or any excipient\n contained in the drug or vehicle formulation for MGA271 or ipilimumab. Radiographic and pathologic staging consistent with pancreatic cancer, locally advanced, unresectable (per NCCN criteria) Laparoscopic confirmation that PDAC is locally advanced. Biliary stents are permitted The subject has metastatic disease or has locally advanced disease that is not amendable to curative treatment Previous systemic therapy for locally advanced or metastatic disease is not allowed. In the phase Ib portion, must have locally advanced or metastatic GIST and have progressed on imatinib Stage IV or locally advanced cancers for which no alternative therapies with proven survival advantage are available Locally advanced and/or metastatic disease Locally advanced (T4b, any N; any T, N2-3) or metastatic (M1) disease as determined by the treating investigator Histologic or cytologic evidence of a malignant solid tumor or lymphoma (any histology) and must have advanced disease, defined as cancer that is either metastatic or locally advanced and unresectable (and for which additional radiation therapy or other locoregional therapies are not considered feasible). Melanoma that has progressed during or following at least 1 and up to 5 prior systemic treatments for unresectable locally advanced or metastatic disease, or melanoma patients who are intolerable of or have refused standard cancer therapy. Pre- and on-study biopsy required. In the phase I dose escalation study, must have locally advanced, unresectable or metastatic GIST and have progressed on imatinib Concurrent active inoperable locally advanced or metastatic malignancy (other than malignancies, which the investigator determines are unlikely to interfere with treatment and safety analysis or are less of a treatment priority than their diagnosis of advanced GIST) Unresectable locally advanced or metastatic MPM after locally confirmed progression on 1st line treatment with platinum in combination with pemetrexed. Measurable metastatic disease or locally advanced and unresectable disease Locally advanced (clearly unresectable) or metastatic disease Must have locally advanced or distant metastatic disease that is not surgically curable The participant received >1 line of prior therapy for the treatment of locally advanced and unresectable or metastatic gastric or GEJ (Siewert Types I-III) adenocarcinoma. Subjects can be treatment naive for metastatic or incurable locally advanced HPV-16 positive solid tumors or can have one prior line of treatment Confirmed metastatic or locally advanced, unresectable disease (by computed tomography [CT] scan or clinical evidence) Metastatic or locally advanced (unresectable) colorectal cancer with histological confirmation of adenocarcinoma Phase I: patients with any locally advanced or metastatic gastrointestinal malignancy which mFOLFOX6 is indicated for treatment Locally advanced or metastatic NSCLC Patients must have an unresectable locally advanced or metastatic adenocarcinoma Documented evidence of NSCLC (locally advanced, unresectable, Stage III) Cohort 1: Patients must have had a minimum of 1 and a maximum of 4 prior chemotherapy regimens for recurrent/metastatic disease or locally advanced/unresectable disease; it will be up to the investigator to determine what constitutes a “regimen” in each case; Cohort 2: Patients must have had a minimum of 1 and maximum of any number of prior chemotherapy regimens for recurrent/metastatic disease or locally advanced/unresectable disease; Cohort 3: Patients may have had any number of prior therapies for recurrent/metastatic or locally advanced/unresectable disease; there are no restrictions; all cohorts: The last dose of systemic therapy much have been given at least 28 days prior to initiation of therapy; patients receiving carmustine (BCNU) or mitomycin C must have received their last dose at least 6 weeks prior to initiation of therapy Patients must have received previous treatment with crizotinib for the treatment of locally advanced or metastatic NSCLC. Naïve untreated patients or patients who have progressed on or after any number of prior lines of immunotherapy for unresectable locally advanced or metastatic melanoma Previous systemic chemotherapy for unresectable locally advanced or metastatic melanoma. Patients with borderline resectable, locally advanced or metastatic disease. Written consent from Female or male patients aged 18 years and over. Previously confirmed histological diagnosis of unresectable, locally advanced or metastatic, hereditary or sporadic MTC Objective disease progression within the previous 14 months prior to enrolment, and/or Dose Expansion phase: Metastatic melanoma (locally advanced or metastatic melanoma) Patients must have measurable or non-measurable stage III/locally advanced or metastatic carcinoma of the breast where surgery is not possible; lesions must be evaluated within 4 weeks prior to registration Patients must not have had more than 2 lines of non-hormonal treatment in the locally advanced or metastatic setting, including trastuzumab (Herceptin), bevacizumab, or other agents; treatment in the locally advanced or metastatic setting must have been completed at least 2 weeks prior to study registration Prior aromatase inhibitors (e.g. anastrozole, letrozole, exemestane, aminoglutethamide) are allowed in the locally advanced or metastatic setting Prior tamoxifen is not allowed in the locally advanced or metastatic setting Has locally advanced esophageal carcinoma that is resectable or potentially curable with radiation therapy (as determined by local investigator) Only locally advanced disease Patients must have a clinical diagnosis of Birt-Hogg-Dube syndrome (clinical features consistent with BHD and /or a germline FLCN mutation) and the presence of localized, locally advanced or advanced, renal tumor(s) No more than three prior anticancer regimens (BRAF/MEK inhibitors, IL-2 or investigational agents) including no more than one