Nivolumab and Ipilimumab in Mucinous Colorectal and Appendiceal Tumors

Study Overview
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Brief Summary
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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.

Detailed Description
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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

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

Conditions
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Mucinous Adenocarcinoma of the Colon, Mucinous Adenocarcinoma of the Rectum

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Ipilimumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab and Ipilimumab<br>Treatment will consist of Nivolumab 480mg every 4 weeks and Ipilimumab 1mg/kg every 8 weeks. Subjects will continue on study therapy until disease progression, unacceptable toxicity, withdrawal of consent, or 24 months of therapy. | Drug: Nivolumab<br>* IV infusion per institutional guidelines and the Package Insert<br>* Other names: Opdivo;Drug: Ipilimumab<br>* IV infusion per institutional guidelines and the Package Insert<br>* Other names: Yervoy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Progression-Free Survival at 6 Months | To determine six-month progression-free survival by iRECIST from start of study treatment until 6 months | Start of treatment until 6 months later | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival | to determine Progression-Free survival from start of study treatment until time of documented disease progression or death assessed up to 2 years | start of treatment until disease progression or death, assessed up to 2 years | 
| Overall Survival | Overall survival (OS) is defined as the duration of time from start of treatment to death | From start of treatment until death assessed up to 2 years | 
| Objective Response Rate | The objective response rate is determined by the percentage of individuals on study attaining a complete or partial response as noted by by iRECIST and RECIST v1.1 Criteria | From start of treatment until progression or death assessed up to 2 years | 
| Duration of Response | Time from the first recorded partial or complete response using RECIST v.1.1 criteria until disease progression or death | From the first recorded partial or complete response until progressive disease or death, whichever came first, assessed up to 2 years |