Abbreviated MAPK Targeted Therapy Plus Pembrolizumab in Melanoma

NCT03149029 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 1 other identifier: 16-642
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 3

Brief Summary

This research study is studying a combination of drugs as a possible treatment for unresectable or metastatic melanoma. The drugs involved in this study are:

• Pembrolizumab (Keytruda)
• Trametinib (Mekinist)
• Dabrafenib (Tafinlar)

Conditions

Metastatic Melanoma

Keywords

Metastatic Melanoma

Outcome Measures

Primary Outcomes (1)

• The Rate of Clinical Benefit

  The rate of clinical benefit is defined as the percentage of patients with stable disease, partial response, or complete response 6 months after the start of treatment per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) while remaining off MAPK-targeted therapy after induction. Response to treatment was assessed using radiographic imaging. A partial response (PR) is defined as a decrease in the sum of the longest diameters (SLD) of target lesions greater than or equal to 30%, no new lesions, and no progression of non-target lesions. A complete response (CR) is defined as the disappearance of all lesions and pathologic lymph nodes. Stable disease is defined as no PR, CR, or progressive disease (PD). PD is defined as an increase in the SLD of target lesions greater than or equal to 20% in comparison with the smallest SLD on study, progression of non-target lesions, or the appearance of new lesions.

  6 months

Secondary Outcomes (2)

• Overall Survival at 1 Year

  1 year

• Progression Free Survival (PFS)

  Up to 62 months

Study Arms (2)

BRAFV600 mutant

EXPERIMENTAL

* Pembrolizumab administered intravenously every three weeks * Dabrafenib taken every twelve hours orally * Trametinib taken every twelve hours orally

Drug: Pembrolizumab; Drug: Dabrafenib; Drug: Trametinib

BRAFV600 wild type

EXPERIMENTAL

* Pembrolizumab administered intravenously every three weeks * Trametinib taken every twelve hours orally

Drug: Pembrolizumab; Drug: Trametinib

Interventions

Dabrafenib DRUG

Dabrafenib is also a cell inhibitor and works by stopping the cancer cell from duplicating

Also known as: Tafinlar

BRAFV600 mutant

Trametinib DRUG

Trametinib is a cell inhibitor that binds to the cancer cells to inhibit the cancer cells' signals to decrease cell growth

Also known as: Mekinist

BRAFV600 mutant; BRAFV600 wild type

Pembrolizumab DRUG

Pembrolizumab is a type of antibody that inhibits the cancer cell growth

Also known as: Keytruda

BRAFV600 mutant; BRAFV600 wild type

Eligibility Criteria

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

You may qualify if:

• Participants must have histologically confirmed metastatic or unresectable melanoma.
• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥10 mm with spiral CT scan. See section 11 for the evaluation of measureable disease.
• Participants may have previously received ipilimumab, adjuvant anti-PD1 therapy, or high-dose IL-2. They may not have previously been treated with BRAF inhibitors (vemurafenib, dabrafenib, encorafenib), MEK inhibitors (selumetinib, trametinib, binimetinib, cobimetinib), and/or anti-PD1/PDL1 monoclonal antibodies for metastatic or unresectable disease. Participants must allow 2 weeks between prior chemotherapy targeted small molecule therapy, or radiation therapy prior to study Day 1 or recovery (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
• Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of the combination of trametinib with or without dabrafenib, and pembrolizumab in participants less than 18 years of age, children are excluded from this study.
• ECOG performance status ≤1.
• Life expectancy of greater than three months.
• Participants must have normal organ and marrow function as defined below:
• Leukocytes ≥ 3,000/mcL
• Absolute neutrophil count ≥ 1,500/mcL
• Platelets ≥ 100,000/mcL
• total bilirubin ≤ 1.5 X institutional upper limits of normal; total bilirubin \> 1.5X above institutional upper limits of normal will be allowed if direct bilirubin is within normal limits or if patients has a documented history of Gilbert's disease
• AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal
• Creatinine within normal institutional limits or creatinine clearance ≥ 60 mL/min/1.73 m2 for subjects with creatinine levels about institutional normal.

You may not qualify if:

• Participants treated with prior chemotherapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
• Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Participants previously treated with BRAF inhibitors (vemurafenib, dabrafenib, encorafenib), MEK inhibitors (selumetinib, trametinib, binimetinib, cobimetinib), and/or anti-PD1/PDL1 monoclonal antibodies for metastatic or unresectable disease. Any other prior therapy will be allowed (including ipilimumab, adjuvant anti-PD1 therapy, high-dose IL-2).
• Participants with symptomatic brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Subjects with asymptomatic, stable brain metastases and/or who have been previously treated for these conditions that are asymptomatic in the absence of corticosteroid therapy are allowed to enroll. Brain metastasis must be stable with verification by imaging (brain MRI completed at screening demonstrating no current evidence of progressive brain metastases.
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Patients may not be receiving any other anti-neoplastic agents.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Pregnant women are excluded from this study because both dabrafenib and trametinib are class D agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with either dabrafenib and trametinib, breastfeeding should be discontinued if the mother is treated with either dabrafenib, trametinib, or the combination of dabrafenib and trametinib.
• Participants known to be HIV-positive and on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with either dabrafenib or trametinib. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
• Participants who have had major surgery \< 2 weeks prior to entering the study.
• Has a known history of active TB (Bacillus Tuberculosis)
• Hypersensitivity to pembrolizumab or any of its excipients.
• No symptomatic or untreated leptomeningeal disease.
• Participants are not permitted to receive enzyme inducing anti-epileptic drugs.

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (3)

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02115, United States

Location

Massachusetts general Hospital

Boston, Massachusetts, 02115, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

MeSH Terms

Conditions

Melanoma

Interventions

pembrolizumab; dabrafenib; trametinib

Condition Hierarchy (Ancestors)

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

Limitations and Caveats

Only 5/14 BRAFV600 mutant patients had clinical benefit and the threshold for opening the BRAFV600 wild type cohort was 9/14 patients. Therefore, no BRAFV600 wild type patients were enrolled.

Results Point of Contact

• Title: Ryan J. Sullivan, MD
• Organization: Massachusetts General Hospital Cancer Center

RSULLIVAN7@mgh.harvard.edu

617-643-3614

Study Officials

• Ryan J Sullivan, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: May 8, 2017
• First Posted: May 11, 2017
• Study Start: November 27, 2017
• Primary Completion: December 31, 2021
• Study Completion (Estimated): December 31, 2026
• Last Updated: April 21, 2026
• Results First Posted: September 8, 2023

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)