chemotherapy-containing regimen for advanced (recurrent, locally advanced or metastic) disease. Failed more than 3 treatment regimens for locally advanced or metastatic NSCLC. Patients with locally advanced BCC are required to have disease that is considered inoperable due to significant functional compromise or to have a medical contraindication to surgery No prior chemotherapy for locally advanced or metastatic disease Subjects greater than or equal to (>=) 18 years of age with locally advanced unresectable or metastatic pancreatic adenocarcinoma proven by histology or cytology and previously untreated with chemotherapy or systemic therapy other than: Patient has borderline resectable, locally advanced unresectable or advanced metastatic disease; patients with adenocarcinoma of the distal pancreatic body or tail are ineligible; patients with endocrine tumors, lymphoma of the pancreas, or ampullary cancer are also ineligible Patient has localized resectable, locally advanced unresectable or advanced metastatic disease; patients with adenocarcinoma of the pancreatic body or tail are ineligible Metastatic disease as documented by CT scan or MRI (locally advanced disease only NOT eligible) Previous chemotherapy for locally advanced or metastatic disease Locally advanced or metastatic solid tumors; No prior systemic therapy for inoperable locally advanced or metastatic UC Subjects must have metastatic or unresectable locally advanced malignant solid tumor. Diagnosis of NSCLC with locally advanced or metastatic disease Metastatic or locally advanced disease Locally advanced or metastatic disease Inoperable metastatic or locally advanced unresectable disease Presence of locally advanced or metastatic disease with at least one measurable lesion. Stage IV disease or inoperable locally advanced disease. Subject with more than 2 prior cytotoxic therapies (not including treatment administered for locally curable disease) for unresectable or metastatic gastroesophageal adenocarcinoma. Presence of locally advanced or metastatic disease with at least one measurable lesion. Prior hormonal therapy for locally advanced or metastatic disease is allowed but this must have been discontinued prior to enrollment; no washout period will be required More than 1 prior chemotherapy given for locally advanced or metastatic disease Documented evidence of advanced (locally recurrent, locally advanced and/or metastatic) adipocytic (restricted to subtypes listed in Inclusion 1) or leiomyosarcoma, incurable by surgery and/or radiotherapy. Unresectable locally advanced or metastatic HCC; Patients must have “advanced disease”; usually, this will mean metastatic disease; this may also be multiply recurrent disease or locally advanced disease; locally advanced disease is defined for this study as disease where a mutilating surgery is required and the patient is more likely than not to die of their disease despite an aggressive operation; patients with metastatic disease that has been resected or radiated are allowed to participate; Response Evaluation Criteria in Solid Tumors (RECIST) evaluable disease is not necessary for participation Have borderline resectable or unresectable locally advanced disease or metastatic disease Intraoperative evidence of metastatic or locally-unresectable disease Patients with locally advanced surgically unresectable PDAC Patients with only locally advanced disease Pathologically confirmed locally advanced or metastatic disease per the treating institution's standard of care of the following tumor types: \r\n* Subjects with histologically confirmed locally advanced/unresectable or metastatic melanoma who meet all of the following criteria: \r\n** Subjects have received any number of prior lines of therapy or may be treatment naive \r\n** If the subject has been treated with a prior line of therapy, they must have had disease progression or be refractory to treatment OR \r\n* Subjects with histologically or cytologically confirmed locally advanced/unresectable or metastatic urothelial carcinoma (including mixed histologies of urothelial carcinoma with elements of other subtypes) of the renal pelvis, ureter, bladder or urethra (referred to broadly in this protocol as “bladder cancer”) who meet the following criteria: \r\n** Subjects must have disease progression or refractory disease after their prior line of therapy; subjects must have had at least 1 platinum based chemotherapy regimen for the treatment of metastatic or locally advanced unresectable disease; subjects may have received any number of prior lines of therapy OR \r\n** Subjects with disease recurrence within 1 year of a platinum based neoadjuvant or adjuvant therapy for bladder cancer OR \r\n** The subject actively refuses chemotherapy for the treatment of metastatic or locally advanced disease considered as standard treatment for this disease stage (i.e. a patient who has relapsed > 1 year after treatment with neoadjuvant or adjuvant chemotherapy), despite being informed by the investigator about the treatment options; the subject’s refusal must be documented Unresectable, locally advanced or metastatic disease; diagnosed within 6 weeks prior to screening No prior systemic treatment in the advanced (metastatic or locally advanced) setting with the exception of treatment with letrozole for a maximum of one month prior to starting study treatment. Locally advanced disease which is unresectable, or resectable but suitable for an organ sparing approach Documented disease recurrence or disease progression of: (a) locally advanced disease that is not considered curable by surgery and/or radiation; or (b) metastatic disease. Patients presenting with locally advanced disease in the breast (cT4) and/or in the nodes (cN2/N3) as assessed by clinical exam and imaging Patients who have known metastatic disease or other locally advanced disease in the thoracic or cervical regions Locally advanced or metastatic, unresectable sarcoma that has progressed after treatment with 150 mg/m2 or less of doxorubicin or anthracycline equivalent No prior chemotherapy for inoperable locally advanced or mUC Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is metastatic or locally advanced and unresectable Histologically or cytologically confirmed diagnosis of selected locally advanced or metastatic solid tumors Diagnosed with histologically or cytologically confirmed locally advanced/metastatic NSCLC with EGFR mutation Histologically or cytologically documented locally advanced or metastatic urothelial carcinoma Histologically or cytologically confirmed adenocarcinoma of the breast with unresectable locally advanced disease, or metastatic disease and HER2 IHC 1+ or 2+ OR Histologically or cytologically confirmed adenocarcinoma of the breast with unresectable locally advanced disease, or metastatic disease and HER2 IHC 3+ or positive for HER2 gene amplification Histologically or cytologically confirmed locally advanced or metastatic gastric cancer and HER2 IHC 3+ or positive for HER2 gene amplification OR Patients who have the below specified histologically or cytologically confirmed malignancies that have progressed to the advanced or metastatic stage. Has histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC. Histologically or cytologically confirmed locally advanced or metastatic Triple Negative Breast Cancer. Histologically or cytologically confirmed diagnosis of locally advanced or metastatic ALK-positive NSCLC; at least 1 extracranial measurable target lesion not previously irradiated. CNS metastases allowed if asymptomatic and not currently requiring corticosteroid treatment. Patients must have histologically or cytologically documented carcinoma primary to the intra- or extra-hepatic biliary system or gall bladder with clinical and/or radiologic evidence of unresectable, locally advanced or metastatic disease; patients with ampullary carcinoma are not eligible Must have immune checkpoint naïve histologically/cytologically confirmed advanced or metastatic CRC. Patients must have histologically or cytologically confirmed advanced or metastatic: Documented (histologically- or cytologically-proven) solid tumor malignancy that is locally advanced or metastatic; patients with documented lymphomas. Have histologically or cytologically-documented diagnosis of advanced (metastatic and/or unresectable) thymic carcinoma, for which no curative treatment (including surgery, radiation, or other) is available Documented (histologically- or cytologically-proven) solid tumor malignancy that is locally advanced or metastatic; patients with documented lymphomas. Histologically- or cytologically- confirmed locally advanced or metastatic nonfunctional well differentiated neuroendocrine tumor (WDNET) Patients must have histologically or cytologically confirmed, inoperable or unresectable locally advanced, or metastatic NSCLC Histologically or cytologically confirmed metastatic or unresectable locally advanced, non-squamous, NSCLC Histologically or cytologically confirmed diagnosis of metastatic or unresectable, locally advanced, recurrent NSCLC that has been previously treated (subjects who have failed adjuvant or locally advanced therapy within 6 months are also eligible to participate in the study) Patients must have histologically or cytologically confirmed invasive breast cancer, which is recurrent, locally advanced, unresectable or metastatic Histologically or cytologically confirmed metastatic or locally advanced adenocarcinoma of the pancreas Histologically or cytologically documented locally advanced, inoperable or metastatic solid tumors with documented AKT1, 2, 3 genetic alterations, activating PI3K mutations, PTEN-null, or other known actionable PTEN mutations Patients must have histologically or cytologically documented carcinoma primary to the intra- or extra-hepatic biliary system or gall bladder with clinical and/or radiologic evidence of unresectable, locally advanced or metastatic disease; patients with ampullary carcinoma are not eligible Patients with histologically or cytologically-confirmed, locally advanced, or metastatic solid malignancy that is relapsed, refractory, or progressing following at least 1 prior systemic therapy (Part A) Patients in Part B must have histologically or cytologically-confirmed, locally-advanced, or metastatic solid malignancy within the disease indications of Part A Histologically or cytologically confirmed locally advanced, inoperable, or metastatic tumors: • Carboplatin Plus Paclitaxel Arm: Patients with histologically documented locally advanced, recurrent and/or metastatic NSCLC For dose escalation cohort: patients with histologically or cytologically confirmed locally advanced or metastatic solid tumors who have failed at least one line of therapy Arm 2: histologically or cytologically confirmed adenocarcinoma of the pancreas that is locally advanced or metastatic Histologically or cytologically documented, incurable, unresectable locally advanced, or metastatic breast cancer Phase II: Patients must have histologically or cytologically confirmed locally advanced, unresectable or metastatic carcinoma of the breast Histologically or cytologically confirmed diagnosis of metastatic or locally advanced unresectable tumors Histologically or cytologically documented disease Documented (histologically- or cytologically-proven) solid tumor malignancy that is locally advanced or metastatic; patients with documented lymphomas. Histologically or cytologically confirmed advanced (unresectable and/or metastatic) HCC Part 1: Has a histologically- or cytologically-documented, locally-advanced or metastatic solid malignancy and has received ?1 and <6 prior line of cancer treatment regimen(s). Histologically or cytologically proven metastatic or locally advanced disease. Specifically: Histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma with locally advanced or metastatic disease Patients must have histologically or cytologically confirmed advanced leiomyosarcoma of the uterus (ULMS); advanced ULMS is defined as metastatic ULMS or unresectable primary ULMS - Histologically or cytologically confirmed metastatic or unresectable locally advanced\n NSCLC Patients must have histologically or cytologically confirmed metastatic or unresectable locally advanced adenocarcinoma of the pancreas with no prior systemic therapy for metastatic or locally advanced disease Histologically or cytologically confirmed diagnosis of relapsed or refractory advanced or metastatic malignancies: Has histologically- or cytologically-confirmed diagnosis of locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma Histologically or cytologically documented, locally advanced or metastatic NSCLC. Postmenopausal women with histologically or cytologically confirmed locally advanced or metastatic ER positive breast cancer Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is either metastatic, or locally advanced and unresectable; NOTE: in the event that both cecal and appendiceal primaries are considered, patient is eligible if it is concluded by the treating oncologist to most likely be cecal based on pathological, surgical, and clinical interpretation Females 18 years old and greater with histologically or cytologically confirmed diagnosis of advanced or metastatic adenocarcinoma of the breast. Subjects with cytologically or histologically confirmed locally advanced or metastatic solid tumor malignancy Histologically or cytologically confirmed locally advanced or metastatic colon or rectal adenocarcinoma Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy Patients must have histologically or cytologically documented carcinoma primary to the intra- or extra-hepatic biliary system or gall bladder with clinical and/or radiologic evidence of unresectable, locally advanced or metastatic disease; patients with ampullary carcinoma are not eligible Patients must have histologically or cytologically confirmed advanced or metastatic cancer for which capecitabine treatment is considered a standard treatment option Histologically or cytologically confirmed metastatic or recurrent NSCLC; primary or metastatic site may be used for histology Phase Ib: Patients must have histologically or cytologically confirmed locally advanced renal cell carcinoma Histologically or cytologically confirmed breast cancer that is either locally recurrent or metastatic. Participants must have histologically or cytologically confirmed locally advanced or metastatic pancreatic adenocarcinoma Patients with cytologically or histologically confirmed recurrent locally advanced or metastatic NSCLC have received at least one prior recognized systemic therapy for therapy for advanced disease, (recognized therapy must include a platinum doublet unless contraindicated due to organ dysfunction) Histologically or cytologically proven diagnosis of unresectable B3 thymoma or thymic carcinoma recurrent or progressing after more than one prior systemic therapy for advanced / metastatic disease Histologically or cytologically confirmed diagnosis of metastatic or unresectable, locally advanced, recurrent NSCLC that has been previously treated (subjects who have failed adjuvant or locally advanced therapy within 6 months are also eligible to participate in the study) Has histologically- or cytologically-confirmed diagnosis of locally advanced unresectable or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the esophagogastric junction (EGJ) Cytologically or histologically and radiologically confirmed solid tumor that is inoperable, locally advanced, metastatic, or recurrent: Histologically or cytologically proved diagnosis of locally advanced recurrent or metastatic non-squamous NSCLC that is not suitable for local curative treatment. Histologically or cytologically confirmed metastatic or unresectable locally advanced/metastatic NSCLC Subject has definitive histologically or cytologically confirmed locally advanced unresectable or metastatic pancreatic adenocarcinoma (islet cell neoplasms are excluded) that is measurable by RECIST Version 1.1 guidelines. Patients with a histologically/cytologically confirmed diagnosis of advanced and/or unresectable disease of any of the following tumors: Histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma (UC) Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with EGFR activating mutation (excluding exon 20 insertion); measurable disease per RECIST 1.1 Histologically or cytologically documented unresectable, locally advanced or metastatic breast cancer or gastric cancer refractory to standard therapy. Cytologically or histologically confirmed advanced gastric or GEJ adenocarcinoma that is metastatic or locally advanced and unresectable. Histologically or cytologically confirmed advanced/metastatic SCLC or NSCLC Patients with a documented (histologically- or cytologically-proven) solid tumor malignancy that is locally advanced or metastatic. For paclitaxel combination arms: histologically or cytologically documented adenocarcinoma of the breast with locally recurrent or metastatic disease For docetaxel combination arms: histologically or cytologically documented adenocarcinoma of the breast with locally recurrent or metastatic disease or histologically documented advanced (Stage IV) or recurrent NSCLC Patients with a documented (histologically- or cytologically-proven) epithelial cell/adenocarcinoma of the pancreas that is relapsed, locally advanced, or metastatic. Histologically or cytologically confirmed and documented adenocarcinoma of the breast with metastatic or locally advanced disease not amenable to curative resection Histologically or cytologically confirmed, locally advanced or metastatic squamous NSCLC Subject has histologically or cytologically confirmed metastatic or locally advanced, unresectable solid tumors harboring EGFR mutations. Histologically or cytologically confirmed locally advanced or metastatic adenocarcinoma of the stomach or GEJ in participants who have not received prior systemic therapy for metastatic disease Histologically 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 disease Subject has histologically or cytologically documented diagnosis of pancreatic adenocarcinoma with metastatic disease. Locally advanced subjects are not eligible. Patients must have histologically or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease. Patients must have histologically confirmed epithelioid hemangioendothelioma which is metastatic or locally advanced (unresectable) Must have histologically confirmed advanced CRC that is metastatic. Dose escalation: Histologically or cytologically confirmed diagnosis of unresectable/locally advanced and/or metastatic HER2+ solid tumor malignancy and for which standard therapies are not available, are no longer effective, are not tolerated, or have been declined by the patient. Expansion cohort: Locally advanced or metastatic HER2+ solid tumors considered likely to respond to a HER2-targeted CD137 agonist (e.g. gastric/gastroesophageal/esophageal, breast, bladder). Histologically confirmed locally advanced melanoma (pembrolizumab only), metastatic NSCLC (pembrolizumab only) locally advanced or metastatic urothelial carcinoma (atezolimumab only). Histologically confirmed breast adenocarcinoma that is unresectable loco-regionally advanced or metastatic. Part B: Subjects must have one of the histologically- or cytologically-confirmed unresectable (locally advanced or metastatic) solid malignancies listed below, AND have measurable disease at study entry defined by RECIST 1.1. AND be considered suitable for treatment with pembrolizumab; in this study pembrolizumab will be considered an investigational study drug. Patients must have a histologically confirmed metastatic and/or locally advanced sarcoma by the enrolling institution. PHASE IB: Histologically confirmed refractory locally-advanced unresectable or metastatic pancreatic or biliary cancer Patients with advanced and/or metastatic, histologically documented solid tumors. Phase 1: Patients with histologically or cytologically confirmed locally advanced (unresectable) or metastatic solid tumors and with progressive disease during or after treatment with a PD-1 or PD-L1-inhibitor who meet one of the following criteria: Histologically confirmed metastatic or unresectable locally advanced non-squamous NSCLC with documented EGFR mutation-positive disease Subjects must have a histologically confirmed metastatic and/or locally advanced sarcoma Have histologically confirmed, locally advanced unresectable or metastatic (stage IV) colorectal adenocarcinoma Histologically confirmed, unresectable advanced solid malignancy with documented disease progression after at least 1 prior systemic therapy Histologically confirmed locally advanced and unresectable or metastatic melanoma Histologically confirmed diagnosis of metastatic or locally advanced unresectable tumors Patients with locally advanced or metastatic RMC histologically confirmed by expert pathology review and loss of SMARCB1 staining by immunohistochemistry. Patients with advanced or metastatic unclassified renal cell carcinoma with medullary phenotype (a rare SMARCB1 negative RMC variant occurring in individuals without sickle hemoglobinopathies) are also eligible. The principal investigator (PI) is the final arbiter in questions related to eligibility. Female patients with histologically-confirmed, unresectable locally advanced or metastatic breast cancer; Patients must have histologically confirmed breast cancer that is metastatic or locally advanced and unresectable Subjects must have a histologically confirmed metastatic and/or locally advanced sarcoma Histologically confirmed diagnosis of metastatic or advanced unresectable tumors that progressed on standard therapy Patients with histologically confirmed locally advanced or metastatic solid carcinomas in Arm 1 Patients with histologically confirmed locally advanced or metastatic colon cancer in Arm 2 Patients with histologically confirmed locally advanced or metastatic cholangiocarcinomas in Arm 3 Patients with histologically confirmed locally advanced or metastatic colon, gastric, ovarian, bladder cancers, as well as cholangiocarcinomas or hepatomas in Arm 4 patients with a histologically confirmed diagnosis of advanced, unresectable, and/or metastatic solid tumours (any type). patients with a histologically confirmed diagnosis of select advanced, unresectable, and/or metastatic solid tumours with specific histology/tumour types and/or specific genetic profiles Stage IV or locally advanced histologically confirmed solid tumors for which no alternative therapies with proven survival advantage are available Histologically documented non-keratinizing locally advanced recurrent or metastatic NPC. Histologically and radiologically confirmed advanced metastatic CCRCC in patients who have had at least one prior systemic therapy, which can include axitinib Advanced malignancies (except leukemias), histologically proven at diagnosis; Histologically confirmed advanced malignancies that are known to be sensitive to PF-03241066 inhibition, e.g. ALK, c-MET and ROS ARM C COHORT 4: Patients must have a histologically or cytologically proven diagnosis of advanced (unresectable or metastatic) gallbladder cancer or cholangiocarcinoma and be candidates for first line therapy with gemcitabine and cisplatin Histologically-confirmed, mesothelin-expressing metastatic or advanced non-metastatic disease (tumour type specific inclusion criteria) Patients with histologically proven small cell carcinoma of the bladder, or elsewhere along the urothelium, which is locally advanced or metastatic (i.e. > or = cT3b, > or = pT3b, N+, or M+) at the time of presentation or cystectomy who have been treated with chemotherapy Patients with histologically confirmed, locally advanced, unresectable, or metastatic solid tumors or hematological malignancies that progressed while on or after PD-1/PD-L1 containing