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