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Clinical Trial 19680

Cancer Type: Gastrointestinal Tumor
Interventions:BMS-936558 (Nivolumab); Ipilimumab; Nivolumab; Panitumumab; Vectibix (Panitumumab); Yervoy (Ipilimumab)

Study Type: Treatment
Phase of Study: Phase II
Investigators:

  • Iman Imanirad

Call 813-745-6100
or 1-800-679-0775
Overview

Study Title

Phase II Multicenter Trial of Panitumumab, Nivolumab, and Ipilimumab for KRAS/NRAS/BRAF Wild-Type MSS Refractory Metastatic Colorectal Adenocarcinoma

Summary

Objective

Primary Objective: To evaluate the clinical efficacy of panitumumab/nivolumab/ipilimumab or panitumumab/nivolumab therapy in subjects with unresectable refractory KRAS/NRAS/BRAF wild-type MSS mCRC, by determining overall response rate (ORR) at 12 weeks by RECIST 1.1 criteria. 2.2 Secondary Objectives: 2.2.1 To determine the best overall response associated with panitumumab/nivolumab/ipilimumab or panitumumab/nivolumab therapy in subjects with unresectable refractory KRAS/NRAS/BRAF wild-type MSS metastatic colorectal adenocarcinoma based on both RECIST1.1 and irRECIST criteria. 2.2.2 To determine the overall response rate (ORR) associated with panitumumab/nivolumab/ipilimumab or panitumumab/nivolumab therapy in subjects with unresectable refractory KRAS/NRAS/BRAF wild-type MSS metastatic colorectal adenocarcinoma at 12 weeks by irRECIST criteria. 2.2.3 To determine PFS associated with panitumumab/nivolumab/ipilimumab or panitumumab/nivolumab therapy in subjects with unresectable refractory KRAS/NRAS/BRAF wild-type MSS metastatic colorectal adenocarcinoma based on both RECIST 1.1 and irRECIST criteria. 2.2.4 To determine OS of subjects with unresectable refractory KRAS/NRAS/BRAF wild-type MSS metastatic colorectal adenocarcinoma treated with panitumumab/nivolumab/ipilimumab or panitumumab/nivolumab therapy. 2.2.5 To determine the duration of response of subjects with unresectable refractory KRAS/NRAS/BRAF wild-type MSS metastatic colorectal adenocarcinoma treated with panitumumab/nivolumab/ipilimumab or panitumumab/nivolumab therapy based on both RECIST1.1 and irRECIST criteria 2.2.6 To evaluate the toxicity of panitumumab/nivolumab/ipilimumab in subjects with unresectable refractory KRAS/NRAS/BRAF wild-type MSS mCRC, by determining the number of treatment-emergent grade 3 and 4 toxicities as defined by National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03). 2.3 Exploratory Objectives: 2.3.1 To collect peripheral blood longitudinally to identify mechanisms of resistance to anti-EGFR antibodies, possibly including assays of circulating tumor DNA like circulating mutant KRAS and NRAS and EGFR ligands like epiregulin and amphiregulin. 2.3.2 To collect peripheral blood longitudinally to perform peripheral immune monitoring, including flow cytometric assays. 2.3.3 To collect archival tumor tissue to assay baseline genomic and immune characteristics including immune cell infiltration and PD-L1 staining. 2.3.4 To collect on-treatment biopsies to determine alterations in immunologic cell infiltrates and tumors upon treatment with anti-EGFR and immune checkpoint antibodies.

Inclusion Criteria

  • Histologically or cytologically confirmed colorectal adenocarcinoma, with unresectable metastatic or locally advanced disease documented on diagnostic imaging studies.
  • 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.
  • 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.
  • 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
  • Radiographically measurable disease present per RECIST 1.1
  • Age ≥ 18 years at the time of consent.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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

  • Past treatment with an antibody targeting EGFR including cetuximab or panitumumab.
  • Past treatment with an antibody targeting immune checkpoints including CTLA-4, PD-1, PD-L1, PD-L2, or CD137.
  • Known untreated brain metastasis or brain metastasis treated within 3 months prior to enrollment in this trial.
  • Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
  • 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.
  • 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
  • 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.
  • 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).
  • 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.
  • Inability or unwillingness to comply with study and/or follow-up requirements.
  • 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.
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug.
  • 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.
  • 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.
  • Active infection requiring intravenous systemic therapy.