Back to resultsPhase 1 Safety and Tolerability of MEDI4736 in Combination With Dabrafenib and Trametinib or With Trametinib Alone
Primary Purpose
Melanoma
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Durvalumab
Dabrafenib
Trametinib
Sponsored by
About this trial
This is an interventional treatment trial for Melanoma focused on measuring Metastatic or Unresectable Melanoma, durvalumab (MEDI4736), dafrafenib, trametinib, BRAF-mutation positive, wild-type BRAF, PD-L1, PD-1
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
Sites / Locations
- Research Site
- Research Site
- Research Site
- Research Site
- Research Site
- Research Site
- Research Site
- Research Site
- Research Site
- Research Site
- Research Site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Experimental
Arm Label
Cohort A1: Durvalumab (3 mg/kg) + Dabrafenib +Trametinib
Cohort A2: Durvalumab (10 mg/kg) + Dabrafenib +Trametinib
Cohort B: Durvalumab (10 mg/kg) +Trametinib (Concurrent)
Cohort C: Durvalumab (10 mg/kg) +Trametinib (Sequential)
Arm Description
Participants will receive intravenous (IV) dose of 3 milligrams per kilogram (mg/kg) durvalumab every 2 weeks (Q2W) from Day 1 up to 12 months along with oral 150 mg dabrafenib capsule twice daily (BID) and oral 2 mg trametinib tablet once daily (QD) until confirmed disease progression (PD), initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 3 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib.
Participants will receive IV dose of 10 mg/kg durvalumab Q2W from Day 1 up to 12 months along with oral doses of dabrafenib 150 mg capsule BID and trametinib 2 mg tablet QD until confirmed PD, initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib.
Participants will receive concurrent doses of IV 10 mg/kg durvalumab Q2W from Day 1 up to 12 months along with oral dose of trametinib 2 mg tablet QD until confirmed PD, initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months and continued the treatment of trametinib.
Participants will receive sequential doses of oral trametinib tablet 2 mg QD from Day 1 to Day 42 and IV durvalumab 10 mg/kg Q2W starting from Day 29 (Week 5) up to 12 months. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months.
Outcomes
Primary Outcome Measures
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.
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.
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.
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs
Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported.
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
Maximum Observed Plasma Concentration after First Dose (Cmax, 1st) of Durvalumab
Maximum observed plasma concentration of durvalumab after first dose is reported.
Maximum Observed Plasma Concentration at Steady State (Cmax, ss) of Durvalumab
Maximum observed plasma concentration of durvalumab at steady state is reported.
Trough Concentration at Steady State (Ctrough) of Durvalumab
Trough concentration of durvalumab pre-dose at steady state is reported.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02027961
Brief Title
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
2. Study Status
Record Verification Date
May 2019
Overall Recruitment Status
Completed
Study Start Date
December 20, 2013 (Actual)
Primary Completion Date
April 24, 2018 (Actual)
Study Completion Date
April 24, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
MedImmune LLC
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Melanoma
Keywords
Metastatic or Unresectable Melanoma, durvalumab (MEDI4736), dafrafenib, trametinib, BRAF-mutation positive, wild-type BRAF, PD-L1, PD-1
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
68 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort A1: Durvalumab (3 mg/kg) + Dabrafenib +Trametinib
Arm Type
Experimental
Arm Description
Participants will receive intravenous (IV) dose of 3 milligrams per kilogram (mg/kg) durvalumab every 2 weeks (Q2W) from Day 1 up to 12 months along with oral 150 mg dabrafenib capsule twice daily (BID) and oral 2 mg trametinib tablet once daily (QD) until confirmed disease progression (PD), initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 3 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib.
Arm Title
Cohort A2: Durvalumab (10 mg/kg) + Dabrafenib +Trametinib
Arm Type
Experimental
Arm Description
Participants will receive IV dose of 10 mg/kg durvalumab Q2W from Day 1 up to 12 months along with oral doses of dabrafenib 150 mg capsule BID and trametinib 2 mg tablet QD until confirmed PD, initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib.