therapy; Histologically proven, metastatic or locally advanced non resectable, or recurrent post surgery GIST Patients must have histologically confirmed locally advanced or metastatic pancreas cancer Patients must have histologically confirmed localized or locally advanced breast cancer for which the treatment plan includes chemotherapy with 4 cycles of standard TC (docetaxel 75 mg/m^2 and cyclophosphamide 600mg/m^2) Histologically proven adenocarcinoma of the breast in the primary or metastatic setting; stage: locally advanced (inoperable) or metastatic Patient has histologically proven advanced (unresectable) or metastatic cancer as outlined below according to study phase and disease type: Subjects with histologically confirmed locally advanced or metastatic disease of the following tumor types: Metastatic or locally-advanced, histologically documented TNBC (absence of HER2, ER, and PR expression) Histologically confirmed locally advanced (e.g. unresectable) or metastatic angiosarcoma that has progressed by RECIST following treatment with prior systemic treatment. . Prior pazopanib is allowed if the drug was not discontinued for toxicity (Phase 2 angiosarcoma cohort). Histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumors that have a NTRK1, NTRK2, NTRK3, ROS1, or ALK molecular alteration. Histologically or cytologically confirmed invasive BC: incurable, unresectable, locally advanced BC previously treated with multimodality therapy or metastatic BC Histologically confirmed inoperable advanced adenocarcinoma of the colon or rectum Histologically confirmed inoperable advanced adenocarcinoma of the colon or rectum Histologically confirmed inoperable locally advanced or metastatic adenocarcinoma of the stomach or GEJ which have progressed on at least 1 prior systemic therapy or line of treatment for unresectable/metastatic disease Subjects must have histologically confirmed, locally advanced or metastatic solid cancers of the following histological types: Histologically confirmed unresectable advanced or recurrent esophageal cancer Histologically-confirmed, locally advanced or metastatic adenocarcinoma of the breast Patients must have histologically documented advanced or metastatic adenocarcinoma of the colon or rectum Histologically-proven locally advanced or metastatic solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma who is no longer benefiting from standard anti-cancer treatment or for whom, in the opinion of the treating physician, no such treatment is available or indicated Histologically-proven, unresectable, locally advanced or metastatic melanoma, SCCHN, NSCLC, and other cancers that express B7-H3. Histologically confirmed diagnosis of a locally advanced or metastatic solid tumor. Patients must have a histologically confirmed stage IV or unresectable locally advanced adrenocortical carcinoma Histologically-proven advanced/metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the EGJ Histologically-proven locally advanced unresectable or metastatic high colorectal carcinoma Histologically confirmed diagnosis of advanced (metastatic, recurrent, or unresectable) cancer with mutations in any of the following genes: TSC1, TSC2, NF1, NF2, or STK11 Histologically confirmed PRCC, which is locally advanced or metastatic. Histologically confirmed, locally advanced (T4 primary tumor and stage IIIB or IIIC disease) or metastatic breast cancer that progressed after treatment with standard treatment regimens in the adjuvant or neoadjuvant setting Cohort A: patients with histologically proven metastatic or locally advanced MSI colorectal adenocarcinoma Cohort B: patients with histologically proven metastatic or locally advanced microsatellite stable (MSS) colorectal adenocarcinoma Cohort C: patients with histologically proven metastatic or locally advanced non-colorectal MSI solid tumor malignancies Cohort D: Patients with histologically proven metastatic or locally advanced solid tumor malignancies that are microsatellite stable with a documented mutation burden level measured at > 20 mutations per megabase pairs (MB) Patients must have histologically confirmed adenocarcinoma of colorectal origin that is metastatic or locally advanced and unresectable Presence of metastasized or locally advanced, inoperable (curative intent) at enrollment time, histologically proven, midgut carcinoid tumour (to be centrally confirmed). Participants must have histologically confirmed adenocarcinoma of the colon or rectum that is metastatic or locally advanced (unresectable); patients with resected primary tumors who have documented metastases are eligible; documentation of residual disease by computed tomography (CT) scan or surgeon’s notes is required for all patients, and histologic confirmation of metastases is strongly encouraged Histologically or cytologically confirmed locally advanced, inoperable (where surgery is not indicated due to disease extension, co-morbidities, or other technical reasons), or metastatic iCCA or mixed histology tumors (combined hepatocellular-cholangiocarcinoma [cHCC-CCA]) Histologically confirmed Papillary Renal Cell Carcinoma, which is unresectable and locally advanced or metastatic with measurable disease as per RECIST 1.1. Indication A - ASPS: Histologically proven, unresectable, locally advanced or metastatic alveolar soft part sarcoma. Indication B - LMS: Histologically proven, unresectable, recurrent, locally advanced or metastatic leiomyosarcoma (of soft tissue, cutaneous origin, vascular origin and of the bone). Indication C - SS: Histologically proven, unresectable, recurrent, locally advanced or metastatic synovial sarcoma. Confirmed diagnosis of unresectable, locally advanced or metastatic hereditary or sporadic Medullary Thyroid Cancer. Part 2: Subjects with histologically confirmed, locally advanced or refractory TGCT (including metastatic disease) that has been deemed unresectable by an orthopedic surgeon or similar qualified personnel. PANCREATIC CANCER COHORT (COHORT 4 ONLY): Subjects with recurrent, locally advanced unresectable or metastatic adenocarcinoma of the pancreas; the diagnosis will be confirmed by the Laboratory of Pathology/CCR/NCI Histologically confirmed, unresectable locally advanced or metastatic transitional cell carcinoma of the urothelium Part 2a, Part 2c, and Part 2f (GIST patients): Histologically confirmed locally advanced, metastatic and/or unresectable GIST. Patients must have a metastatic or unresectable locally advanced malignant solid tumor, histologically confirmed by the Laboratory of Pathology, National Cancer Institute (NCI); in the case of chordoma, unresectable, locally recurrent, or metastatic tumors are acceptable for enrollment, given that this represents incurable disease; efforts will be made, as much as possible, to enroll patients with tumor types with known increased expression of brachyury (such as lung, breast, ovarian, prostate, colorectal, pancreatic, or chordoma; other tumors may be included as data on the level of brachyury in those tumors becomes available) Histologically confirmed, locally advanced or metastatic HCC. Subjects with histologically confirmed, locally advanced or metastatic, refractory solid tumors who are not candidates for standard therapy Patients must have histologically confirmed, radiologically measurable metastatic or locally advanced unresectable colorectal adenocarcinoma that is amenable to image-guided biopsy; disease in previously radiated regions may not be considered measurable unless there has been demonstrated progression in the lesion Histologically confirmed GIST that is locally advanced or metastatic Histologically documented, incurable, locally advanced or metastatic disease for which no standard therapy exists, consisting of one of the following: Unresectable pancreatic ductal adenocarcinoma or platinum-resistant ovarian cancer Histologically documented advanced or metastatic solid tumors or lymphomas Diagnosis of histologically-confirmed esophageal, gastric, pancreatic, or colorectal that is metastatic or locally-advanced (unresectable) Histologically and/or cytologically proven unresectable locally advanced or metastatic tumors that express B7-H3 on the membrane or vasculature. The requirement for previous systemic therapy may be waived if a person was intolerant of standard front-line therapy Histologically documented advanced or metastatic solid tumors. Have histologically confirmed solid malignancy including but not limited to: pancreas, lung, stomach, colon, rectum, bladder, breast, ovary, renal or lymphoma (hematologic), with locally advanced or metastatic disease Dose Escalation Segment: histologically and / or cytological confirmed locally advanced, recurrent or relapsed, or metastatic incurable solid malignancy with no limit on the number of prior lines of standard therapy. Advanced Solid Malignancies: Histologically documented metastatic or locally advanced, incurable solid malignancy (Parts A and B); histologically documented metastatic or locally advanced, incurable solid malignancy for which gemcitabine is clinically appropriate (e.g., non-small cell lung, breast, ovarian, pancreatic, and renal cancer); histologically documented metastatic or locally advanced, incurable solid malignancy for which pembrolizumab (Part D) or nivolumab (Part E) is approved. NOTE: Parts D and E only: Subject has either (1) received treatment with pembrolizumab or nivolumab for ?4 months with a best response of stable disease and plans to continue treatment with either pembrolizumab or nivolumab in accordance with package insert; or (2) is not currently taking, but is eligible for treatment with, pembrolizumab or nivolumab in accordance with the approved indications for each as referenced in the package insert. Metastatic and/or unresectable (cT4b) disease Primary unresectable rectal cancer; a tumor is considered unresectable when invading adjacent organs and an en bloc resection will not achieve negative margins Patient must have unresectable disease Participants must have histologically confirmed melanoma that is metastatic or unresectable Have histologically confirmed unresectable or metastatic nonsquamous NSCLC and having received no prior systemic therapy for metastatic disease. Must have unresectable or inoperable stage IIIA or IIIB disease; subjects must be considered unresectable or inoperable based on the judgment of the treating physician Has cSCC that is either metastatic defined as disseminated disease, and/or unresectable disease that is not curable by surgery, radiation, or systemic therapy. Patients must have histologically confirmed MCM or ALM that is metastatic or unresectable Patients who have received prior immunotherapy for unresectable or metastatic disease SAFETY RUN-IN: Disease stage: unresectable metastatic disease Extent of disease\r\n* Unresectable Patients with unresectable disease are eligible Has received prior systemic treatment for unresectable or metastatic melanoma (except BRAF directed therapy). Unresectable or metastatic GIST Metastatic or unresectable solid tumor malignancy Patients must be considered unresectable or inoperable Subjects must have histologically confirmed solid malignancy that is metastatic or unresectable Unresectable disease. Patients with resectable disease may be enrolled after having refused surgery after a documented consultation with a surgeon. Patients may be potentially resectable or unresectable Cohort A: unresectable or metastatic melanoma Participants must not have had prior systemic anticancer therapy for unresectable or metastatic melanoma Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses Patients who have histologically confirmed metastatic or unresectable GIST. Deemed to have unresectable disease by surgeon Metastatic and/or unresectable (cT4b) urothelial cancer. Measurable disease according to RECIST 1.1 within 30 days prior to registration. Unresectable thymoma or thymic carcinoma. Patients must have metastatic or unresectable