Presence of deficient (d) DNA mismatch repair (dMMR); MMR status must be assessed by immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicates dMMR; dMMR may be determined either locally or by site-selected reference lab; Note: loss of MLH1 and PMS2 commonly occur together; formalin-fixed paraffin-embedded (FFPE) tumor tissue is required for subsequent retrospective central confirmation of dMMR status
Patients with testing that did not show dMMR (loss of MMR protein) are not eligible to participate; patients whose tumors show MSI-H by polymerase chain reaction (PCR)-based assay are not eligible to participate unless they also have MMR testing by IHC and are found to have dMMR (i.e. loss of one or more MMR proteins)
Tumor determined to be mismatch-repair deficient (dMMR) by Clinical Laboratory Improvement Act (CLIA)-certified immunohistochemical (IHC) assay with a panel of all four IHC markers, including MLH1, MSH2, PMS2, and MSH6; Note: microsatellite instability high (MSI-H) diagnosed by microsatellite instability (MSI) testing (either Bethesda markers or Pentaplex panel) or by next-generation sequencing (NGS) is not eligible unless dMMR is confirmed by CLIA-certified immunohistochemical (IHC) assay with a panel of all four IHC markers including MLH1, MSH2, PMS2 and MSH6
The tumor must have been determined to be microsatellite stable (MSS).
Microsatellite instability-high or mismatch repair deficient colorectal carcinoma or endometrial carcinoma;
Any solid malignancy known to be MSI high/MMR deficient per local test results, including but not limited to: CRC, stomach adenocarcinoma, esophageal adenocarcinoma and endometrial cancer
Metastatic colorectal cancer (mCRC) categorized as microsatellite stable (MSS) by polymerase chain reaction (PCR) per local assay at any time prior to Screening or by the central laboratory.
Molecular testing results from CLIA-certified laboratories (using tissue) demonstrating programmed death-ligand 1 (PD-L1) copy number gain/amplification, deficiency in mismatch repair enzymes (dMMR), high levels of microsatellite instability (MSI-H) or elevated tumor mutational burden (TMB >=10 mutations/ MB).
Any advanced solid tumor, with the exception of colorectal carcinoma (CRC), which is Microsatellite Instability (MSI)-High (MSI-H)
Participants with known microsatellite (MSI)-high status
Phase II only: patients with colorectal cancer with known microsatellite instability (MSI)-high disease who have previously been treated with immunotherapy or who have refused treatment with immunotherapy
Microsatellite instability (MSI) phenotype of archival tissue biopsy determined by treating institution by polymerase chain reaction (PCR) and immunohistochemistry (IHC) assay
Methylation CHFR gene promoter in archival tissue biopsy\r\n* A patient will be considered to have CHFR methylation if he/she has a methylation specific band on methylation-specific PCR (MSP) for the CHFR gene or lack of expression by IHCs; MSP primers are publicly reported and developed at Oncomethylome in a Clinical Laboratory Improvement Amendments (CLIA) laboratory; patients who test positive for MSI at any of the 5 loci will be considered MSI+ as per standard convention or who have absent expression of mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), or PMS2 postmeiotic segregation increased 2 (PMS2) by IHC\r\n* Results from another institution’s CLIA-certified MSI/IHC will be considered for eligibility\r\n* Patients with microsatellite instability and a family history supportive for a possible diagnosis of hereditary nonpolyposis colorectal cancer will be referred to a genetics counselor for further evaluation and recommendations
Confirmation of: a) Cohort A: MSI-H CRC either by immunohistochemistry (IHC) for loss of protein expression in one of 4 mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) or by detection of microsatellites within the tumor DNA as per institutional practices; b) Cohort B: CMS4 CRC classification on pretreatment primary tumor; c) Cohort C: MSI-H non-CRC solid tumor either by IHC for loss of protein expression in one of 4 mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) or by detection of microsatellites within the tumor DNA as per institutional practices.
Tumors harboring non-hotspot POLE or POLD1 mutations that show clear evidence of microsatellite instability (MSI) will be excluded
Known microsatellite stable (MSS) status by either immunohistochemistry (IHC) or polymerase chain reaction (PCR). Known or evaluable BRAF and KRAS status.
