A Phase 2 Study of Pembrolizumab (MK-3475) in Combination With Azacitidine in Subjects With Chemo-refractory Metastatic Colorectal Cancer
Condition: Metastatic Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: Pembrolizumab; Azacitidine
Intervention description: Pembrolizumab will be given at 200 mg every 21 days; Azacitidine will be given at 100 mg daily subcutaneous injection on days 1-5 every 21 days.
Intervention MeSH terms: Pembrolizumab; Azacitidine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 31.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is an open label, single-arm, Phase 2 trial to evaluate the anti-tumor activity, safety,
      and tolerability of Pembrolizumab in combination with azacitidine in subjects with
      chemo-refractory mCRC without any further standard treatment options

      Dosage and regimen for all study periods

        -  Pembrolizumab will be given at 200 mg every 21 days.

        -  Azacitidine will be given at 100 mg daily subcutaneous injection on days 1-5 every 21
           days.

      The first assessment of tumor response will be performed after cycle 3 (9 weeks), and
      thereafter approximately every 9 weeks, every 3 cycles of therapy. The modified RECIST 1.1
      will be used to establish disease response or progression.

      All patients will be evaluated and graded for adverse events according to the NCI Common
      Terminology for Adverse Events, version 4.0 (NCI-CTCAE).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Be willing and able to provide written informed consent/assent for the trial.

          2. Be 18 years of age or older on day of signing informed consent.

          3. The diagnosis of mCRC will be based on histologic or cytologic confirmation.

          4. Have mCRC that has been previously treated with currently approved standard therapies.

          5. Have measurable disease based on RECIST 1.1.

          6. At least 1 of the tumor sites must be amenable to core needle biopsy and this may not
             be the site of disease used to measure antitumor response. Patient must agree to this
             mandatory biopsy.

          7. Have a performance status of 0 or 1 on the ECOG Performance Scale.

          8. Demonstrate adequate organ function, all screening labs should be performed within 14
             days of treatment initiation.

          9. Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of study medication. If
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required.

         10. Female subjects of childbearing potential should be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the course
             of the study through 120 days after the last dose of study medication. Subjects of
             childbearing potential are those who have not been surgically sterilized or have not
             been free from menses for > 1 year.

         11. Male subjects should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 120 days after the last dose of study therapy.

        Exclusion Criteria:

          1. Is currently participating in or has participated in a study of an investigational
             agent or using an investigational device within 4 weeks of the first dose of
             treatment.

          2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment.

          3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not
             recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents
             administered more than 4 weeks earlier.

          4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from adverse events due to a previously administered agent.

             - Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may
             qualify for the study.

          5. Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, or in situ cervical cancer that has undergone potentially curative therapy..

          6. Has extensive metastatic tumor burden in the liver with serum albumin <3.0 g/dL.

          7. Has known renal tubular acidosis with serum bicarbonate <20 mEq/L.

          8. Has a known hypersensitivity to azacitidine or mannitol.

          9. Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least four weeks
             prior to the first dose of trial treatment and any neurologic symptoms have returned
             to baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroids for at least 7 days prior to trial treatment.

         10. Has an active autoimmune disease requiring systemic treatment within the past 3 months
             or a documented history of clinically severe autoimmune disease, or a syndrome that
             requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or
             resolved childhood asthma/atopy would be an exception to this rule. Subjects that
             require intermittent use of bronchodilators or local steroid injections would not be
             excluded from the study. Subjects with hypothyroidism stable on hormone replacement or
             Sjorgen's syndrome will not be excluded from the study.

         11. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

         12. Has an active infection requiring systemic therapy.

         13. 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.

         14. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         15. Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment.

         16. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
             anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
             ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
             or checkpoint pathways).

         17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

        Has received a live vaccine within 30 days prior to the first dose of trial treatment.