disease, including those with HER2+ disease Participants must have histologically confirmed metastatic or unresectable melanoma Diagnosed with advanced (metastatic or unresectable) leiomyosarcoma or liposarcoma Has unresectable disease or is medically inoperable Unresectable metastases Have metastatic or unresectable sarcoma Patients with unresectable tumor Disease is termed unresectable or the patient refuses resection Metastatic or unresectable disease documented on diagnostic imaging studies Patients must be considered unresectable or inoperable Unresectable tumor Subject has unresectable disease; i.e. in the opinion of the surgical oncologist, all of the subject’s melanoma cannot be completely removed with a clear margin Patients whose tumors are deemed unresectable by clinical/imaging criteria Patient must have disease that is unresectable or borderline resectable with < 70% liver involvement by cancer The cancer must be unresectable The cancer must be unresectable Tumor progression during or after first-line treatment for advanced unresectable / metastatic ESCC Receipt of 2 or more prior systemic treatments for advanced/metastatic unresectable ESCC Patients must have histologically confirmed solid malignancy or lymphoma that is metastatic or unresectable Advanced (clinical stage T4b, unresectable) or metastatic disease Pathologically confirmed, advanced (unresectable or metastatic): Unresectable disease Histologically confirmed breast adenocarcinoma that is unresectable loco regional, or metastatic Has received prior systemic treatment for unresectable or metastatic melanoma (except BRAF directed therapy) Disease must be considered incurable; incurable is defined as metastatic disease or a local or regional recurrence in a previously irradiated site that is unresectable (or patient declines resection) Must have colorectal cancer with unresectable metastatic disease to the liver (unresectable unilobar or bilobar disease) who have disease progression in the liver with oxaliplatin or irinotecan based first line chemotherapy is unresectable or metastatic Subjects with recurrent (unresectable) or metastatic CRC: Treatment-naïve participants (no prior systemic anticancer therapy for unresectable or metastatic melanoma) Have received no prior systemic chemotherapy for advanced/unresectable (inoperable) or metastatic urothelial cancer. Subject has not been treated by systemic anticancer therapy for unresectable or metastatic melanoma Metastatic or unresectable cancer that expresses KIT as documented in the patient's pathology report. A diagnosis of metastatic or unresectable sarcoma Have 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. Histologic diagnosis of unresectable or metastatic BRAF V600 mutant melanoma Locally unresectable or metastatic carcinoid or pNET Participants must have unresectable or metastatic histologically confirmed intrahepatic cholangiocarcinoma Metastatic or unresectable disease documented on diagnostic imaging studies Must have unresectable or inoperable stage IIIA or IIIB disease. Patients are considered unresectable or inoperable based on the judgment of the treating physician Patients with unresectable melanoma Unresectable disease or subject refused surgery. Patients with unresectable or metastatic histologically confirmed sporadic or NF1 associated high grade MPNST Tumor tissue from an unresectable or metastatic site of disease for biomarker analyses Locally unresectable or metastatic carcinoid tumors Patients must have histologically confirmed malignancy that is metastatic or unresectable Unresectable or metastatic sporadic or NF1 associated high-grade MPNST Patients with unresectable lung metastases Patients with diffuse tumor throughout bladder that is deemed unresectable by surgeon Patients must have metastatic or unresectable disease Patients must have histologically confirmed adenocarcinoma of the small bowel or ampulla of Vater that is either unresectable or metastatic Unresectable disease or medically inoperable Patients must have unresectable disease as determined by the multidisciplinary evaluation or patient is not considered operable due to medical reasons Unresectable or metastatic disease Tumors clinically staged as unresectable disease Metastatic or recurrent disease that is deemed partially resectable or unresectable based on preoperative imaging A diagnosis of a metastatic or unresectable sarcoma Must 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. Failed 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. Patients must have unresectable or metastatic disease Unresectable disease or subject refused surgery. Treatment with at least two prior systemic therapies for advanced (unresectable locoregional or metastatic) disease Subject must have unresectable or metastatic gastroesophageal adenocarcinoma. Subject with previously untreated unresectable or metastatic gastroesophageal adenocarcinoma. Unresectable disease or patient refused surgery. Tumor deemed unresectable or metastatic Disease must be considered unresectable at the time of preoperative evaluation NET and GIST tumors must be unresectable Surgically unresectable or metastatic disease. technically unresectable HGG Primary tumor deemed unresectable by hepatobiliary surgeon Advanced unresectable or metastatic disease Unresectable or metastatic SCCHN. Patients must have received at least one prior therapy for unresectable disease; patients with recurrence within 6 months of completion of neoadjuvant or adjuvant therapy may be considered as having received one prior therapy for unresectable disease Patients with metastatic or locally unresectable PDAC* (resectability is as defined by MSKCC pancreatic surgeon) Diagnosed with advanced (metastatic or unresectable) sarcoma Is unresectable or metastatic Diagnosis of unresectable or metastatic melanoma Current or pending participation in a clinical trial examining therapy for the\n treatment of any cancer (including unresectable or metastatic melanoma)