Nivolumab and Ipilimumab in Mucinous Colorectal and Appendiceal Tumors

A Phase II Study of Nivolumab and Ipilimumab in Mucinous Colorectal and Appendiceal Tumors

This is a single-arm phase II study of twenty-one subjects with mucinous adenocarcinoma of the colon, rectum, or appendix with prior systemic therapy with a fluoropyrimidine, oxaliplatin, and irinotecan. Treatment will consist of nivolumab 480mg every 4 weeks and ipilimumab 1mg/kg every 8 weeks until disease progression, unacceptable toxicity, or 2 years of therapy.

Treatment will consist of nivolumab 480mg every 4 weeks and ipilimumab 1mg/kg every 8 weeks (within a 56-day cycle, (Nivolumab administered on days 1 and 29, and Ipilimumab administered on day 1 of each cycle). Imaging assessments will be conducted every 8 weeks (+/-2 weeks) for the first 24 weeks then every 8-12 weeks (+/-2 weeks). If progression is noted on imaging in the setting of clinical stability, subjects may remain on study and have confirmatory imaging in 4-8 weeks per iRECIST criteria

Inclusion Criteria:

• Subjects must have signed and dated an IRB-approved written informed consent form prior to the performance of any protocol-related procedures that are not part of standard care.

• Colorectal or appendiceal mucinous adenocarcinoma with peritoneal-only metastatic disease. It is recognized that in some patients, peritoneal disease will predominate without distinction of the site of origin, and such patients will be eligible.

• Microsatellite stable by PCR and/or mismatch repair proficient by immunohistochemistry

• ECOG performance status of 0 or 1

• Prior therapy with a fluoropyrimidine, oxaliplatin, and irinotecan unless contraindicated or refused. Prior treatment with antiangiogenic and/or anti-EGFR antibody therapy is permitted but not required

• Measurable disease by RECIST v. 1.1

• Laboratory parameters:

  • Absolute neutrophil count > 1500/μL
  • Platelets > 100,000/μL
  • Hemoglobin > 9.0 g/dL
  • PT/INR or PTT < 1.5xULN
  • Creatinine < 1.5xULN OR creatinine clearance > 50 mL/min by Cockcroft-Gault formula
  • Total bilirubin < 1.5xULN
  • Subjects with Gilbert's Syndrome must have a total bilirubin level of < 3.0xULN
  • Albumin > 3.0 g/dL
  • AST and/or ALT: < 3.0×ULN

• Subjects with HIV are permitted provided they meet the following criteria:

  • CD4+ cell count > 250 cells/mm3
  • No history of AIDS-defining conditions other than low CD4+ count
  • If subject is on antiretroviral therapy, there must not be expected significant drug-drug interactions with study treatment

Exclusion Criteria:

• Bowel obstruction within the past 60 days

• Subjects who are currently pregnant, planning to become pregnant, or breast-feeding.

  • Females participants of child-bearing potential are required to use an effective contraception method or abstain from intercourse during treatment and for at least 5 months following the last dose
  • Males participants with partners of child-bearing potential are required to use an effective contraception method or abstain from intercourse during treatment and for at least 7 months following the last dose

• Subjects who, in the opinion of the physician, would not be clinically appropriate for receipt of the therapy regimen associated with participation

• Subjects with contraindications to immune checkpoint therapy, as follows:

  • Interstitial lung disease that is symptomatic or may interfere with the detection and management of suspected drug-related pulmonary toxicity

  • Prior organ allograft or allogeneic bone marrow transplantation

  • Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication

  • Active autoimmune disease, except for vitiligo, type 1 diabetes mellitus, asthma, atopic dermatitis, or endocrinopathies manageable by hormone replacement; other autoimmune conditions may be allowable at the discretion of the principal investigator

  • Condition requiring systemic treatment with corticosteroids

    • Systemic steroids at physiologic doses (equivalent to dose of oral prednisone 10 mg) are permitted.
    • Intranasal, inhaled, topical, intra-articular, and ocular corticosteroids with minimal systemic absorption are permitted.

• Established non-peritoneal metastatic disease, including but not limited to metastases to the liver, lung, brain, extra-abdominal lymph nodes, and bone

• A second primary malignancy that, in the judgment of the investigator, may affect interpretation of results

• Prior treatment with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody

• Toxicities attributed to prior anti-cancer therapy other than alopecia, fatigue, and peripheral neuropathy must have resolved to Grade 1 or baseline before administration of study drug. In addition, a washout period will be required for prior therapies as specified:

  • No chemotherapy within 14 days prior to first dose
  • No investigational product(s) (IPs) and/or biologic therapy within 28 days or 5 half-lives, whichever is longer, prior to first dose
  • No major surgery within 28 days prior to first dose. Any surgery-related AE(s) must have resolved at least 14 days prior to first dose.
  • No radiation therapy with curative intent within 28 days prior to first dose. Prior focal palliative radiotherapy must have been completed at least 14 days prior to first dose.

• Active hepatitis B or hepatitis C, defined as the following:

  • Hepatitis B surface antigen positive or HBV DNA PCR >100 IU/mL
  • Hepatitis C antibody positive unless HCV RNA PCR is negative (i.e. undetectable viral load)

• Prisoners or participants who are involuntarily incarcerated. (Note: under specific circumstances a person who has been imprisoned may be included as a participant. Strict conditions apply and BMS approval is required.)

• Participants who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness