Adaptive BRAF-MEK Inhibitor Therapy for Advanced BRAF Mutant Melanoma

Pilot Study of Adaptive BRAF-MEK Inhibitor Therapy for Advanced BRAF Mutant Melanoma

This pilot early phase I trial studies how well encorafenib, binimetinib, and nivolumab work in treating patients with BRAF mutant stage IIIC-IV melanoma. Encorafenib and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with nivolumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving encorafenib, binimetinib, and nivolumab may kill more tumor cells.

Study Overview

• Status: Recruiting
• Conditions: Skin Cancer; Melanoma (Skin); Skin Carcinoma; Skin Melanoma
• Intervention / Treatment: Drug: Encorafenib; Drug: Binimetinib; Drug: Nivolumab

Detailed Description

Vemurafenib and cobimetinib are already U.S. Food and Drug Administration (FDA)-approved for the treatment of BRAF-mutant metastatic melanoma; however, melanoma often develops resistance to these drugs over time, and the tumors start to re-grow. Investigators will use the participant's LDH (lactate dehydrogenase) levels obtained from routine blood work, along with CT scans to decide when to hold or resume their study treatment. Investigators hypothesize that this type of dosing schedule with vemurafenib and cobimetinib may potentially delay the time to progression and re-growth of their melanoma.

• Study Type: Interventional
• Enrollment (Estimated): 13
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • Recruiting
      • H. Lee Moffitt Cancer Center and Research Institute
      • Contact: Malik Hall; Phone Number: 813-745-5170; Email: Malik.Hall@moffitt.org
      • Principal Investigator: Zeynep Eroglu, M.D.

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients must be 18 years of age or above
• Subjects must have cytologically or histologically-confirmed unresectable melanoma that harbors a BRAF V600E mutation determined by pyrosequencing assay or equivalent genotyping assay in a Clinical Laboratory Improvement Act (CLIA) certified laboratory, meeting one of the following American Joint Committee on Cancer (AJCC) (8th edition) staging criteria:
• AJCC stage IV
• AJCC stage IIIC or IIID with unresectable nodal/locoregional involvement
• Subjects must have baseline plasma ctDNA >= 0.5 copy/ul at time of study enrollment
• Hemoglobin >= 8.0 g/dL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 75,000/mcL
• Total bilirubin =< 2 institutional upper limit of normal (ULN), unless suspected Gilbert's syndrome
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN (in participants with liver metastases =< 5 x ULN)
• Creatinine =< 2.0 institutional ULN
• Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
• Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women. Women of non-childbearing potential may be included without serum pregnancy test if they are either surgically sterile or have been postmenopausal for >= 1 year
• Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician. (NOTE: Patients must agree to not use hormonal contraceptives, as encorafenib can result in decreased concentration and loss of efficacy.)
• Patients on non-biologic disease modifying agents (e.g. methotrexate) or patients on corticosteroids =< 10 mg prednisone daily or equivalent are permitted to enroll
• Patients must not have had grade 3 or 4 immune-related adverse events on nivolumab that required more than 12 weeks of immune suppression with corticosteroids
• No anti-PD-1/PD-L1 or BRAF/MEK inhibitor therapy in the metastatic setting is allowed; these treatments are allowed if given in neoaduvant or adjuvant setting > 24 weeks ago. Prior radiation therapy is permitted. All adverse events associated with prior systemic therapy or radiation therapy must have resolved to =< grade 1 prior to start of study
• Subjects must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

Exclusion Criteria:

• Female subjects who are pregnant, intend to become pregnant or are nursing
• Patients previously treated with BRAF/MEK inhibitor or anti-PD-1/PD-L1 therapy in the metastatic setting
• Uncontrolled intercurrent illness including, but not limited to, serious infection. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2B or better
• Patients with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 90 days prior to randomization
• Patients with untreated or uncontrolled brain metastases. Patients with asymptomatic brain metastases which have been previously treated (with locoregional treatment such as radiation or surgery) and are clinically stable (i.e. not requiring corticosteroids) at the time of study start will be eligible
• Previous malignancy is not an exclusion provided that the other malignancy is considered under control, patient is not on concomitant anti-cancer drug therapy, and target lesions from melanoma are clearly defined for response assessment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: BRAF-MEK Inhibitor Therapy; Participants will receive 450 mg Encorafenib daily, along with 45 mg Binimetinib twice daily and 240 mg Nivolumab IV every 2 weeks.	Drug: Encorafenib; 450 mg encorafenib daily by mouth; Other Names: BRAFTOVI; BRAF/MEK-inhibitor; Drug: Binimetinib; 45 mg binimetinib daily by mouth; Other Names: MEKTOVI; BRAF/MEK-inhibitor; Drug: Nivolumab; 240 mg Nivolumab IV every 2 weeks; Other Names: Opdivo
Active Comparator: Arm B; Participants will receive 240 mg Nivolumab IV every 2 weeks	Drug: Nivolumab; 240 mg Nivolumab IV every 2 weeks; Other Names: Opdivo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
8 Week Completion Rate	Number of participants who reach 8 weeks with the prescribed on/off schedule without progression of disease. Progression as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.	At the end of the first 8 week treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Treatment Failure	Time to treatment failure, defined as the time from the day of first dose of study drugs to the first day of treatment with another regimen or with the same regimen in a non-adaptive fashion.	Up to 5 years
Objective Tumor Response Rate	Number of participants with tumor response. Response according to RECIST 1.1.	Up to 5 years

Collaborators and Investigators

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Investigators: Principal Investigator: Zeynep Eroglu, M.D., H. Lee Moffitt Cancer Center and Research Institute

Publications and helpful links

Helpful Links

• Moffitt Cancer Center Clinical Trials website

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2018
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

• First Submitted: May 21, 2018
• First Submitted That Met QC Criteria: May 21, 2018
• First Posted (Actual): June 1, 2018

Study Record Updates

• Last Update Posted (Actual): March 22, 2024
• Last Update Submitted That Met QC Criteria: March 21, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: MCC-19441

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No