Clinical Trials /

Panitumumab With or Without Trametinib in Treating Patients With Stage IV Colorectal Cancer

NCT03087071

Description:

This phase II clinical trial studies how well panitumumab with or without trametinib works in treating patients with stage IV colorectal cancer. Immunotherapy with monoclonal antibodies, such as panitumumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving panitumumab with or without trametinib may work better in treating patients with stage IV colorectal cancer.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Panitumumab With or Without Trametinib in Treating Patients With Stage IV Colorectal Cancer
  • Official Title: A Phase II Enrichment Study of Panitumumab as a Single Agent or in Combination With Trametinib in Cetuximab-Refractory Stage IV Colorectal Cancer Patients

Clinical Trial IDs

  • ORG STUDY ID: 2016-0338
  • SECONDARY ID: NCI-2017-00868
  • SECONDARY ID: 2016-0338
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03087071

Conditions

  • BRAF NP_004324.2:p.V600X
  • Colorectal Adenocarcinoma
  • KRAS Gene Mutation
  • NRAS Gene Mutation
  • Recurrent Colorectal Carcinoma
  • Stage IV Colorectal Cancer AJCC v7
  • Stage IVA Colorectal Cancer AJCC v7
  • Stage IVB Colorectal Cancer AJCC v7

Interventions

DrugSynonymsArms
PanitumumabABX-EGF, ABX-EGF Monoclonal Antibody, ABX-EGF, Clone E7.6.3, MoAb ABX-EGF, Monoclonal Antibody ABX-EGF, VectibixCohort 1 (panitumumab)
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistCohort 2 (panitumumab, trametinib)

Purpose

This phase II clinical trial studies how well panitumumab with or without trametinib works in treating patients with stage IV colorectal cancer. Immunotherapy with monoclonal antibodies, such as panitumumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving panitumumab with or without trametinib may work better in treating patients with stage IV colorectal cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the anti-tumor efficacy of panitumumab monotherapy in patients who were
      initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior cetuximab therapy
      and subsequently have detectable EGFR ectodomain mutation post-progression in circulating
      free tumor deoxyribonucleic acid (DNA).

      II. To evaluate the anti-tumor efficacy of panitumumab and trametinib combination therapy in
      patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior
      cetuximab therapy and subsequently have detectable levels of KRAS, NRAS, and/or BRAF mutation
      post-progression in circulating free tumor DNA.

      III. To evaluate the anti-tumor efficacy of panitumumab monotherapy in patients who were
      initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior cetuximab therapy
      and subsequently do not have detectable KRAS, NRAS, BRAF, or EGFR ectodomain mutation
      post-progression in circulating free tumor DNA.

      SECONDARY OBJECTIVES:

      I. To evaluate the toxicities of panitumumab and trametinib combination therapy.

      II. To evaluate the anti-tumor efficacy of panitumumab and trametinib combination therapy in
      patients who were initially KRAS/NRAS/BRAF wild-type at baseline who progressed on prior
      cetuximab therapy, developed detectable EGFR ectodomain mutations, and progress through
      retreatment with panitumumab.

      III. To evaluate the anti-tumor efficacy of panitumumab and trametinib combination therapy in
      patients who were initially KRAS/NRAS/BRAF wild-type at baseline who progressed on prior
      cetuximab therapy, did not develop detectable mutations in KRAS, NRAS, BRAF, or EGFR
      ectodomain, and progress through retreatment with panitumumab.

      IV. To evaluate clinical outcomes with panitumumab monotherapy in patients who were initially
      KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior cetuximab therapy and
      subsequently have detectable EGFR ectodomain mutation post-progression in circulating free
      tumor DNA.

      V. To evaluate clinical outcomes with panitumumab and trametinib combination therapy in
      patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior
      cetuximab therapy and subsequently have detectable levels of KRAS, NRAS, and/or BRAF mutation
      post-progression in circulating free tumor DNA.

      VI. To evaluate clinical outcomes with panitumumab monotherapy in patients who were initially
      KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior cetuximab therapy and
      subsequently do not have detectable KRAS, NRAS, BRAF, or EGFR ectodomain mutation
      post-progression in circulating free tumor DNA.

      VII. To study the biological basis of development of primary and secondary resistance to
      anti-EGFR antibodies and MEK inhibitors.

      OUTLINE: Patients are assigned to 1 of 3 cohorts.

      COHORT 1: Patients with EGFR ectodomain mutation receive panitumumab intravenously (IV) over
      30-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or
      unacceptable toxicity. Patients with disease progression may crossover to Cohort 2.

      COHORT 2: Patients with KRAS, NRAS, or BRAF mutation receive trametinib orally (PO) once
      daily (QD) on days 1-14 and panitumumab as in Cohort 1. Courses repeat every 14 days in the
      absence of disease progression or unacceptable toxicity.

      COHORT 3: Patients without EGFR ectodomain, KRAS, NRAS, or BRAF mutation receive panitumumab
      as in Cohort 1. Courses repeat every 14 days in the absence of disease progression or
      unacceptable toxicity. Patients with disease progression may crossover to Cohort 2.

      After completion of study treatment, patients are followed up for 4 weeks and then every 3
      months for 24 months.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1 (panitumumab)ExperimentalPatients with EGFR ectodomain mutation receive panitumumab IV over 30-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Cohort 2.
  • Panitumumab
Cohort 2 (panitumumab, trametinib)ExperimentalPatients with KRAS, NRAS, or BRAF mutation receive trametinib PO QD on days 1-14 and panitumumab as in Cohort 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
  • Panitumumab
  • Trametinib
Cohort 3 (panitumumab)ExperimentalPatients without EGFR ectodomain, KRAS, NRAS, or BRAF mutation receive panitumumab as in Cohort 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Cohort 2.
  • Panitumumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed colorectal adenocarcinoma, with metastatic
             disease documented on diagnostic imaging studies

          -  Progression during or within 6 months after fluoropyrimidine, irinotecan, and
             oxaliplatin; for oxaliplatin-based therapy, failure of therapy will also include
             patients who progressed within 12 months of adjuvant therapy and patients who had
             oxaliplatin discontinued secondary to toxicity or allergic reaction; patients with a
             known history of Gilbert's disease who cannot receive irinotecan or patients who are
             intolerant of irinotecan or fluoropyrimidine are eligible

          -  Confirmed wild-type status in KRAS exons 2, 3, and 4; NRAS exons 2, 3, and 4; and
             BRAF, by standard of care testing of tumor specimen; tissue used for testing may have
             been collected prior to treatment with cetuximab

          -  Patient must have been already tested and have available results of the mutations
             status of KRAS/NRAS/BRAF and EGFR from the circulating tumor DNA within 10 weeks prior
             to starting study therapy

          -  Previous treatment with cetuximab with evidence of clinical benefit, as defined by
             complete response, partial response, or prolonged stable disease with 16 or more weeks
             of treatment without radiographic progression, as assessed by the treating physician
             and documented in the medical record; this treatment may have occurred at any point in
             the patient's clinical course for treatment of metastatic colorectal cancer

          -  Ultimate progression through previous treatment with cetuximab, with documented
             clinical progression; patients who discontinued cetuximab for any other reason, such
             as decline in performance status, hypersensitivity, or other adverse effects of
             therapy, are not eligible

          -  All prior treatment-related toxicities must be Common Terminology Criteria for Adverse
             Events (CTCAE) (version 4.0) =< grade 1 (except =< grade 2 for alopecia peripheral
             neuropathy)

          -  Radiographically measurable disease present per Response Evaluation Criteria in Solid
             Tumors (RECIST) 1.1

          -  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/mm^3

          -  Blood counts performed within 3 weeks prior to starting study therapy must have
             platelets >= 100,000/mm^3

          -  Blood counts performed within 3 weeks prior to starting study therapy must have
             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)

          -  Liver function tests performed within 3 weeks prior to starting study therapy must
             have alanine aminotransferase and aspartate aminotransferase =< 2.5 x ULN (or =< 5 x
             ULN if liver metastases are present)

          -  Liver function tests performed within 3 weeks prior to starting study therapy must
             have 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) of
             >= 50 mL/minute

          -  Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
             time (PTT) performed within 3 weeks prior to starting study therapy must be =< 1.5 x
             ULN

          -  Left ventricular ejection fraction (LVEF) >= lower limit of normal (LLN) by
             echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 3 weeks prior
             to starting study therapy

          -  Women of childbearing potential must have a negative serum pregnancy test within 14
             days prior to randomization and must agree to use effective contraception throughout
             the treatment period and for 4 months after the last dose of study treatment

          -  Ability to sign informed consent form; informed consent form for this study must be
             signed prior to the performance of any study-specific procedures and initiation of any
             study therapy

          -  Ability to swallow and retain oral medication, with no clinically significant
             gastrointestinal abnormalities that may alter absorption such as malabsorption
             syndrome or major resection of the stomach or bowels

          -  In cohort 1, must have EGFR S492R or other ectodomain mutation detected from
             circulating tumor DNA from plasma collected after progression to prior cetuximab; may
             have a concomitant mutation in KRAS, NRAS, or BRAF, if there is at least a 5-fold
             higher allele frequency of the most prevalent EGFR mutation than the most prevalent
             KRAS/NRAS/BRAF mutation

          -  In cohort 2, must have one or more mutations found in KRAS exon 2, 3, or 4; NRAS exon
             2, 3, or 4; BRAF codon 600; may have a concomitant EGFR ectodomain mutation, if the
             most prevalent EGFR ectodomain mutation does not have over a 5-fold higher allele
             frequency than the most prevalent KRAS/NRAS/BRAF mutation

          -  In cohort 3, must not have EGFR ectodomain mutation or any mutations in KRAS, NRAS, or
             BRAF

        Exclusion Criteria:

          -  Past treatment with any MEK or ERK inhibitor or with panitumumab

          -  Previous retreatment with cetuximab following progression on initial course of
             cetuximab therapy

          -  Known untreated brain metastasis or brain metastasis treated within 3 months prior to
             enrollment in this trial

          -  Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression

          -  History of interstitial lung disease or pneumonitis

          -  History of any other malignancy within 3 years, except for adequately treated
             carcinoma in situ of the cervix or non-melanoma skin cancer and/or subjects with
             indolent second malignancies are eligible

          -  Prior treatment within 21 days of the first dose of study drug with any other
             chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational
             treatment, 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

          -  Any major surgery, extensive radiotherapy, chemotherapy with 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

          -  Impaired cardiac function or clinically significant cardiac disease, as defined: a)
             left ventricular ejection fraction < lower limit of normal (LLN) on multiple gated
             acquisition scan (MUGA) or echocardiogram; b) congenital long QT syndrome or family
             history of unexpected sudden cardiac death; c) corrected QT (QTc) corrected with
             Bazett's formula (QTcB) >= 480 ms.; d) history or evidence of current clinically
             significant uncontrolled arrhythmias; note subjects with atrial fibrillation
             controlled for > 30 days prior to dosing are eligible; e) history of acute coronary
             syndromes (including myocardial infarction and unstable angina), coronary angioplasty,
             or stenting within 6 months prior to randomization; f) history or evidence of current
             >= class II congestive heart failure as defined by New York Heart Association (NYHA);
             g) treatment refractory hypertension defined as a blood pressure of systolic > 140
             mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive
             therapy; h) patients with intra-cardiac defibrillators

          -  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

          -  History of retinal vein occlusion (RVO)

          -  Pregnant or breastfeeding, or planning to become pregnant within 6 months after the
             end of treatment

          -  History of organ allograft or other history of immunodeficiency

          -  Inability or unwillingness to comply with study and/or follow-up requirements

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO)

          -  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

          -  Current use of a prohibited medication
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate
Time Frame:Up to 24 months
Safety Issue:
Description:Will be evaluated along with the exact 95% confidence interval.

Secondary Outcome Measures

Measure:Complete response
Time Frame:Up to 24 months
Safety Issue:
Description:The incidence rates will be estimated, along with the exact 95% confidence intervals.
Measure:Partial response
Time Frame:Up to 24 months
Safety Issue:
Description:The incidence rates will be estimated, along with the exact 95% confidence intervals.
Measure:Stable disease
Time Frame:Up to 24 months
Safety Issue:
Description:The incidence rates will be estimated, along with the exact 95% confidence intervals.
Measure:Progression-free survival
Time Frame:Up to 24 months
Safety Issue:
Description:The two-sided log-rank test will be used to assess the differences between groups.
Measure:Overall survival
Time Frame:Up to 24 months
Safety Issue:
Description:The two-sided log-rank test will be used to assess the differences between groups.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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