Clinical Trials /

Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal Cancer

NCT04017650

Description:

This phase I/II trial studies the best dose and side effects of encorafenib, cetuximab, and nivolumab and how well they work together in treating patients with microsatellite stable, BRAFV600E gene mutated colorectal cancer that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Encorafenib and cetuximab may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.Giving encorafenib, cetuximab, and nivolumab may work better in treating patients with colorectal cancer compared to cetuximab alone.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal Cancer
  • Official Title: Phase I/II Trial of Encorafenib, Cetuximab, and Nivolumab in Microsatellite Stable BRAFV600E Metastatic Colorectal Cancer (BMS-MDACC CA209-8P6/ARRAY IST-818-101X)

Clinical Trial IDs

  • ORG STUDY ID: 2018-0993
  • SECONDARY ID: NCI-2019-04169
  • SECONDARY ID: 2018-0993
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04017650

Conditions

  • BRAF NP_004324.2:p.V600E
  • Metastatic Colon Adenocarcinoma
  • Metastatic Microsatellite Stable Colorectal Carcinoma
  • Metastatic Rectal Adenocarcinoma
  • Progressive Disease
  • Recurrent Colorectal Carcinoma
  • Stage III Colorectal Cancer AJCC v8
  • Stage IIIA Colorectal Cancer AJCC v8
  • Stage IIIB Colorectal Cancer AJCC v8
  • Stage IIIC Colorectal Cancer AJCC v8
  • Stage IV Colorectal Cancer AJCC v8
  • Stage IVA Colorectal Cancer AJCC v8
  • Stage IVB Colorectal Cancer AJCC v8
  • Stage IVC Colorectal Cancer AJCC v8
  • Unresectable Colon Adenocarcinoma
  • Unresectable Rectal Adenocarcinoma

Interventions

DrugSynonymsArms
CetuximabCetuximab Biosimilar CDP-1, Cetuximab Biosimilar CMAB009, Cetuximab Biosimilar KL 140, Chimeric Anti-EGFR Monoclonal Antibody, Chimeric MoAb C225, Chimeric Monoclonal Antibody C225, Erbitux, IMC-C225Treatment (encorafenib, cetuximab, nivolumab)
EncorafenibBraftovi, LGX 818, LGX-818, LGX818Treatment (encorafenib, cetuximab, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (encorafenib, cetuximab, nivolumab)

Purpose

This phase I/II trial studies the best dose and side effects of encorafenib, cetuximab, and nivolumab and how well they work together in treating patients with microsatellite stable, BRAFV600E gene mutated colorectal cancer that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Encorafenib and cetuximab may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.Giving encorafenib, cetuximab, and nivolumab may work better in treating patients with colorectal cancer compared to cetuximab alone.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To describe overall response rate (ORR) upon treatment with encorafenib, cetuximab, and
      nivolumab.

      II. To determine the safety and tolerability of nivolumab, encorafenib, and cetuximab.

      SECONDARY OBJECTIVES:

      I. To estimate median progression-free survival (PFS) upon treatment with encorafenib,
      cetuximab, and nivolumab.

      II. To estimate median overall survival (OS) upon treatment with encorafenib, cetuximab, and
      nivolumab.

      III. To estimate median time to response (TTR) upon treatment with encorafenib, cetuximab,
      and nivolumab.

      IV. To estimate median duration of response (DOR) upon treatment with encorafenib, cetuximab,
      and nivolumab.

      V. To estimate disease control rate (DCR) upon treatment with encorafenib, cetuximab, and
      nivolumab.

      EXPLORATORY OBJECTIVES:

      I. To assess genomic and immune changes upon treatment with encorafenib, cetuximab, and
      nivolumab.

      II. To demonstrate feasibility of establishing humanized patient-derived xenograft models in
      matched patients with BRAFV600E metastatic colorectal cancer (mCRC).

      OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

      Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab
      intravenously (IV) over 1 hour on days 1 and 15, and nivolumab IV over 30 minutes on day 1.
      Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 and 100 days, at 3
      months, and then every 3 months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (encorafenib, cetuximab, nivolumab)ExperimentalPatients receive encorafenib PO QD on days 1-28, cetuximab IV over 1 hour on days 1 and 15, and nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Cetuximab
  • Encorafenib
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Provision of signed informed consent prior to any screening procedures being performed

          -  Histologically (or cytologically) confirmed diagnosis of adenocarcinoma of the colon
             or rectum, with clinical confirmation of unresectable and/or metastatic disease that
             is measurable according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
             criteria

          -  Confirmation of BRAFV600E tumor as detected by a Clinical Laboratory Improvement
             Amendments (CLIA)-certified laboratory

          -  Confirmation of microsatellite stable (MSS) status in a CLIA-certified laboratory

          -  Prior treatment with at least one, but no more than two, systemic chemotherapy
             regimen(s) for mCRC, or recurrence/progression with development of unresectable or
             metastatic disease within 6 months of adjuvant chemotherapy for resected colorectal
             cancer

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< to 1

          -  Absolute neutrophil count (ANC) >= 1.0 x 10^9/L

          -  Hemoglobin (Hgb) >= 9 g/dL with or without transfusions

          -  Platelets (PLT) >= 100 x 10^9/L without transfusions

          -  Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 2.5 x upper
             limit of normal (ULN)

          -  Total bilirubin =< to 1.5 x ULN and < 2 mg/dL

               -  Note: Patients who have a total bilirubin level > 1.5 x ULN will be allowed if
                  their indirect bilirubin level is =< 1.5 x ULN

