Clinical Trials /

Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Hypermutation Status

NCT03519412

Description:

In this study, metastatic colorectal cancer (CRC) patients with RAS-extended mutations will be tested for MMR-deficiency. MMRd patients who failed standard therapies will undergo treatment with pembrolizumab while MMR-proficient patients will be tested for o6-methylguanine-DNA-methyltransferase (MGMT) expression (IHC) and then for MGMT promoter methylation. MGMT IHC-negative, promoter methylation positive patients will be treated with temozolomide (TMZ). Patients progressing under temozolomide will be tested for tumor mutational burden (TMB) and proceed to pembrolizumab if TMB is > 20 mutations/Mb. The primary study hypothesis is that tumors with acquired resistance to temozolomide become hypermutated and are sensitive to pembrolizumab.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Hypermutation Status
  • Official Title: Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Dynamic Hypermutation Status

Clinical Trial IDs

  • ORG STUDY ID: IFOM-CPT002/2018/PO001
  • SECONDARY ID: 2018-001441-14
  • NCT ID: NCT03519412

Conditions

  • Colorectal Neoplasms
  • Microsatellite Instability

Interventions

DrugSynonymsArms
temozolomide (induction),methazolastone, Temodal, TemodarMMR-proficient (MMRp)
pembrolizumab (treatment)Keytruda, Lambrolizumab, MK-3475, SCH 900475MMR-proficient (MMRp)

Purpose

In this study, metastatic colorectal cancer (CRC) patients with RAS-extended mutations who failed standard therapies will be tested for MMR-deficiency. MMRd patients will undergo treatment with pembrolizumab while MMR-proficient patients will be tested for o6-methylguanine-DNA-methyltransferase (MGMT) expression (IHC) and then for MGMT promoter methylation. MGMT IHC-negative, promoter methylation positive patients will be treated with temozolomide (TMZ). Patients progressing under temozolomide will be tested for tumor mutational burden (TMB) and proceed to pembrolizumab if TMB is > 20 mutations/Mb. The primary study hypothesis is that tumors with acquired resistance to temozolomide become hypermutated and are sensitive to pembrolizumab.

Detailed Description

      Arethusa consists of three different phases - SCREENING Phase, PRIMING phase, and TRIAL
      Phase.

        -  SCREENING PHASE: RAS-mutated metastatic CRC patients who have failed standard therapies
           are tested for MMR status. MMR-Deficient (MMR-D) patients proceed directly to TRIAL
           Phase and are treated with pembrolizumab. MMR-Proficient (MMR-P) patients are further
           tested for O6-methylguanine-DNA methyltransferase (MGMT) expression by
           immunohistochemistry and promoter methylation analysis. MGMT negative patients proceed
           to PRIMING phase. MGMT positive patients go off-study.

        -  PRIMING PHASE: MMR-P MGMT-negative patients receive TMZ therapy until progression. At PD
           (disease progression) patients are biopsied to determine the tumor mutational burden
           (TMB). Patients with TMB < 20 mutations/megabase go off-study. Patients with TMB >20
           mutations/megabase, proceed to trial phase.

        -  TRIAL PHASE: Eligible patients are treated with pembrolizumab until disease progression,
           unacceptable toxicity, or up to 24 months in patients without disease progression.
    

Trial Arms

NameTypeDescriptionInterventions
MMR-proficient (MMRp)ExperimentalMGMT-IHC-negative, MGMT promoter methylation-positive patient population is selected for treatment with temozolomide (induction) orally until disease progression or unacceptable toxicity whichever comes first, followed by pembrolizumab IV if Tumor Mutational Burden post Temozolomide is > 20 Muts/Mb
  • temozolomide (induction),
MMR-deficient (MMRd)OtherPatients receive Pembrolizumab (treatment) IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first

    Eligibility Criteria

            Inclusion Criteria:
    
            Entry criteria for SCREENING Phase
    
              1. Histological confirmed diagnosis of metastatic colorectal cancer;
    
              2. Documented RAS-extended mutations in the archival sample.
    
              3. ECOG performance status 0-1.
    
              4. SCREENING phase informed consent signed.
    
              5. Understanding and accepting the need for undergoing at least two tumor biopsies if
                 eligible for PRIMING Phase.
    
              6. Age ≥ 18 years;
    
              7. Imaging documented failure of previous standard CRC therapies including
                 fluoropyrimidine, oxaliplatin, plus or minus anti-angiogenics agents (bevacizumab,
                 regorafenib, others);
    
              8. At least one measurable tumor lesion as per RECIST v1.1. Lesions in previously
                 irradiated areas or those that have received other loco-regional therapies (i.e.
                 percutaneous ablation) should not be considered measurable unless there is clear
                 documented evidence of progression of the lesion since therapy. Imaging must be
                 performed maximum within 28 days prior to registration;
    
              9. Availability of all diagnostic FFPE block or slides (primary tumor, metastases).
                 Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
    
             10. Normal organ functions (see Table 6.1.4 below);
    
            Entry Criteria for PRIMING Phase
    
              1. Fulfillment of all the SCREENING inclusion criteria;
    
              2. PRIMING informed consent signed;
    
              3. Confirming the willingness to undergo at least two tumor biopsies,
    
              4. Acceptance that if the mutational load determination from either one mandatory biopsy
                 is unfeasible for technical reasons (not enough tissue, substandard test performance,
                 etc.), access to TRIAL phase will not be possible.
    
