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

Melanoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02027961
• Other study ID #: CD-ON-MEDI4736-1161
• Status: Completed
• Phase: Phase 1
• Start date: December 20, 2013
• Est. completion date: April 24, 2018

Study information

• Verified date: May 2019
• Source: MedImmune LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 68
• Est. completion date: April 24, 2018
• Est. primary completion date: April 24, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Melanoma

Intervention

Biological:
• Durvalumab
Intravenous dose of 3 or 10 mg/kg durvalumab.

Drug:
• Dabrafenib
Oral dose of 150 mg dabrafenib capsule.
• Trametinib
Oral dose of 2 mg trametinib tablet.

Locations

Country	Name	City	State
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Toronto	Ontario
France	Research Site	Villejuif
Italy	Research Site	Napoli
United States	Research Site	Boston	Massachusetts
United States	Research Site	Chicago	Illinois
United States	Research Site	Los Angeles	California
United States	Research Site	Miami Beach	Florida
United States	Research Site	Saint Louis	Missouri
United States	Research Site	San Francisco	California
United States	Research Site	Scottsdale	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
MedImmune LLC

Countries where clinical trial is conducted

United States,  Canada,  France,  Italy, 

References & Publications (2)

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).

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).

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	From first dose of study drug (Day 1) until the planned 3rd dose of durvalumab (Day 29)
Primary	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.	From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)
Primary	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.	From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)
Primary	Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs	Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported.	From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)
Primary	Number of Participants With Abnormal Electrocardiograms (ECGs) and Echocardiograms (ECHOs) Reported as TEAEs	Number of participants with abnormal electrocardiograms (ECGs) and echocardiograms (ECHOs) reported as TEAEs are reported.	From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)
Secondary	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.	From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
Secondary	Duration of Response (DOR)	Duration of response: Duration from first documentation of OR to first documented PD or death due to any cause, whichever occurs first. CR: 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. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of >= 5 mm, taking as reference smallest sum of diameters since treatment started including baseline sum of diameters.	From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
Secondary	Progression-free Survival (PFS)	Progression-free Survival is defined as duration from the start of treatment with study drug until the first documented PD or death, whichever comes first. PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of >= 5 mm, taking as reference smallest sum of diameters since treatment started including baseline sum of diameters. For participants who are alive and progression-free at the time of data cut-off for analysis, PFS was to be censored at the last tumor assessment date.	From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
Secondary	Overall Survival	Overall survival (OS) is measured from the start of treatment until death. For participants who are alive at the end of study or lost to follow-up, OS was censored on the last date when participants are known to be alive.	From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
Secondary	Percentage of Participants With Disease Control	Disease control is defined as confirmed CR or PR, or stable disease (SD) that was maintained for >= 12 weeks based on 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. CR: 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. A SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of diameters while on study.	From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
Secondary	Maximum Observed Plasma Concentration after First Dose (Cmax, 1st) of Durvalumab	Maximum observed plasma concentration of durvalumab after first dose is reported.	Cohorts A and B: End of infusion on Day 1; Cohort C: End of infusion on Day 29
Secondary	Maximum Observed Plasma Concentration at Steady State (Cmax, ss) of Durvalumab	Maximum observed plasma concentration of durvalumab at steady state is reported.	Cohorts A and B: end of infusion on Day 141; Cohort C: end of infusion on Day 169
Secondary	Trough Concentration at Steady State (Ctrough) of Durvalumab	Trough concentration of durvalumab pre-dose at steady state is reported.	Cohorts A and B: Pre-dose on Day 141; Cohort C: Pre-dose on Day 169
Secondary	Number of Participants With Postive Anti-Drug Antibodies (ADA) Titer to Durvalumab	The number of participants with positive serum antibodies to durvalumab post dosing are reported.	Cohorts A and B: Days 1 and 29; Cohort C: Days 29 and 57