Clinical Trials /

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

NCT03442569

Description:

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.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: PhII Trial Panitumumab, Nivolumab, Ipilimumab in Kras/Nras/BRAF Wild-type MSS Refractory mCRC
  • Official Title: Phase II Multicenter Trial of Panitumumab, Nivolumab, and Ipilimumab for KRAS/NRAS/BRAF Wild-type MSS Refractory Metastatic Colorectal Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: LCCC1632
  • NCT ID: NCT03442569

Conditions

  • Colon Cancer

Interventions

DrugSynonymsArms
PanitumumabVectibixOpen-label, single arm, Phase II
NivolumabOpdivoOpen-label, single arm, Phase II
IpilimumabYervoyOpen-label, single arm, Phase II

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Open-label, single arm, Phase IIExperimentalNivolumab and ipilimumab with panitumumab
  • Panitumumab
  • Nivolumab
  • Ipilimumab

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.
      
Maximum Eligible Age:120 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:12 weeks
Safety Issue:
Description:Overall Response Rate (ORR) = CR + PR Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) 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

Secondary Outcome Measures

Measure:Overall Response Rate per irRECIST
Time Frame:12 weeks
Safety Issue:
Description: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
Measure:Length of Progression Free Survival
Time Frame:Up to 3 years
Safety Issue:
Description:Time from first day of treatment until disease progression as defined by RECIST, irRECIST, or death from any cause
Measure:Length of Overall Survival
Time Frame:Up to 3 years
Safety Issue:
Description:Time from first day of treatment until death from any cause
Measure:Duration of Response
Time Frame:Up to 3 years
Safety Issue:
Description:Time from documentation of tumor response to disease progression
Measure:Toxicity of Treatment
Time Frame:Up to 36 months
Safety Issue:
Description: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)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

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