Nivolumab With Trametinib and Dabrafenib, or Encorafenib and Binimetinib in Treating Patients With BRAF Mutated Metastatic or Unresectable Stage III-IV Melanoma

NCT02910700 | Active Not Recruiting Phase 2 FDA Drug

• 2 other identifiers: 2015-0605NCI-2016-01940
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial studies the side effects and how well nivolumab with trametinib and dabrafenib, or encorafenib and binimetinib work in treating patients with BRAF-mutated stage III-IV melanoma that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as nivolumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Trametinib, dabrafenib, encorafenib, and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known if nivolumab with trametinib and dabrafenib, or encorafenib and binimetinib may work better in treating patients with BRAF-mutated melanoma.

Conditions

Metastatic Malignant Neoplasm in the Brain; Metastatic Melanoma; Stage III Cutaneous Melanoma AJCC v7; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Unresectable Melanoma

Outcome Measures

Primary Outcomes (1)

• Objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors version 1.1 on both arms

  The ORR for each treatment group will be computed along 95% credible intervals.

  From the time of initial response until documented tumor progression, assessed up to 3 years

Secondary Outcomes (6)

• Incidence of adverse events assessed using National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.0

  Up to 3 years

• Complete response

  Up to 3 years

• Partial response

  Up to 3 years

• Incidence of stable disease

  From the start of the treatment until the criteria for progression are met, assessed up to 3 years

• Overall survival (OS)

  From treatment start date to last known vital sign, assessed up to 3 years

Other Outcomes (1)

• Circulating and tumor markers

  Baseline up to 3 years

Study Arms (3)

Arm A (NDT, CLOSED)

EXPERIMENTAL

Patients receive nivolumab IV over 30 minutes on day 1, dabrafenib PO BID on days 1-28, and trametinib PO QD on days 1-28. Cycles repeats every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity.

Drug: Dabrafenib; Other: Laboratory Biomarker Analysis; Biological: Nivolumab; Other: Pharmacological Study; Drug: Trametinib

Arm B (NT, closed to accrual)

EXPERIMENTAL

Patients receive nivolumab IV over 30 minutes on day 1 and 15, and trametinib PO QD on days 1-28. Cycles repeats every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity.

Other: Laboratory Biomarker Analysis; Biological: Nivolumab; Other: Pharmacological Study; Drug: Trametinib

Arm C (NEB)

EXPERIMENTAL

Patients receive nivolumab IV over 30 minutes on day 1 and 15, encorafenib PO QD on days 1-28, and binimetinib PO BID on days 1-28. Cycles repeats every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity.

Drug: Binimetinib; Drug: Encorafenib; Other: Laboratory Biomarker Analysis; Biological: Nivolumab; Other: Pharmacological Study

Interventions

Binimetinib DRUG

Given PO

Arm C (NEB)

Dabrafenib DRUG

Given PO

Arm A (NDT, CLOSED)

Encorafenib DRUG

Given PO

Arm C (NEB)

Laboratory Biomarker Analysis OTHER

Correlative studies

Arm A (NDT, CLOSED); Arm B (NT, closed to accrual); Arm C (NEB)

Nivolumab BIOLOGICAL

Given IV

Arm A (NDT, CLOSED); Arm B (NT, closed to accrual); Arm C (NEB)

Pharmacological Study OTHER

Correlative studies

Arm A (NDT, CLOSED); Arm B (NT, closed to accrual); Arm C (NEB)

Trametinib DRUG

Given PO

Arm A (NDT, CLOSED); Arm B (NT, closed to accrual)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed metastatic melanoma (stage IV) or unresectable Stage III that have progressed on or after receiving prior PD-1 directed therapy; only patients with BRAF V600 mutated melanoma are eligible; please note that patients with brain metastasis are not required to have prior PD-1
• Prior therapies for metastatic melanoma are allowed, including chemo-, cytokine-, immuno, biological and vaccine-therapy as long as they did not include BRAFi, MEKi; patients who have progressed on or after receiving anti-PD-1therapy in the adjuvant setting are also allowed; prior ipilimumab and/or PD-1 directed therapy will be allowed with a washout period of 2 weeks and if all autoimmune adverse events have resolved to grade 1 (except endocrine abnormalities that require continuous replacement)
• Evidence of evaluable disease
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Patients with melanoma brain metastases are allowed regardless of prior PD-1 exposure. Subjects with brain metastases are eligible if:
• Metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 2 weeks after treatment is complete and within 14 days of the first dose of nivolumab administration; or
• If they are untreated but asymptomatic; or
• If they are untreated and symptomatic but symptoms are controlled on stable or decreasing doses of steroids for 14 days prior to drug administration; or
• If they have untreated leptomeningeal disease (LMD) as long as they fulfill all other eligibility requirements.
• Note: Patients are excluded if they require high doses of systemic corticosteroids (\> 8 mg equivalent of dexamethasone) to control central nervous system (CNS) symptoms.
• White blood cells (WBC) \>= 2000 /uL (within one week prior to registration)
• Neutrophils \>= 1500 /uL (within one week prior to registration)
• Platelets \>= 100 x 10\^3 /uL (within one week prior to registration)
• Hemoglobin \> 9.0 g/dL (within one week prior to registration)
• Serum creatinine =\< 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) \>= 40 mL/min (if using the Cockcroft-Gault formula) (within one week prior to registration)

You may not qualify if:

• Patients that had grade 3/4 immune-related adverse events (AEs) on ipilimumab or nivolumab that required more than 12 weeks of immune suppression with corticosteroids
• History of interstitial lung disease or pneumonitis
• History of known glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Active, known or suspected autoimmune disease; subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism and/or hypophysitis due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
• Require systemic treatment with either corticosteroids (\> 8 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses are permitted in the absence of active autoimmune disease
• Known history of a positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS); HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with dabrafenib and trametinib; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
• History of allergy or adverse drug reaction to the study drug components (nivolumab, dabrafenib, or trametinib) or drugs of similar chemical or biologic composition; patients with a history of severe hypersensitivity reaction to any monoclonal antibody should also be excluded
• Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Uncontrolled intercurrent illness (requiring IV antibiotic treatment) including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant and/or breastfeeding women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab, dabrafenib, and trametinib, breastfeeding should be discontinued if the mother is treated with nivolumab, dabrafenib, and trametinib; these potential risks may also apply to other agents used in this study

Sponsors & Collaborators

• National Cancer Institute (NCI): collaborator
• M.D. Anderson Cancer Center: lead

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• MD Anderson Cancer Center Website

MeSH Terms

Conditions

Brain Neoplasms; Melanoma

Interventions

binimetinib; dabrafenib; encorafenib; Nivolumab; trametinib

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Hussein A Tawbi

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 20, 2016
• First Posted: September 22, 2016
• Study Start: December 9, 2016
• Primary Completion (Estimated): December 8, 2027
• Study Completion (Estimated): December 8, 2027
• Last Updated: December 17, 2025

Record last verified: 2025-12

Locations

US (1)