          -  Serum creatinine =< 1.5 x ULN, or calculated creatinine clearance (determined as per
             Cockcroft-Gault) >= 50 mL/min at screening

          -  Corrected QT (QTc) interval =< 480 ms (preferably the mean) from triplicate
             electrocardiograms (ECGs)

          -  Able to take oral medications

          -  Female patients are either postmenopausal for at least 1 year, are surgically sterile
             for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy
             from screening through follow-up if of childbearing potential. Note: Permitted
             contraception methods should be communicated to the patients and their understanding
             confirmed. For all females, the pregnancy test result must be negative within 24 hours
             of starting treatment with nivolumab. Males to avoid fathering a child from screening
             through 100 days following the end of therapy

        Exclusion Criteria:

          -  Concurrent corticosteroid therapy or concurrent use of any other immunosuppressive
             medication (corticosteroid use on study as a pre-medication for IV contrast
             allergies/reactions is allowed). Subjects who are receiving daily steroid replacement
             therapy (the equivalent of prednisone =< 10 mg daily) serve as an exception to this
             rule

          -  Prior treatment with a BRAF inhibitor, MEK inhibitor, or ERK inhibitor (of note,
             regorafenib is not considered a BRAF inhibitor for the context of eligibility
             criteria)

          -  Prior treatment with anti-EGFR therapies

          -  Prior immune checkpoint therapy including, but not limited to, an anti-PD-1,
             anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated
             antigen-4 (CTLA-4) antibody, or any other prior immune-modulating agent administered
             with antineoplastic intent (monoclonal antibodies used against VEGF are permitted)

          -  Prior allogeneic tissue/solid organ transplant

          -  History of (non-infectious) pneumonitis that has required oral or IV steroids

          -  Receipt of a live vaccine within 30 days prior to the first administration of study
             medication. Seasonal flu vaccines that do not contain a live virus are permitted

          -  History of a grade 3 or 4 allergic reaction attributed to humanized or human
             monoclonal antibody therapy

          -  Active infection requiring concurrent antibiotic use

          -  Any symptomatic brain metastasis. Note: Patients previously treated or untreated for
             this condition who are asymptomatic in the absence of corticosteroid and
             anti-epileptic therapy are allowed. Brain metastases must be stable for > or equal to
             4 weeks, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography
             [CT]) demonstrating no current evidence of progressive brain metastases at screening

          -  Leptomeningeal disease

          -  Previous or concurrent malignancy within 3 years of study entry, with the following
             exceptions: adequately treated basal or squamous cell skin cancer, superficial bladder
             cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other
             noninvasive or indolent malignancy; other solid tumors treated curatively without
             evidence of recurrence for at least 3 years prior to study entry

          -  History of acute coronary syndromes (including myocardial infarction, unstable angina,
             coronary artery bypass grafting, coronary angioplasty, or stenting) < 6 months prior
             to screening, symptomatic chronic heart failure (i.e. grade 2 or higher), history or
             current evidence of clinically significant cardiac arrhythmia and/or conduction
             abnormality < 6 months prior to screening except atrial fibrillation and paroxysmal
             supraventricular tachycardia

          -  Uncontrolled hypertension defined as persistent elevation of systolic blood pressure
             >= 170 mmHg or diastolic blood pressure >= 100 mm Hg, despite current therapy

          -  Known positive serology for HIV (human immunodeficiency virus), active hepatitis B,
             and/or active hepatitis C infection

          -  Known history of acute or chronic pancreatitis (history of acute pancreatitis with no
             recurrent events in the prior 24 months are permitted)

          -  Patients with a history of inflammatory bowel disease, including ulcerative colitis
             and Crohn's disease, are excluded from this study, as are patients with a history of
             symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive
             sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g.,
             Wegener's granulomatosis]); central nervous system (CNS) or motor neuropathy
             considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis,
             multiple sclerosis). Patients with Graves' disease will be allowed

          -  Impaired gastrointestinal function or disease that may significantly alter the
             absorption of study drug (e.g., ulcerative diseases, uncontrolled vomiting,
             malabsorption syndrome, small bowel resection with decreased intestinal absorption)

          -  Any other condition that would, in the investigator's judgment, contraindicate the
             patient's participation in the clinical study due to safety concerns or compliance
             with clinical study procedures

          -  Major surgery =< 6 weeks prior to starting study drug or failure to recover from side
             effects of such procedure at the discretion of the treating investigator

          -  Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
             female after conception and until the termination of gestation, confirmed by a
             positive human chorionic gonadotropin (hCG) laboratory test

          -  Medical, psychiatric, cognitive or other conditions, according to investigator
             judgment, that may compromise the patient's ability to understand the patient
             information, give informed consent, comply with the study protocol or complete the
             study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best radiographic response
Time Frame:Within 6 months of initiation of study treatment
Safety Issue:
Description:Radiographic response will be defined as a complete response or partial response according to immune-related response criteria (Immune-Modified Response Evaluation Criteria in Solid Tumors) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame:Up to 5 years
Safety Issue:
Description:Will be defined according to RECIST 1.1 criteria.
Measure:Overall survival
Time Frame:Up to 5 years
Safety Issue:
Description:Will be defined according to RECIST 1.1 criteria.
Measure:Time to response
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Duration of response
Time Frame:Up to 5 years
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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