One of the following advanced solid malignancies** which qualifies for standard of care pembrolizumab treatment per Food and Drug Administration (FDA) approval:\r\n* Locally advanced or metastatic urothelial carcinoma that has progressed during or following platinum-based chemotherapy or within 12 months of neoadjuvant/adjuvant platinum-based therapy, ONLY in the second- or later-line setting\r\n* Unresectable or metastatic MSI-H or dMMR solid tumors that have progressed during or following prior treatment and have no satisfactory alternative treatment options (including MSI-H or dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan)\r\n* Recurrent locally advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma expressing PD-L1 (as determined by an FDA-approved test) that have progressed on or after two or more systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy\r\n**Patients who, due to the MSI-H or dMMR status of their disease, qualify for enrollment in more than one cohort (e.g. patients with MSI-H gastric adenocarcinoma) will be enrolled in the MSI-H/dMMR cohort
Have locally confirmed MSS or pMMR CRC; MSS is defined as 0-1 allelic shifts among 3-5 tumor microsatellite loci using a PCR-based assay; pMMR is defined as presence of protein expression of 4 MMR enzymes (MLH1, MSH2, MSH6 and PMS2) by immunohistochemistry
Microsatellite stable disease as determined by IHC and/or PCR, or mismatch repair proficient disease as determined by IHC.
High microsatellite instability (MSI-H) colorectal cancer patients must have received an approved PD-1 targeted agent prior to enrolling in this trial
Participants with known microsatellite instability-high (MSI-H) genotype or known wild type tumor protein 53 (TP53) per local testing.
Patients tumors must be documented to be microsatellite-stable (MSS) either by genetic analysis or immunohistochemistry OR microsatellite-high with documented disease progression following anti-PD1/PDL1 therapy
Known or suspected high-frequency microsatellite instability (MSI-H) CRC
Eastern Cooperative Oncology Group (ECOG) performance status =< 1 for MSS participants or < 2 for microsatellite instability (MSI) participants
Colorectal patients must have documentation of microsatellite status; immunohistochemistry (IHC) is acceptable
Patients are included regardless of KRAS/NRAS, BRAF, p53, or microsatellite instability (MSI) status
Metastatic colorectal cancer with mismatch repair deficiency (MMR-D or microsatellite instability [MSI]-high)
Patients should have microsatellite stable (MSS) tumor by polymerase chain reaction (PCR) assay or mismatch repair protein proficient (MMRP) tumor by immunohistochemistry as confirmed by the presence of MLH1, MSH2, MSH6, and PMS2; the diagnosis of colorectal cancer should be confirmed by pathology either on the primary tumor or from a prior biopsy of a metastatic disease site
Pathologically confirmed, mismatch repair-proficient adenocarcinoma of colorectum, who have received at least two prior lines of therapy in the metastatic setting\r\n* Mismatch repair proficiency can be assessed for eligibility by immunohistochemistry (intact expression of MLH1, MSH2, PMS2, and MSH6) or by molecular testing in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory for microsatellite instability (0 or 1 microsatellites unstable)
Tumor must be mismatch repair (MMR) proficient as determined by microsatellite instability or immunohistochemistry for MMR proteins\r\n* Microsatellite instability testing must be microsatellite instability (MSI)-stable or MSI-low\r\n* Or immunohistochemistry (IHC) for MMR proteins must demonstrate intact MMR proteins
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nPatients must be microsatellite instability (MSI)-stable (or low)
The tumor must have been determined to be mismatch repair proficient or microsatellite stable through CLIA approved testing (Immunohistochemistry [IHC], polymerase chain reaction [PCR], or Next-Generation Sequencing [NGS] assays).
Microsatellite instability-high (MSI-H) / mismatch repair-deficient (dMMR) tumors must have received prior therapy with pembrolizumab or nivolumab (where approved in the country) and must have progressed on that therapy.
Locally confirmed dMMR or MSI-H stage IV colorectal carcinoma
Subjects with microsatellite instability high (MSI-H) tumors will enroll in the MSI-H Cohort (mStage and cStage groups), the C3 Cohort, and the C5 Cohort.
Subjects with phenotypes that are non-microsatellite instability high (non-MSI-H) will enroll in the non- MSI-H Safety Cohort and the C6, C4 Cohorts.
Phase 2 expansion: MSI high CRC
MSI status is, respectively, determined by examining CRC tumor.
Have histologically confirmed microsatellite stable (MSS) CRC.
Locally confirmed MMR deficient or MSI-H status.
Has a locally determined non microsatellite instability high/ proficient mismatch repair (non-MSI-H/pMMR) tumor status
Tumor is confirmed to be one of the following:\r\n* MSI-high, or\r\n* MMR-deficient, or\r\n* Hypermutated defined as >= 20 somatic mutations in the tumor by MSK-IMPACT
CRC: at least 2 prior systemic regimens in the metastatic setting, and as appropriate in patients whose tumors are microsatellite instability-high (MSI-H), pembrolizumab as well.
Participants must have one of the following tumor types: NSCLC, UC, HNSCC, TNBC, RCC, melanoma, cervical cancer, anal cancer, Merkel-cell carcinoma, microsatellite instability (MSI)-High tumors, squamous cell carcinoma of the skin, hepatocellular carcinoma (non-viral), and CRC including microsatellite stable (MSS) and MSI-Low
Microsatellite instability as determined by MSI-plus assay
Participants must be classified into one of two cohorts of recurrent or persistent endometrial cancer of any histology:\r\n* The first cohort (MSI/POLE cohort) includes endometrial cancers that are: MSI-H as determined by immunohistochemical complete loss of expression (absence of nuclear immunoreactivity) of at least one of the mismatch repair genes MSH2, MSH6, MLH1 and PMS2; this test is now done routinely for every newly diagnosed endometrial cancer patient in most centers in the United States (US); and/OR: POLE-mutated, i.e. endometrial cancers known to harbor mutations in the exonuclease domain (amino acid residues 268–471) of polymerase e (POLE) as determined by targeted sequencing or other next generation sequencing assay; any Clinical Laboratory Improvement Amendments (CLIA)-approved genomic test documenting mutations in the exonuclease domain of POLE gene (amino acid residues 268–471) in the tumor will be accepted as proof of presence of POLE mutations and will lead to classification into this patient cohort\r\n* The second cohort (MSS cohort) includes: endometrial cancers that are MSS as determined by normal immunohistochemical nuclear expression of all the mismatch repair genes MSH2, MSH6, MLH1 and PMS2; tumors which have not been sequenced for POLE mutations (i.e. their POLE mutations status is unknown) but are MSS, will be included in this cohort
Histological or cytological documentation of an invasive malignancy that was diagnosed as locally advanced/metastatic or relapsed/refractory and is of one of the following tumor types:: bladder; cervical; colorectal (includes appendix); esophagus, squamous cell; head and neck; melanoma; malignant pleural mesothelioma (MPM); non-small-cell lung cancer (NSCLC), prostate; Microsatellite Instability-High/deficient mismatch repair (MSI-H/dMMR) tumor (Part 1B and Part 2B) and Human Papilloma Virus (HPV)-positive or Epstein-Barr (EBV)-positive tumor (Part 1B and Part 2B.
Documented MSI-H or dMMR-positive tumor as determined by local laboratory for Part 1B and Part 2B pembrolizumab combination MSI-H/dMMR expansion cohorts only.
Hemodynamic instability
Participants must have Lynch syndrome defined as meeting any of the following: (1) Mutation-positive Lynch syndrome: carriers or obligate carriers (by pedigree) of a pathogenic mutation in one of the deoxyribonucleic acid (DNA) mismatch repair (MMR) genes (i.e. MLH1, MSH2/EPCAM, MSH6, or PMS2) or (2) Mutation-negative Lynch syndrome: patients with a personal history of a non-sporadic MMR deficient premalignant lesion (i.e. polyp) or a non sporadic MMR deficient malignant tumor (where non-sporadic MMR deficient is defined by: microsatellite instability high by either immunohistochemistry or microsatellite instability (MSI) testing or both, but no evidence of MLH1 promoter methylation in cases with loss of both MLH1 and PMS2, and/or no evidence of BRAF mutation in cases with loss of both MLH1 and PMS2) but germline MMR genetic testing showed either a variant of unknown significance or mutation negative result or had declined germline MMR genetic testing.
Participants must have Lynch syndrome defined as meeting any of the following:\r\n* “Mutation-positive Lynch syndrome”: carriers or obligate carriers (by pedigree) of a pathogenic mutation in one of the DNA mismatch repair (MMR) genes (i.e. mutL homolog 1 [MLH1], mutS homolog 2 [MSH2]/epithelial cell adhesion molecule [EPCAM], mutS homolog 6 [MSH6], or PMS2 postmeiotic segregation increased 2 [S. cerevisiae] [PMS2]) or\r\n* “Mutation-negative Lynch syndrome”: patients with a personal history of a non-sporadic MMR deficient premalignant lesion (i.e. polyp) or a non-sporadic MMR deficient malignant tumor (where “non-sporadic MMR deficient” is defined by: microsatellite-instability high by either immunohistochemistry or microsatellite instability [MSI] testing or both, but no evidence of MLH1 promoter methylation in cases with loss of both MLH1 and PMS2, and/or no evidence of v-raf murine sarcoma viral oncogene homolog B [BRAF] mutation in cases with loss of both MLH1 and PMS2) but germline MMR genetic testing showed either a variant of unknown significance or mutation negative result or had declined germline MMR genetic testing
Clinical instability
Histopathological evidence of glioblastoma (WHO grade IV) on a progressive tumor specimen after treatment with temozolomide or PCV chemotherapy; the diagnosis of glioblastoma must be confirmed on central review by a study-designated neuropathologist at New York University Langone Medical Center (NYULMC) at screening; exceptions to this eligibility include the following:\r\n* Any progressive glioma with IDH1 or IDH2 mutation, regardless of WHO grade, histopathological diagnosis, or prior therapy, will be eligible if the progressive tumor specimen is found to have one of the genetic alterations below:\r\n** >= 20 somatic mutations per Mb by whole-exome sequencing\r\n** High mutation burden or microsatellite instability (MSI) identified by Foundation Medicine panel next-generation sequencing (FoundationOne, FoundationOne CDx); Foundation Medicine's threshold for high mutation burden (HMB) in their panel next generation sequencing (NGS) assays is >= 20 somatic mutations per megabase (Mb); Foundation Medicine's panel NGS assay has been validated by whole-exome and whole-genome sequencing to correlate tightly with tumor mutation burden (R^2 = 0.94)\r\n** Mutation in a mismatch repair gene or other genes known to be associated with hypermutator phenotypes or microsatellite instability, including but not limited to MSH2, MSH6, MLH1, POLE, PMS2, POLD as determined by validated methods\r\n** Microsatellite instability as identified by polymerase chain reaction (PCR) or other validated methods\r\n* Progressive oligodendroglioma (with 1p/19q codeletion) that has hallmark histopathological features of glioblastoma (i.e. necrosis, pseudopalisading necrosis, or microvascular proliferation) is eligible as IDH1/2 mutant, 1p/19q codeleted oligodendrogliomas that have progressed after chemotherapy have been shown to develop hypermutation phenotype
Is MMR-proficient [selected by the site based on microsatellite instability assay (MSI) and/or immunohistochemistry (IHC) for MMR proteins]
Newly diagnosed with colorectal adenocarcinoma at Ohio State University (OSU) (or a participating Ohio hospital) with sufficient tumor available to perform the microsatellite instability (MSI) test, regardless of age at diagnosis or family history
Patients with symptomatic peripheral vascular disease are not eligible
Patients with history of active collagen vascular disease
Symptomatic peripheral vascular disease
No symptomatic peripheral arterial disease
Patients with known cardiac disease per the New York Heart Association definition such as myocardial infarction, severe or unstable angina, peripheral vascular disease, or congestive heart failure or peripheral vascular disease are not eligible
ischemic peripheral vascular disease, myocardial infarction within the past 6 months,
Known active collagen vascular disease
Active collagen vascular disease
systemic vascular disease or vasculitis
Vascular invasion
Any history of peripheral vascular infarction, including visceral infarction
Subject has a grade II or greater peripheral vascular disease
Clinically significant peripheral vascular disease
Symptomatic peripheral vascular disease
Clinically significant peripheral vascular disease
Symptomatic systemic vascular disease is defined as cardiovascular disease which prevents any procedure in MRI where ECG cannot be obtained (i.e. coronary disease). These patients must be excluded
Severe peripheral vascular disease that would preclude catheterization
Severe peripheral vascular disease that would preclude catheterization
History of stroke, coronary arterial disease, angina, or vascular disease
Subjects with prosthetic cardiac valves, vascular grafts, pacers, or other non-removable vascular foreign body, with the exception of coronary stents and peripheral stents;
Has arterial vascular involvement
Active collagen-vascular disease
Patients who had, within the past 6 months, a cardiovascular accident (CVA) or at risk for arterial thrombus such as severe peripheral vascular disease (PVD) and carotid artery disease (CAD)
Clinically significant peripheral vascular disease
Symptomatic peripheral vascular disease
Patients are excluded if they have symptomatic peripheral vascular disease
Patients with active vascular disease, either myocardial or peripheral (i.e. acute coronary syndrome, cerebral stroke, transient ischemic attack or arterial thrombosis or symptomatic peripheral vascular disease within the past 3 months);
Patients with known proliferative and/or vascular retinopathy;
Clinically significant peripheral vascular disease
Patients with clinically significant peripheral vascular disease
Symptomatic peripheral vascular disease
Has any condition known to effect wound healing, such as collagen vascular disease
No severe peripheral vascular disease
Symptomatic peripheral vascular disease
Significant vascular disease
Significant vascular disease
Subject either currently has central vascular access or is a candidate to receive central vascular access or peripheral vascular access for leukapheresis procedure.
Patients with symptomatic peripheral vascular disease are ineligible
Clinically significant peripheral vascular disease
Patients with symptomatic peripheral vascular disease are not eligible
Symptomatic arterial peripheral vascular disease
None of the following conditions within 6 months prior to enrollment: myocardial infarction, stroke or symptomatic peripheral vascular disease
None of the following conditions within 6 months prior to enrollment: myocardial infarction, stroke or symptomatic peripheral vascular disease
Subjects with benign vascular tumor
Clinically significant peripheral vascular disease
Symptomatic peripheral vascular disease
Subject has a grade II or greater peripheral vascular disease
Clinically significant peripheral vascular disease
Significant cardiac or peripheral vascular arterial disease
Subject has peripheral vascular disease
Clinically significant peripheral vascular disease
History of significant vascular disease.
Significant vascular disease
Severe peripheral vascular disease in subjects whose Study Lesions are located in an extremity
Significant vascular disease.
CTCAE grade 3 or greater peripheral vascular disease
Neurologic, metabolic, or vascular diseases that may negatively impact erectile function, such as: diabetes mellitus, peripheral vascular disease, coronary artery disease, stroke, multiple sclerosis, Parkinson’s disease, multiple systems atrophy, epilepsy, or spinal cord injury.
Vascular disease resulting in clinically apparent compromise in blood flow to the treatment extremity (i.e. peripheral vascular disease with diminished pulses, venous insufficiency with clinical evidence of vascular congestion)
Active collagen vascular disease
Patients with collagen vascular disease are excluded
No symptomatic peripheral vascular obstructions
Previous diagnosis of collagen vascular disorder or vasculitis
The subject has a history of peripheral vascular disease
A history of cardiovascular disease, hypertension, or peripheral arterial/vascular disease;
Subject has known lympho-vascular invasion
Hospitalization in the past 2 months for any cardiovascular disease, including but not limited to:\r\n* Angina\r\n* Myocardial infarction\r\n* Peripheral vascular disease\r\n* Stroke
Participants with known active collagen vascular disease
Measurable hepatic disease and/or presence of vascular tumor thrombosis
Participants with known active collagen vascular disease
Have collagen vascular disease
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to start of study treatment. Any previous venous thromboembolism > National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 3.
(Bevacizumab-related exclusion) Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior of study enrollment
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis ? 6 months of study enrollment
Significant vascular disease or recent peripheral arterial thrombosis
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to enrollment;
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to cycle 1, day 1
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1 of FOLFIRI + bevacizumab initiation
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
Patient must not have had significant vascular disease (i.e. Moya-Moya, aortic aneurysm requiring surgical repair)
Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1
Patients must not have had significant vascular disease (eg, aortic aneurysm requiring surgical repair, deep venous or arterial thrombosis) within the last 6 months prior to study entry
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to study enrolment.
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to cycle 1, day 1
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1 of study drug
Patients with significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to registration will not be eligible
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis) within 6 months prior to Day 1 of treatment.
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1.
Significant vascular disease (e.g. aortic aneurysm surgical repair or recent peripheral arterial thrombosis) =< 6 months prior to randomization
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day -3
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1
Significant vascular (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
(continued from no. 13) CTCAE Grade 2 or greater peripheral vascular disease (at least brief (<24 hrs) episodes of ischemia managed non-surgically and without permanent deficit); Prior history of hypertensive crisis or hypertensive encephalopathy; Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
Significant vascular disease or recent peripheral arterial thrombosis
History of significant vascular disease (i.e., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis) within 6 months prior to registration
Significant vascular disease (such as aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months of first study dose
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1
Significant vascular disease (such as aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 3 months of first study dose
Patient must not have had significant vascular disease (e.g., Moya-Moya, aortic aneurysm requiring surgical repair, deep venous or arterial thrombosis) =< 6 months prior to study entry
Participants with any of the following:\r\n* History of myocardial infarction within six months\r\n* Unstable angina\r\n* History of cerebrovascular accident (CVA) within 6 months\r\n* New York Heart Association grade II or greater congestive heart failure\r\n* Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)\r\n* Clinically significant peripheral vascular disease
Significant vascular disease (e.g., aortic aneurysm, aortic dissection, symptomatic peripheral vascular disease)
Clinically significant peripheral vascular disease or vascular disease (abdominal aortic aneurysm > 5 cm) or aortic dissection; if known history of abdominal aortic aneurysm with >= 4 cm in diameter, all of the following must be met\r\n* An ultrasound within the last 6 months required to document that it is =< 5 cm\r\n* Patient must be asymptomatic from the aneurysm\r\n* Blood pressure must be well controlled as defined in this protocol
Significant known vascular disease (e.g. aortic aneurysm, aortic dissection)
Uncontrolled intercurrent illness including, but not limited to, severe or unstable angina, myocardial infarction, symptomatic congestive heart failure (defined as New York Heart Association grade II or greater), arterial or venous thromboembolic events (e.g., pulmonary embolism), or clinically significant ventricular arrhythmias, significant vascular disease (e.g. aortic aneurysm, aortic dissection), or symptomatic peripheral vascular disease within 6 months prior to registration
Significant vascular disease (e.g., aortic aneurysm, aortic dissection, symptomatic peripheral vascular disease including claudication, Leo Buerger's disease). Treated peripheral vascular disease that is stable for at least 6 months is allowed.
History of cardiac or aortic surgery,
Known cardiac valvular disease (e.g. bicuspid aortic valve) or arterial aneurysm(s) that may allow a nidus of infection.
