Phase 1 Safety and Tolerability of MEDI4736 in Combination With Dabrafenib and Trametinib or With Trametinib Alone

Phase 1CompletedNCT02027961

MedImmune LLC68 enrolled

Overview

The purpose of this study is to determine the maximum tolerated dose and characterize the safety profile of durvalumab (MEDI4736) in combination with dabrafenib and trametinib or with trametinib alone in participants with metastatic or unresectable melanoma with BRAF-mutation positive or wild-type (WT) BRAF, respectively.

This is a multicenter, open-label study with a dose escalation phase followed by an expansion phase of durvalumab administered in combination with dabrafenib and trametinib or with trametinib alone in participants with BRAF V600 mutation-positive and WT unresectable or metastatic melanoma, respectively.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Melanoma

Interventions

DurvalumabBIOLOGICAL

Intravenous dose of 3 or 10 mg/kg durvalumab.

DabrafenibDRUG

Oral dose of 150 mg dabrafenib capsule.

TrametinibDRUG

Oral dose of 2 mg trametinib tablet.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Adults \>= 18 years old * Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic) and determined to be BRAF V600E or V600K mutation-positive (cohort A) or mutation-negative (cohorts B and C) * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Measurable disease by radiographic or physical examination * Adequate organ and marrow function * Willingness to provide consent for biopsies positive or BRAF WT measurable disease and adequate organ and marrow function Exclusion Criteria: * Prior treatment with a BRAF inhibitor or MEK inhibitor * Any prior Grade \>= 3 immune-related adverse event while receiving immunotherapy * Active or prior documented autoimmune disease within the past 2 years * History of or current risk for retinal vein occlusion (RVO) or central serous retinopathy (CSR) * History of or current cardiovascular risk including myocardial infarction, \>= Class II congestive heart failure, uncontrolled arrhythmias, or refractory hypertension * Active, untreated central nervous system (CNS) metastases * Women who are pregnant or lactating

Locations (11)

Research Site

Scottsdale, Arizona, United States

Research Site

Los Angeles, California, United States

Research Site

San Francisco, California, United States

Research Site

Outcomes

Primary Outcomes

Number of Participants With Dose Limiting Toxicities (DLTs)

Dose limiting toxicities are defined as any Grade 3 or higher treatment-related (related to any study drug) toxicity that occurs during the DLT evaluation period. Number of participants with DLTs are reported.

Time frame: From first dose of study drug (Day 1) until the planned 3rd dose of durvalumab (Day 29)

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event is any AE that resulted in death, life threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, is a congenital anomaly/birth defect in offspring of a study participant, is an important medical event that may jeopardize the participant or may require medical intervention. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.

Time frame: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAEs

Number of participants with abnormal vital signs and physical examinations reported as TEAEs are reported.

Time frame: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs

Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported.

Time frame: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

Number of Participants With Abnormal Electrocardiograms (ECGs) and Echocardiograms (ECHOs) Reported as TEAEs

Data from ClinicalTrials.gov

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Secondary Outcomes

Percentage of Participants With Objective Response (OR)

Objective Response is defined as confirmed complete response (CR) or confirmed partial response (PR) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). A confirmed CR is defined as two CRs that were separated by at least 28 days. A confirmed PR is defined as two PRs or an un-confirmed PR and an un-confirmed CR that were separated by at least 28 days. A CR is defined as disappearance of all target and non-target lesions, normalization of tumor marker level and any pathological lymph nodes selected as target lesions must have a reduction in short axis to less than 10 mm. A PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.