Clinical trial NCT03693846: Nivolumab and Ipilimumab in Mucinous Colorectal and Appendiceal Tumors
Official title: A Phase II Study of Nivolumab and Ipilimumab in Mucinous Colorectal and Appendiceal Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Mucinous Adenocarcinoma of the Colon
Mucinous Adenocarcinoma of the Rectum
Lead sponsor: Abramson Cancer Center at Penn Medicine
Sponsor class: OTHER
First posted: 2018-10-03
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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

Eligibility 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

Primary outcomes:
measure: Number of Participants With Progression-Free Survival at 6 Months
timeFrame: Start of treatment until 6 months later
Secondary outcomes:
measure: Progression-Free Survival
timeFrame: start of treatment until disease progression or death, assessed up to 2 years
measure: Overall Survival
timeFrame: From start of treatment until death assessed up to 2 years
measure: Objective Response Rate
timeFrame: From start of treatment until progression or death assessed up to 2 years
measure: Duration of Response
timeFrame: From the first recorded partial or complete response until progressive disease or death, whichever came first, assessed up to 2 years
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Abramson Cancer Center of the University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: Abramson Cancer Center
name: Thomas Karasic, MD
role: PRINCIPAL_INVESTIGATOR
References: