Clinical trial NCT02027961: Phase 1 Safety and Tolerability of MEDI4736 in Combination With Dabrafenib and Trametinib or With Trametinib Alone
Official title: A Phase 1 Open-label Study of Safety and Tolerability of MEDI4736 in Subjects With Metastatic or Unresectable Melanoma in Combination With Dabrafenib and Trametinib or With Trametinib Alone
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Melanoma
Keywords: Metastatic or Unresectable Melanoma, durvalumab (MEDI4736), dafrafenib, trametinib, BRAF-mutation positive, wild-type BRAF, PD-L1, PD-1
Lead sponsor: MedImmune LLC
Sponsor class: INDUSTRY
First posted: 2014-01-06
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: From first dose of study drug (Day 1) until the planned 3rd dose of durvalumab (Day 29)
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)
measure: Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAEs
timeFrame: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)
measure: Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs
timeFrame: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)
measure: Number of Participants With Abnormal Electrocardiograms (ECGs) and Echocardiograms (ECHOs) Reported as TEAEs
timeFrame: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)
Secondary outcomes:
measure: Percentage of Participants With Objective Response (OR)
timeFrame: From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
measure: Duration of Response (DOR)
timeFrame: From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
measure: Progression-free Survival (PFS)
timeFrame: From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
measure: Overall Survival
timeFrame: From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
measure: Percentage of Participants With Disease Control
timeFrame: From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
measure: Maximum Observed Plasma Concentration after First Dose (Cmax, 1st) of Durvalumab
timeFrame: Cohorts A and B: End of infusion on Day 1; Cohort C: End of infusion on Day 29
measure: Maximum Observed Plasma Concentration at Steady State (Cmax, ss) of Durvalumab
timeFrame: Cohorts A and B: end of infusion on Day 141; Cohort C: end of infusion on Day 169
measure: Trough Concentration at Steady State (Ctrough) of Durvalumab
timeFrame: Cohorts A and B: Pre-dose on Day 141; Cohort C: Pre-dose on Day 169
measure: Number of Participants With Postive Anti-Drug Antibodies (ADA) Titer to Durvalumab
timeFrame: Cohorts A and B: Days 1 and 29; Cohort C: Days 29 and 57
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Research Site
state: Arizona
city: Los Angeles
country: United States
facility: Research Site
state: California
city: San Francisco
country: United States
facility: Research Site
state: California
city: Miami Beach
country: United States
facility: Research Site
state: Florida
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Villejuif
country: France
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
Study officials:
affiliation: MedImmune LLC
name: MedImmune LLC
role: STUDY_DIRECTOR
References:
citation: Gordon MS, Lutzky J, Lawrence D, Butler M, Ascierto PA, Hug B, et al. Phase 1 study evaluating safety and tolerability of MEDI4736, an anti-programmed cell death ligand-1 (PD-L1) antibody, in combination with dabrafenib and trametinib or trametinib alone in patients with unresectable or metastatic melanoma. Ann Oncol 2014; 25(suppl_4): iv374-iv393 (abstract 8004).
citation: Ribas A, Butler M, Lutzky J, Lawrence DP, Robert C, Miller W, et al. Phase 1 study combining anti-PD-L1 (MEDI4736) and BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J Clin Oncol 2015; 33 (15_suppl): (abstract 3003).
citation: Ribas A, Algazi A, Ascierto PA, Butler MO, Chandra S, Gordon M, Hernandez-Aya L, Lawrence D, Lutzky J, Miller WH Jr, Campbell KM, Delafont B, Marshall S, Mueller N, Robert C. PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma. Nat Commun. 2020 Dec 7;11(1):6262. doi: 10.1038/s41467-020-19810-w.