              5. ECOG performance status 0 or 1;
    
              6. Following results in the SCREENING Phase tests:
    
                   -  Proficient MMR status on tissue assessed by the IHC MSI test, (Bethesda panel);
    
                   -  Negative score for the MGMT protein expression IHC test;
    
                   -  Positive score for the MGMT promoter methylation Methyl BEAMing test performed on
                      plasma.
    
              7. Subjects and their partners must be willing to avoid pregnancy.
    
              8. Normal organ functions as defined in the Table 6.1.4 below.
    
            Entry Criteria for TRIAL Phase
    
              1. Fulfillment of all the SCREENING inclusion criteria and Deficient or Proficient MMR
                 status on tissue assessed by the IHC MSI test, (Bethesda panel)
    
              2. Fulfillment of all the PRIMING Phase inclusion criteria (only cohort P);
    
              3. TRIAL Phase informed consent signed;
    
              4. Imaging documented PD (Disease Progression) to TMZ (only cohort P).
    
              5. A mutational load value > 20 mutations/MB at B-ML assay (only cohort P) ;
    
              6. Women with childbearing potential and their partners must agree to continue using
                 highly contraceptive methods (see appendix 3).
    
              7. Normal organ functions as defined in the Table 6.1.4 below. Specimens must be
                 collected within 10 days prior to the start of study treatment.
    
            Exclusion Criteria:
    
              1. A woman of child bearing potential who has a positive urine pregnancy test within 72
                 hours prior to allocation (see Appendix 3). If the urine test is positive or cannot be
                 confirmed as negative, a serum pregnancy test will be required.
    
              2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti‑PD‑L2 agent or with
                 an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,
                 OX‑40, CD137).
    
              3. Has received prior systemic anti-cancer therapy including investigational agents
                 within 4 weeks [could consider shorter interval for kinase inhibitors or other short
                 half-life drugs] prior to allocation.
    
                   1. Note: Participants must have recovered from all AEs due to previous therapies to
                      ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
    
                   2. Note: If participant received major surgery, they must have recovered adequately
                      from the toxicity and/or complications from the intervention prior to starting
                      study treatment.
    
              4. Has received prior radiotherapy within 2 weeks of start of study treatment (with
                 pembrolizumab). Participants must have recovered from all radiation-related
                 toxicities, not require corticosteroids, and not have had radiation pneumonitis. A
                 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to
                 non-CNS disease.
    
              5. Has received a live vaccine within 30 days prior to the first dose of study drug.
                 Examples of live vaccines include, but are not limited to, the following: measles,
                 mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, and typhoid
                 vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines
                 and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live
                 attenuated vaccines and are not allowed.
    
              6. Is currently participating in or has participated in a study of an investigational
                 agent or has used an investigational device within 4 weeks prior to the first dose of
                 study treatment.
    
                 a. Note: Participants who have entered the follow-up phase of an investigational study
                 may participate as long as it has been 4 weeks after the last dose of the previous
                 investigational agent.
    
              7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
                 (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
                 immunosuppressive therapy within 7 days prior to the first dose of study drug.
    
              8. Has a known additional malignancy that is progressing or has required active treatment
                 within the past 3 years. Note: Participants with basal cell carcinoma of the skin,
                 squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma,
                 cervical cancer in situ) that have undergone potentially curative therapy are not
                 excluded.
    
              9. Has known active CNS metastases and/or carcinomatous meningitis. Participants with
                 previously treated brain metastases may participate provided they are radiological
                 stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
                 (note that the repeat imaging should be performed during study screening), clinically
                 stable and without requirement of steroid treatment for at least 14 days prior to
                 first dose of study treatment.
    
             10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
    
             11. Has severe hypersensitivity (≥Grade 3) to temozolomide and/or any of its excipients.
    
             12. Has active autoimmune disease that has required systemic treatment in the 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.
    
             13. Has a history of (non-infectious) pneumonitis that required steroids or has current
                 pneumonitis.
    
             14. Has an active infection requiring systemic therapy.
    
             15. Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is
                 required.
    
             16. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
                 reactive) or known active Hepatitis C virus infection. Note: no testing for Hepatitis
                 B and Hepatitis C is required unless mandated by local health authority.
    
             17. Has a known history of active TB (Bacillus Tuberculosis).
    
             18. Has a history or current evidence of any condition, therapy, or laboratory abnormality
                 that might confound the results of the study, interfere with the subject's
                 participation for the full duration of the study, or is not in the best interest of
                 the subject to participate, in the opinion of the treating investigator.
    
             19. Has known psychiatric or substance abuse disorders that would interfere with
                 cooperation with the requirements of the trial
    
             20. Is pregnant or breastfeeding, or expecting to conceive or father children within the
                 projected duration of the study, starting with the screening visit through 120 days
                 after the last dose of trial treatment..
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Overall response rate (ORR)
    Time Frame:Tumor assessments every 8-9 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months
    Safety Issue:
    Description:Overall response rate (ORR) to pembrolizumab according to RECIST v1.1 and iRECIST

    Secondary Outcome Measures

    Measure:Progression Free Survival
    Time Frame:assessments every 8-9 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months
    Safety Issue:
    Description:Progression Free Survival in MMRp pembrolizumab treated patients
    Measure:Overall Survival
    Time Frame:assessments every 8-9 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months
    Safety Issue:
    Description:Overall Survival in MMRp pembrolizumab treated patients
    Measure:Toxicity
    Time Frame:assessments every 3 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months
    Safety Issue:
    Description:Toxicity according to CTCAE version 4.03

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:IFOM, The FIRC Institute of Molecular Oncology

    Trial Keywords

    • DNA Mismatch Repair
    • Pembrolizumab

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