Arm Title
Cohort B: Durvalumab (10 mg/kg) +Trametinib (Concurrent)
Arm Type
Experimental
Arm Description
Participants will receive concurrent doses of IV 10 mg/kg durvalumab Q2W from Day 1 up to 12 months along with oral dose of trametinib 2 mg tablet QD until confirmed PD, initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months and continued the treatment of trametinib.
Arm Title
Cohort C: Durvalumab (10 mg/kg) +Trametinib (Sequential)
Arm Type
Experimental
Arm Description
Participants will receive sequential doses of oral trametinib tablet 2 mg QD from Day 1 to Day 42 and IV durvalumab 10 mg/kg Q2W starting from Day 29 (Week 5) up to 12 months. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months.
Intervention Type
Biological
Intervention Name(s)
Durvalumab
Intervention Description
Intravenous dose of 3 or 10 mg/kg durvalumab.
Intervention Type
Drug
Intervention Name(s)
Dabrafenib
Intervention Description
Oral dose of 150 mg dabrafenib capsule.
Intervention Type
Drug
Intervention Name(s)
Trametinib
Intervention Description
Oral dose of 2 mg trametinib tablet.
Primary Outcome Measure Information:
Title
Number of Participants With Dose Limiting Toxicities (DLTs)
Description
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)
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Description
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)
Title
Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAEs
Description
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)
Title
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs
Description
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)
Title
Number of Participants With Abnormal Electrocardiograms (ECGs) and Echocardiograms (ECHOs) Reported as TEAEs
Description
Number of participants with abnormal electrocardiograms (ECGs) and echocardiograms (ECHOs) 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)
Secondary Outcome Measure Information:
Title
Percentage of Participants With Objective Response (OR)
Description
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.
Time Frame
From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
Title
Duration of Response (DOR)
Description
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.
Time Frame
From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
Title
Progression-free Survival (PFS)
Description
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.
Time Frame
From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
Title
Overall Survival
Description
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.
Time Frame
From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
Title
Percentage of Participants With Disease Control
Description
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.
Time Frame
From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
Title
Maximum Observed Plasma Concentration after First Dose (Cmax, 1st) of Durvalumab
Description
Maximum observed plasma concentration of durvalumab after first dose is reported.
Time Frame
Cohorts A and B: End of infusion on Day 1; Cohort C: End of infusion on Day 29
Title
Maximum Observed Plasma Concentration at Steady State (Cmax, ss) of Durvalumab
Description
Maximum observed plasma concentration of durvalumab at steady state is reported.
Time Frame
Cohorts A and B: end of infusion on Day 141; Cohort C: end of infusion on Day 169
Title
Trough Concentration at Steady State (Ctrough) of Durvalumab
Description
Trough concentration of durvalumab pre-dose at steady state is reported.
Time Frame
Cohorts A and B: Pre-dose on Day 141; Cohort C: Pre-dose on Day 169
Title
Number of Participants With Postive Anti-Drug Antibodies (ADA) Titer to Durvalumab
Description
The number of participants with positive serum antibodies to durvalumab post dosing are reported.
Time Frame
Cohorts A and B: Days 1 and 29; Cohort C: Days 29 and 57
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
MedImmune LLC
Organizational Affiliation
MedImmune LLC
Official's Role
Study Director
Facility Information:
Facility Name
Research Site
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85258
Country
United States
Facility Name
Research Site
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Research Site
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Research Site
City
Miami Beach
State/Province
Florida
ZIP/Postal Code
33140
Country
United States
Facility Name
Research Site
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Research Site
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Research Site
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Research Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
Facility Name
Research Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3A 1A1
Country
Canada
Facility Name
Research Site
City
Villejuif
ZIP/Postal Code
94805
Country
France
Facility Name
Research Site
City
Napoli
ZIP/Postal Code
80131
Country
Italy
12. IPD Sharing Statement
Citations:
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).
Results Reference
background
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).
Results Reference
result
PubMed Identifier
33288749
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. Erratum In: Nat Commun. 2021 Aug 12;12(1):5022.
Results Reference
derived
Learn more about this trial
Phase 1 Safety and Tolerability of MEDI4736 in Combination With Dabrafenib and Trametinib or With Trametinib Alone
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