Patients with clinically significant cardiovascular disease are excluded\r\n* Inadequately controlled hypertension (HTN) (systolic blood pressure [SBP] > 160 mmHg and/or diastolic blood pressure [DBP] > 90 mmHg despite antihypertensive medication)\r\n* History of cerebrovascular accident (CVA) within 6 months\r\n* Myocardial infarction or unstable angina within 6 months\r\n* Serious and inadequately controlled cardiac arrhythmia\r\n* Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)\r\n* Clinically significant peripheral vascular disease
Clinically significant peripheral vascular disease or known abdominal aortic aneurysm ( > 5 cm in diameter) or history of aortic dissection; patients with known history of abdominal aortic aneurysm (AAA) with >= 4 cm in diameter, a repeat ultrasound (US) within the last 6 months prior to randomization will be required to document that it is =< 5 cm, and patient must be asymptomatic from the aneurysm, and the blood pressure must be well controlled as required in this protocol
Clinically-significant cardiac disease:\r\n* Recent myocardial infarction (=< 6 months prior to day 1)\r\n* Unstable angina pectoris\r\n* Uncontrolled congestive heart failure (New York Heart Association > class II)\r\n* Uncontrolled hypertension (>= Common Terminology Criteria for Adverse Events [CTCAE] version [v]4.03 grade 3)\r\n* Prior history of hypertensive crisis or hypertensive encephalopathy\r\n* Uncontrolled cardiac arrhythmias\r\n* Clinically-significant vascular disease (e.g. aortic aneurysm, or dissecting aneurysm)\r\n* Severe aortic stenosis\r\n* Clinically significant peripheral vascular disease\r\n* >= Grade 3 cardiac toxicity following prior chemotherapy\r\n* Corrected QT interval (QTc) > 470 for females and > 450 for males
Clinically significant peripheral vascular disease or abdominal aortic aneurysm (> 5 cm) or aortic dissection; if known history of abdominal aortic aneurysm with >= 4 cm in diameter, all of the following must be met: \r\n* An ultrasound (US) within the last 6 months prior to registration will be required to document that it is =< 5 cm\r\n* Patient must be asymptomatic from the aneurysm\r\n* Blood pressure must be well controlled as defined in this protocol
PHASE I STUDY ELIGIBILITY CRITERIA:\r\nPatients who have the following clinical conditions are considered to be at increased risk for cardiac toxicities; patients with any cardiac history of the following conditions within 1 year prior to MEDI+O study or within 2 years prior to MEDI+C or MEDI+O+C enrollment are excluded from the study:\r\n* Prior events including myocardial infarction, clinically significant pericardial effusion, and myocarditis\r\n* Prior cardiac arrhythmia including atrial fibrillation and atrial flutter, or requiring concurrent use of drugs or biologics with pro-arrhythmic potential\r\n* New York Heart Association (NYHA) class II or greater heart failure\r\n* If cardiac function assessment is clinically indicated or performed, an left ventricular ejection fraction (LVEF) less than normal per institutional guidelines, or < 55%, if threshold for normal is not otherwise specified by institutional guidelines\r\n* Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia’s correction or other significant ECG abnormality noted within 14 days of treatment\r\n* Hypertensive crisis or hypertensive encephalopathy\r\n* Clinically significant peripheral vascular disease or vascular disease, including rapidly growing aortic aneurysm or abdominal aortic aneurysm > 5 cm or aortic dissection\r\n* Unstable angina
PHASE II STUDY COHORT 1 OVARIAN CANCER ELIGIBILITY CRITERIA (MEDI+O, MEDI+C AND MEDI+O+C):\r\nPatients with any cardiac history of the following conditions within 1 year prior to MEDI+O arm or within 2 years prior to MEDI+C or MEDI+O+C arm enrollment are excluded from the study:\r\n• Prior events including myocardial infarction, clinically significant pericardial effusion, and myocarditis\r\n• Prior cardiac arrhythmia including atrial fibrillation (except chronic atrial fibrillation with controlled vascular rate), and atrial flutter, or requiring concurrent use of drugs or biologics with pro-arrhythmic potential\r\n• NYHA class II or greater heart failure\r\n• If cardiac function assessment is clinically indicated or performed, an LVEF less than normal per institutional guidelines, or < 55%, if threshold for normal is not otherwise specified by institutional guidelines\r\n• Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3 (ECGs) using Fridericia’s correction or other significant ECG abnormality noted within 14 days of treatment\r\n• Hypertensive crisis or hypertensive encephalopathy\r\n• Clinically significant peripheral vascular disease or vascular disease, including rapidly growing aortic aneurysm or abdominal aortic aneurysm > 5 cm or aortic dissection\r\n• Unstable angina
PHASE II STUDY COHORT 5 TRIPLE NEGATIVE BREAST CANCER ELIGIBILITY CRITERIA (MEDI+O ONLY):\r\nPatients with any cardiac history of the following conditions within 1 year prior to study enrollment are excluded from the study:\r\n* Prior events including myocardial infarction, clinically significant pericardial effusion, and myocarditis\r\n* Prior cardiac arrhythmia including atrial fibrillation (except chronic atrial fibrillation with controlled vascular rate) and atrial flutter, or requiring concurrent use of drugs or biologics with pro-arrhythmic potential\r\n* NYHA class II or greater heart failure\r\n* If cardiac function assessment is clinically indicated or performed, an LVEF less than normal per institutional guidelines, or < 55%, if threshold for normal is not otherwise specified by institutional guidelines\r\n* Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia’s correction or other significant ECG abnormality noted within 14 days of treatment\r\n* Clinically significant peripheral vascular disease or vascular disease, including rapidly growing aortic aneurysm or abdominal aortic aneurysm > 5 cm or aortic dissection\r\n* Unstable angina
PHASE II STUDY NON-SMALL CELL LUNG CANCER (COHORT 2; MEDI+O AND MEDI+C) AND SMALL CELL LUNG CANCER (COHORT 3; MEDI+O ONLY) ELIGIBILITY CRITERIA:\r\nPatients with any cardiac history of the following conditions within 1 year prior to MEDI+O study or within 2 years prior to MEDI+C study enrollment are excluded from the study:\r\n* Prior events including myocardial infarction, clinically significant pericardial effusion, and myocarditis\r\n* Prior cardiac arrhythmia including atrial fibrillation (except chronic atrial fibrillation with controlled vascular rate) and atrial flutter, or requiring concurrent use of drugs or biologics with pro-arrhythmic potential\r\n* NYHA class II or greater heart failure\r\n* If cardiac function assessment is clinically indicated or performed, an LVEF less than normal per institutional guidelines, or < 55%, if threshold for normal is not otherwise specified by institutional guidelines\r\n* Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia’s correction or other significant ECG abnormality noted within 14 days of treatment\r\n* Hypertensive crisis or hypertensive encephalopathy\r\n* Clinically significant peripheral vascular disease or vascular disease, including rapidly growing aortic aneurysm or abdominal aortic aneurysm > 5 cm or aortic dissection\r\n* Unstable angina
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nPatients with any cardiac history of the following conditions within 2 years prior to study enrollment are excluded from the study:\r\n* Prior events including myocardial infarction, clinically significant pericardial effusion, and myocarditis\r\n* Prior cardiac arrhythmia including atrial fibrillation and atrial flutter, or requiring concurrent use of drugs or biologics with pro-arrhythmic potential\r\n* NYHA Class II or greater heart failure\r\n* If cardiac function assessment is clinically indicated or performed, an LVEF less than normal per institutional guidelines, or < 55%, if threshold for normal is not otherwise specified by institutional guidelines\r\n* Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia’s correction or other significant ECG abnormality noted within 14 days of treatment\r\n* Hypertensive crisis or hypertensive encephalopathy\r\n* Clinically significant peripheral vascular disease or vascular disease, including rapidly growing aortic aneurysm or abdominal aortic aneurysm > 5 cm or aortic dissection\r\n* Unstable angina
Clinically significant peripheral vascular disease or vascular disease (including aortic aneurysm or aortic dissection)
Significant valvular disease; (aortic stenosis [AS] with aortic valve area [AVA] < 1.5 and severe aortic regurgitation [AR] and mitral regurgitation [MR])
Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, significant vascular disease (e.g. aortic aneurysm, aortic dissection), symptomatic peripheral vascular disease, or psychiatric illness/social situations that would limit compliance with study requirements
Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis within 6 months prior to day 1
Patients with clinically significant cardiovascular disease are excluded\r\n* Inadequately controlled hypertension (HTN) (systolic blood pressure [SBP] > 160 mmHg and/or diastolic blood pressure [DBP] > 90 mmHg despite antihypertensive medication)\r\n* History of cerebrovascular accident (CVA) within 6 months (see additional requirement for adjuvant protocols)\r\n* Myocardial infarction or unstable angina within 6 months (see additional requirement for adjuvant protocols)\r\n* New York Heart Association grade II or greater congestive heart failure \r\n* Serious and inadequately controlled cardiac arrhythmia\r\n* Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)\r\n* Clinically significant peripheral vascular disease
Significant valvular disease; (aortic stenosis [AS] with aortic valve area [AVA] < 1.5 and severe aortic regurgitation [AR] and mitral regurgitation [MR])
Clinical significant peripheral vascular disease or vascular disease (aortic aneurysm or aortic dissection)
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, severe or unstable angina, myocardial infarction, symptomatic congestive heart failure (defined as New York Heart Association grade II or greater), arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks) or clinically significant ventricular arrhythmias within 6 months prior to randomization; or significant vascular disease (e.g., aortic aneurysm, aortic dissection), symptomatic peripheral vascular disease
Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
No clinically significant cardiovascular disease\r\n* Patients with a history of hypertension must be well controlled (< 150/90) on a regimen of antihypertensive therapy\r\n* History of arterial thrombotic events within the past 6 months, including transient ischemic attack (TIA), cerebrovascular accident (CVA), peripheral arterial thrombus, unstable angina, or angina requiring surgical or medial intervention in the past 6 months, or myocardial infarction (MI); patients with clinically significant peripheral artery disease (i.e., claudication on less than one block), significant vascular disease (i.e., aortic aneurysm, history of aortic dissection) are not eligible\r\n* Patients who have had a deep vein thrombosis or pulmonary embolus within the past 6 months are eligible if they are on stable therapeutic anticoagulation\r\n* No current New York Heart Association classification II, III, or IV congestive heart failure
Patients are excluded if they have known significant vascular disease (e.g., aortic aneurysm, aortic dissection)
Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or clinically significant peripheral vascular disease
Patients with clinically significant cardiovascular disease are excluded\r\n* Inadequately controlled hypertension (HTN) (systolic blood pressure [SBP] >= 160 mmHg and/or diastolic blood pressure [DBP] >= 90 mmHg despite antihypertensive medication)\r\n* History of cerebrovascular accident (CVA) within 6 months\r\n* Myocardial infarction or unstable angina within 6 months\r\n* New York Heart Association class II or greater congestive heart failure \r\n* Serious and inadequately controlled cardiac arrhythmia\r\n* Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)\r\n* Clinically significant peripheral vascular disease
Any other significant vascular disease (e.g., aortic aneurysm, aortic dissection, or carotid stenosis that requires medical or surgical intervention, including angioplasty or stenting)
Participants should not have clinically significant peripheral vascular disease or vascular disease (including aortic aneurysm or aortic dissection)
History of aortic aneurysm, aortic dissection, angina, myocardial infarction, stroke, transient ischemic attack, or other arterial thrombotic events within 6 months of registration; patients on therapeutic non-coumarin anticoagulation are eligible provided that they are on a stable dose of anticoagulants
Clinically significant cardiovascular disease, such as:\r\n* Inadequately controlled hypertension (HTN) (for adults: systolic blood pressure [SBP] > 160 mmHg and/or diastolic blood pressure [DBP] > 90 mmHg despite antihypertensive medication; for children: please refer to \Grading and management of hypertension for adults and for children 6 through 17 years old\ for age-appropriate values indicating >= grade 2)\r\n* History of cerebrovascular accident (CVA) within 12 months\r\n* Myocardial infarction or unstable angina within 12 months\r\n* New York heart association grade II or greater congestive heart failure\r\n* Serious and inadequately controlled cardiac arrhythmia\r\n* Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection)\r\n* Clinically significant peripheral vascular disease
No history of significant vascular disease (eg aortic aneurysm)
Significant vascular disease including aortic aneurysm, aortic dissection
Clinical significant peripheral vascular disease or vascular disease (aortic aneurysm or aortic dissection)
Clinically-significant cardiac disease including:\r\n* Recent myocardial infarction (=< 6 months prior to first dose of mirvetuximab soravtansine)\r\n* Unstable angina pectoris\r\n* Uncontrolled congestive heart failure (New York Heart Association > class II)\r\n* Uncontrolled hypertension (>= Common Terminology Criteria for Adverse Events [CTCAE] version [v]4.03 grade 3), prior history of hypertensive crisis or hypertensive encephalopathy\r\n* Uncontrolled cardiac arrhythmias\r\n* Clinically-significant vascular disease (e.g. aortic aneurysm, or dissecting aneurysm)\r\n* Severe aortic stenosis\r\n* Clinically significant peripheral vascular disease\r\n* Cardiac toxicity >= grade 3 following prior chemotherapy\r\n* Corrected QT (QTc) > 470 for females and > 450 for males
Clinically significant cardiovascular disease defined as follows:\r\n* Inadequately controlled hypertension (i.e., systolic blood pressure [SBP] > 160 mm Hg and/or diastolic blood pressure [DBP] > 90 mm Hg despite antihypertensive therapy)\r\n* History of cerebrovascular accident (CVA) within 6 months\r\n* Myocardial infarction or unstable angina within 6 months\r\n* New York Heart Association classification II, III, or IV cardiovascular disease\r\n* Serious and inadequately controlled cardiac arrhythmia\r\n* Significant vascular disease (i.e., aortic aneurysm, history of aortic dissection)\r\n* Clinically significant peripheral vascular disease
Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection)
Symptomatic aortic stenosis or syncope in the last week
symptomatic severe aortic stenosis,