PhII Trial Panitumumab, Nivolumab, Ipilimumab in Kras/Nras/BRAF Wild-type MSS Refractory mCRC
Condition: Colon Cancer
MeSH terms: Colonic Neoplasms
Intervention: Panitumumab; Nivolumab; Ipilimumab
Intervention description: 6 mg/kg via IV every 2 weeks in combination with nivolumab and ipilimumab; 240 mg via IV every 2 weeks in combination with panitumumab and ipilimumab; 1 mg/kg via IV every 6 weeks in combination with nivolumab and panitumumab
Intervention MeSH terms: Nivolumab; Ipilimumab; Panitumumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: This will be a single-arm, open-label, multicenter Phase II clinical trial investigating the clinical efficacy of nivolumab, ipilimumab, and panitumumab in subjects with unresectable refractory KRAS/NRAS/BRAF wild-type microsatellite stable metastatic colorectal cancer after an initial safety lead-in cohort to ensure the three drug combination is well-tolerated.
Masking: None (Open Label)
Enrollment: 56.0
Sex: All
Minimum age: 18 Years
Maximum age: 120 Years
Healthy volunteers: No

Summary:

      To investigate the combination of nivolumab and ipilimumab with panitumumab in subjects with
      unresectable, refractory, KRAS/NRAS/BRAF wild-type, microsatellite stable (MSS) metastatic
      colorectal cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Histologically or cytologically confirmed colorectal adenocarcinoma, with unresectable
             metastatic or locally advanced disease documented on diagnostic imaging studies.

          2. Previously received 1-2 prior lines of therapy. Subjects who relapse within 6 months
             of adjuvant chemotherapy comprised of oxaliplatin and a fluoropyrimidine will have
             their adjuvant therapy count as one prior line of therapy.

          3. Confirmed wild-type in KRAS and NRAS codons 12, 13, 59, 61, 117, and 146; and BRAF
             codon 600, by standard of care testing of tumor specimen. Tissue used for testing may
             have been collected from primary or metastatic site.

          4. Microsatellite stable as detected by PCR-based assay or CLIA-certified sequencing
             methodology such as Foundation One; or mismatch repair proficient as detected by
             immunohistochemistry showing intact nuclear staining of MLH1, MSH2, MSH6, and PMS2

          5. Radiographically measurable disease present per RECIST 1.1

          6. Age ≥ 18 years at the time of consent.

          7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

          8. Blood counts performed within 3 weeks prior to starting study therapy must have
             absolute neutrophil count ≥ 1,500/mm3, platelets ≥ 100,000/mm3, and hemoglobin ≥ 9
             g/dL.

             *Note: Hematology and other lab parameters that are ≤ grade 2 but still meet criteria
             for study entry are allowed. Furthermore, changes in laboratory parameters during the
             study should not be considered adverse events unless they meet criteria for dose
             modification(s) of study medication outlined by the protocol and/or worsen from
             baseline during therapy.

          9. Liver function tests performed within 3 weeks prior to starting study therapy must
             have total bilirubin ≤ 1.5 x upper limit of normal (ULN), alanine aminotransferase and
             aspartate aminotransferase ≤ 3 x ULN, and albumin ≥ 2.5 g/dL.

         10. Serum creatinine performed within 3 weeks prior to starting study therapy must be ≤
             1.5 x ULN, or have calculated creatinine clearance (using Cockcroft-Gault formula
             provided in Appendix 11.3) of ≥ 50 mL/minute.

         11. Females of childbearing potential must have a negative serum pregnancy test within 24
             hours prior to receiving the first dose of study medication. Females of childbearing
             potential must agree to use 2 methods of effective contraception or abstain from
             heterosexual sex throughout the treatment period and for 5 months after the last dose
             of study treatment. Females of childbearing potential are women who have not been
             surgically sterilized (have undergone a hysterectomy, bilateral tubal ligation, or
             bilateral oophorectomy) or have not been free of menses for >1 year.

         12. Male subjects with female partners must have had a prior vasectomy or agree to use an
             adequate method of contraception (i.e., double barrier method: condom plus spermicidal
             agent) starting with the first dose of study therapy through 7 months after the last
             dose of study treatment.

         13. Written informed consent and HIPAA authorization for release of personal health
             information. NOTE: HIPAA authorization may be included in the informed consent or
             obtained separately.

         14. An adequate amount of archival tumor tissue must be available at baseline to be
             eligible for enrollment in the study. If archival tissue is not available or is
             inadequate, then the subject must consent to undergo a mandatory biopsy at baseline in
             order to participate in the study.

        Exclusion Criteria:

          1. Past treatment with an antibody targeting EGFR including cetuximab or panitumumab.

          2. Past treatment with an antibody targeting immune checkpoints including CTLA-4, PD-1,
             PD-L1, PD-L2, or CD137.

          3. Known untreated brain metastasis or brain metastasis treated within 3 months prior to
             enrollment in this trial.

          4. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

          5. Has a known additional malignancy that is active and/or progressive requiring
             treatment; exceptions include basal cell or squamous cell skin cancer, in situ
             cervical or bladder cancer, or other cancer for which the subject has been disease
             free for at least five years.

          6. Treatment within 21 days of the first dose of study drug with any other chemotherapy,
             immunotherapy, biologic therapy, vaccine therapy, or investigational treatment for the
             treatment of malignancy, or failure to recover from adverse effects of prior therapies
             administered over 4 weeks prior to Study Day 1. All toxicities from prior therapies
             must be ≤ Grade 1 (or ≤ Grade 2 for alopecia or peripheral neuropathy). Prior systemic
             treatment in the adjuvant setting is allowed. See note above under inclusion 3.1.8

          7. Any serious and/or unstable pre-existing medical disorder (aside from malignancy
             exception above), psychiatric disorder, or other conditions that could interfere with
             subject's safety, obtaining informed consent, or compliance to the study procedures.

          8. Pregnant or breastfeeding, or planning to become pregnant within 6 months after the
             end of treatment. (NOTE: breast milk cannot be stored for future use while the mother
             is being treated on study).

          9. History of organ allograft or other history of immunodeficiency, or is receiving
             systemic steroid therapy or any other form of immunosuppressive therapy within 7 days
             before the first dose of investigational treatment.

         10. Inability or unwillingness to comply with study and/or follow-up requirements.

         11. Any major surgery, extensive radiotherapy, chemotherapy with clinically significant
             delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to
             randomization and/or daily or weekly chemotherapy without the potential for delayed
             toxicity within 14 days prior to randomization.

         12. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to study drug.

         13. Known Human Immunodeficiency Virus (HIV), Hepatitis B virus (HBV), or Hepatitis C
             virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV
             infection will be permitted.

         14. Active autoimmune disease requiring systemic treatment in the past 3 months (for
             example with 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. Subjects with vitiligo or resolved childhood asthma/atopy would be
             an exception to this rule. Subjects that require intermittent use of bronchodilators,
             local steroid injections, or inhaled or topical steroids would not be excluded from
             the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren's
             syndrome will not be excluded from the study.

         15. Active infection requiring intravenous systemic therapy.