Details

Details

Title A Phase III Study of Pembrolizumab (MK-3475) vs Chemotherapy in Microsatellite Instability-High or Mismatch Repair Deficient Stage IV Colorectal Carcinoma

IRB MRK2215

CC 16-497

Hospital Main Campus

Stage Stage 4

Phase Phase 3

Disease Colorectal

Drug Pembrolizumab

Description

Description

Primary Objective
  • To compare Progression Free Survival (PFS) per RECIST 1.1 by central imaging vendor.
Secondary Objectives
  • To compare Overall Response Rate (ORR) per RECIST 1.1 by central imaging vendor.
  • To compare Overall Survival (OS).
  • To evaluate the safety and tolerability profiles.
Exploratory Objectives
  • To evaluate Progression Free Survival 2 (PFS2).
  • To evaluate Progression Free Survival (PFS) per irRECIST by central imaging vendor.
  • To evaluate Duration of Response (DOR) per RECIST 1.1 by central imaging vendor.
  • To evaluate score change of health related quality of life using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the EORTC QLQ- CR29 from baseline among subjects treated with pembrolizumab (MK-3475) compared to SOC chemotherapies.
  • To characterize utilities using EuroQol EQ-5D among subjects treated with pembrolizumab (MK-3475) compared to SOC chemotherapies.
  • To explore the relationship between genetic variation and response to the treatment(s) administered. Variation across the human genome (germline and tumor) will be analyzed for association with clinical data collected in this study.
  • To evaluate the surgical conversion rate among subjects treated with pembrolizumab (MK-3475) compared to SOC chemotherapies.
Inclusion Criteria

Inclusion Criteria

  1. Provide written informed consent for the trial.
  2. Be male or female who is ≥ 18 years of age on the date of signing informed consent.
  3. Have locally confirmed MMR deficient (dMMR) or microsatellite instability high (MSI-H) stage IV colorectal carcinoma (refer to Section 4.2.4.4 for details)
  4. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  5. Have life expectancy of at least 3 months
  6. Have measurable disease at baseline based on RECIST 1.1 as determined by the local site Investigator/radiology assessment.
  7. Female subjects of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
  8. Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the course of the study starting with the first dose of study therapy through 180 days after the last dose of study therapy for the chemotherapy arm and 120 days for pembrolizumab (MK-3475) arm, whichever is later. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
  9. Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, starting with the first dose of study therapy through 180 days after the last dose of study therapy for the chemotherapy arm and 120 days for pembrolizumab (MK-3475) arm, whichever is later. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
  10. Demonstrate adequate organ function as defined in Table 4. All screening labs should be performed within 10 days of treatment initiation.
    • Absolute neutrophil count (ANC) ≥1,500 /mcL
    • Platelets ≥100,000 / mcL
    • Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or erythropoietin (EPO) dependency within 7 days.
    • Creatinine OR Measured or calculateda creatinine clearance [Glomerular filtration rate (GFR) can also be used in place of creatinine or CrCl)] ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
    • Total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
    • Aspartate aminotransferase (AST) [Serum glutamic oxaloacetic transaminase (SGOT)] and Alanine Aminotransferase (ALT) [Serum Glutamic Pyruvic Transaminase (SGPT)] ≤ 2.5 X ULN OR ≤5 X ULN for subjects with liver metastases
    • Albumin >2.5 g/dL
    • International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial prothrombin time (PTT) is within therapeutic range of intended use of anticoagulants
    • Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
Exclusion Criteria

Exclusion Criteria

  1. Has received prior systemic therapy for stage IV CRC. Subjects may have received prior adjuvant chemotherapy for CRC as long as it was completed at least 6 months prior to randomization.
  2. Is currently participating and receiving trial treatment in another study, or has participated in a study of an investigational agent and received trial treatment, or used an investigational device within 4 weeks of randomization.
  3. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization.
  5. Has had radiation therapy within 4 weeks prior to randomization of study therapy and who has not recovered to baseline from adverse events due to radiation therapy. Subjects who have been given palliative radiotherapy to peripheral sites (e.g., bone metastasis) may enter the study before 4 weeks have elapsed but must have recovered from any acute adverse effects.
  6. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they have stable brain metastases [without evidence of progression by imaging as confirmed by magnetic resonance imaging (MRI) if MRI was used at prior imaging, or confirmed by computed tomography (CT) imaging if CT used at prior imaging] at least four weeks prior to the first dose of trial treatment; also, any neurologic symptoms must have returned to baseline], and have not used steroids for brain metastases for at least 28 days prior to trial initiation. This exception does not include carcinomatous meningitis, as subjects with carcinomatous meningitis are excluded regardless of clinical stability.
  7. Has had major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization.
  8. Has received prior therapy with an immune checkpoint inhibitor (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2 agent, or anti-CTLA-4 agent, etc).
  9. Has another malignancy that is progressing or requires active treatment. Exceptions include non-melanomatous skin cancer that has undergone potentially curative therapy and in situ cervical carcinoma.
  10. Has received a live vaccine within 30 days of planned start of study therapy (see section 5.5.2).
  11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject�s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
  12. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), active chronic or acute Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  13. Has known history of, or any evidence of interstitial lung disease or active, non - infectious pneumonitis.
  14. Has an active infection requiring systemic therapy.
  15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 180 days after the last dose of trial treatment for standard of care or 120 days after the last dose of pembrolizumab (MK-3475) arm.