PhII Trial Panitumumab, Nivolumab, Ipilimumab in Kras/Nras/BRAF Wild-type MSS Refractory mCRC

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Colon Cancer
• Intervention / Treatment: Drug: Panitumumab; Drug: Nivolumab; Drug: Ipilimumab

Detailed Description

The investigators will conduct a single-arm, open-label Phase II clinical trial investigating the combination of nivolumab and ipilimumab with panitumumab in subjects with unresectable, refractory, KRAS/NRAS/BRAF wild-type, microsatellite stable (MSS) metastatic colorectal cancer (mCRC). There will be an initial safety lead-in cohort to ensure the combination is well-tolerated. The primary objective of this study is to estimate the overall response rate in these subjects at 12 weeks . Secondary objectives include the following: estimating the overall response rate in these subjects at 12 weeks by immune-related RECIST criteria (irRECIST), estimating the best response rate by both RECIST 1.1 and irRECIST criteria, estimating progression-free survival (PFS) and duration of response using both RECIST 1.1 and irRECIST criteria, estimating overall survival (OS), and characterizing the safety issues associated with this regimen. Exploratory objectives involve investigating various biomarkers and peripheral blood and tumor assays.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Melvin and Bren Simon Cancer Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27509
      • University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington - Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open-label, single arm, Phase II; Nivolumab and ipilimumab with panitumumab	Drug: Panitumumab; 6 mg/kg via IV every 2 weeks in combination with nivolumab and ipilimumab; Other Names: Vectibix; Drug: Nivolumab; 240 mg via IV every 2 weeks in combination with panitumumab and ipilimumab; Other Names: Opdivo; Drug: Ipilimumab; 1 mg/kg via IV every 6 weeks in combination with nivolumab and panitumumab; Other Names: Yervoy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	Overall Response Rate (ORR) = CR + PR Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate Per irRECIST	Overall Response Rate (ORR) = irCR + irPR Per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) for target and/or non-target lesions and assessed by imaging: Complete Response (irCR), Disappearance of all lesions, no new lesions, lymph nodes < 10 mm in short axis; Partial Response (irPR), ≥30% decrease in the sum of target lesions and non-target lesions are irNN; Stable response (irSD), not meeting criteria for irCR, irPR, or irPD; Progressive Disease (irPD), ≥20% increase in tumor burden and minimum 5 mm absolute increase in compared to nadir; for no new non-target or (irNN) and where irPR or irPD are confirmed by a repeat, consecutive assessment no less than 4 weeks later	12 weeks
Length of Progression Free Survival	Time from first day of treatment until disease progression as defined by RECIST, irRECIST, or death from any cause	Up to 3 years
Length of Overall Survival	Time from first day of treatment until death from any cause	Up to 3 years
Duration of Response	Time from documentation of tumor response to disease progression	Up to 3 years
Toxicity of Treatment	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)	Up to 36 month

Collaborators and Investigators

• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Collaborators: Bristol-Myers Squibb; Amgen
• Investigators: Principal Investigator: Autumn McRee, MD, University of North Carolina, Chapel Hill

Publications and helpful links

Helpful Links

• University of North Carolina Lineberger Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2018
• Primary Completion (Actual): September 21, 2020
• Study Completion (Estimated): March 31, 2024

Study Registration Dates

• First Submitted: February 14, 2018
• First Submitted That Met QC Criteria: February 20, 2018
• First Posted (Actual): February 22, 2018

Study Record Updates

• Last Update Posted (Estimated): November 16, 2023
• Last Update Submitted That Met QC Criteria: November 14, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Colorectal Neoplasms; Colonic Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Panitumumab; Ipilimumab
• Other Study ID Numbers: LCCC1632

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No