Patient case: 68-year-old male with colon cancer; genetic feature: MLH1 methylation suppression (microsatellite instability)

Clinical trial: M7824 in Consensus Molecular Subtype 4, Treatment-Refractory Metastatic Colorectal Cancer

Summary: The goal of this clinical research study is to learn about the safety of giving M7824 to patients with a certain type of colorectal cancer (Consensus Molecular Subtype 4 [CMS4]). Researchers also want to learn if the study drug can help to control the disease.
  This is an investigational study. M7824 is not FDA approved or commercially available. It is currently being used for research purposes only.
  The study doctor can explain how the study drug is designed to work.
  Up to 59 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed description: Study Drug Administration:
  Each cycle is about 4 weeks.
  If you are found to be eligible to take part in this study, you will receive M7824 by vein for about 1 hour on Days 1 and 15 of each cycle.
  Length of Treatment:
  You may continue taking the study drug for as long as the study doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.
  If the disease appears to be responding to the study drug after 12 months of treatment, you may be able to stop treatment with M7824. Both you and your study doctor will discuss this and make this decision. If you stop receiving the study drug, you will continue to take part in follow-up (described below). If the tumor grows after you stop taking M7824, you may be able to restart treatment.
  Your participation in this study will be over after follow-up.
  Study Visits:
  On Day 1 of Cycles 1 and 2:
  -  You will have a physical exam, including a skin exam.
  -  Blood (about 6 tablespoons) will be drawn to check the status of the disease and for routine, biomarker, and tumor marker testing. If you can become pregnant, part of this sample will be used for a pregnancy test.
  -  Urine will be collected for routine tests.
  -  Blood (about 2 teaspoons) will be drawn before and after your dose of study drug for pharmacokinetic (PK) testing. PK testing measures the amount of study drug in your body at different time points.
  -  During Cycle 2, you will have a core tumor biopsy for biomarker testing.
  On Day 15 of Cycles 1 and 2:
  -  You will have a physical exam, including a skin exam.
  -  Blood (up to 2½ tablespoons) will be drawn for routine tests. During Cycle 1, this sample will be used for PK testing. During Cycle 2, this sample will be used for tumor marker and biomarker testing.
  On Day 1 of Cycle 3 and beyond:
  -  You will have a physical exam, including a skin exam.
  -  Blood (about 6 tablespoons) will be drawn to check the status of the disease and for routine, biomarker, and tumor marker testing. During Cycle 6 (if you are still receiving treatment), this sample will be used for PK testing. If you can become pregnant, part of this sample will be used for a pregnancy test.
  -  Urine will be collected for routine tests.
  On Day 15 of Cycle 3 and beyond:
  -  You will have a physical exam, including a skin exam.
  -  Blood (about 2 tablespoons) will be drawn for routine testing.
  On Day 1 of Cycle 3 and every odd-numbered cycle (Cycles 5, 7, 9, and so on), you will have a CT scan or MRI to check the status of the disease.
  Every 6 weeks, you will have an EKG.
  End-of-Treatment Visit:
  Within 7 days after your last dose of study drug:
  -  You will have a physical exam, including a skin exam.
  -  Blood (about 2 tablespoons) and urine will be collected for routine tests.
  -  If you stopped taking the study drug before Cycle 6, blood (about 2 teaspoons) will be drawn for PK testing.
  Follow-Up:
  About 28 days after the last dose of study drug:
  -  You will have a physical exam including a skin exam.
  -  You will have an EKG.
  -  Blood (about 6 tablespoons) will be drawn to check the status of the disease and for routine, biomarker, and tumor marker testing. If you can become pregnant, part of this sample will be used for a pregnancy test.
  -  Urine will be collected for routine tests.
  Long-Term Follow Up:
  Every 3 months up to 1 year after follow-up, even if you withdraw from the study, you will be called and asked about how you are doing. Each call should last about 5-10 minutes.

Eligibility: Inclusion Criteria:
  1. Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum that is metastatic or unresectable.
  2. Confirmation of: a) Cohort A: MSI-H CRC either by IHC for loss of protein expression in one of 4 mismatch repair proteins (MLH1, mutS homologue 2 (MSH2), mutS homolog 6 (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.
  3. Age >18 years at time of study entry.
  4. Ability to provide written informed consent.
  5. Documented progression to prior therapies: a) Cohort A: Disease progression following prior immune checkpoint blockade therapy; b) Cohort B: Progression or intolerance to at least 2 prior lines of standard therapy for unresectable or metastatic CRC; c) Cohort C: Disease progression following prior immune checkpoint blockade therapy.
  6. Available primary tumor tissue for CMS4 biomarker assessment.
  7. Life expectancy =/>12 weeks as judged by the treating physician.
  8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  9. Measurable disease according to RECIST v1.1.
  10. Adequate hematological function, defined by white blood cell (WBC) count =/> 3 × 10^9/L with absolute neutrophil count (ANC) =/> 1.5 × 10^9/L, lymphocyte count =/> 0.5 × 10^9/L, platelet count =/>100 × 10^9/L, and Hgb =/> 9 g/dL (in absence of blood transfusion).
  11. Adequate hepatic function defined by a total bilirubin level =/< 1.5 × the upper limit of normal (ULN), an AST, level =/< 2.5 × ULN, and an ALT level =/< 2.5 × ULN.
  12. International normalized ratio (INR) < 1.5.
  13. Adequate renal function defined by an estimated creatinine clearance >30 mL/min according to the Cockcroft-Gault formula or be measure for creatinine clearance from 24 hour urine collection.
  14. Highly effective contraception for both male and female subjects if the risk of conception exists. Highly effective contraception must be used 30 days prior to first trial administration, for the duration of trial treatment, and at least for 4 months after stopping trial treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this trial, the treating physician should be informed immediately.
  Exclusion Criteria:
  1. Concurrent treatment with non-permitted drugs and other interventions.
  2. Anticancer treatment within 14 days before the start of trial treatment [e.g., cytoreductive therapy, radiotherapy (with the exception of palliative radiotherapy delivered in a normal organ-sparing technique), immune therapy, or cytokine therapy].
  3. Major surgery as determined by the investigator within 28 days before the start of trial treatment (prior diagnostic biopsy is permitted).
  4. Systemic therapy with immunosuppressive agents within 7 days before the start of treatment; or use of any investigational drug within 28 days before the start of trial treatment.
  5. Cohort A and C only: Intolerance or serious adverse immune related adverse events (irAEs) that were symptomatic or required or continues to require ongoing immunosuppression to previous immune checkpoint therapy.
  6. Cohort B only: prior exposure to any immune checkpoint blockade agent or any other immunomodulatory agent used for antineoplastic therapy for mCRC.
  7. Previous malignant disease (other than the target malignancy to be investigated in this trial) within 3 years prior to study treatment initiation. Subjects with a history of cervical carcinoma in situ, superficial or non-invasive bladder cancer, or basal cell or squamous cell carcinoma in situ, previously treated with curative intent are NOT excluded. Subjects with other localized malignancies treated with curative intent need to be discussed with the Principal investigator.
  8. Subjects with active central nervous system (CNS) metastases are excluded. Subjects with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible unless they have fully recovered from treatment, demonstrated no progression for at least 2 months, and do not require continued steroid therapy.
  9. Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant).
  10. Significant acute or chronic infections including, among others: a) Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome; b) HBV or HCV infection (HBV surface antigen positive and HBV core antibody positive with reflex to positive HBV DNA or HBV core antibody positive alone with reflex to positive HBV DNA or positive HCV antibody with reflex to positive HCV RNA); c) Subjects with active tuberculosis (history of exposure or history of positive tuberculosis test plus presence of clinical symptoms, physical or radiographic findings).
  11. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: a) Subjects with type I diabetes, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible; b) Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses =/< 10mg of prednisone or equivalent per day; c) Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable.
  12. Known severe hypersensitivity reactions to monoclonal antibodies (Grade =/> 3 NCI-CTCAE v4.03), any history of anaphylaxis, or recent (within 5 months) history of uncontrolled asthma.
  13. Persisting toxicity (except alopecia and vitiligo) related to prior oncologic therapy Grade >1 NCI-CTCAE v4.03, however, sensory neuropathy Grade =/< 2 is acceptable.
  14. Clinically significant cardiovascular/ cerebrovascular disease as follows: cerebral vascular accident / stroke (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class >II), or serious cardiac arrhythmia.
  15. Clinically relevant diseases (for example, inflammatory bowel disease) and / or uncontrolled medical conditions, which, in the opinion of the Investigator, might impair the subject's tolerance or ability to participate in the trial.
  16. Vaccine administration within 4 weeks of M7824 administration. Vaccination with live vaccines while on trial is prohibited. Administration of inactivated vaccines is allowed (for example, inactivated influenza vaccines).

Relevance to patient case: not relevant