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

NCT02027961

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Completed

Phase:

Phase 1

URL:

https://clinicaltrials.gov/show/NCT02027961

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: CD-ON-MEDI4736-1161
  • NCT ID: NCT02027961

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
DurvalumabCohort A1: Durvalumab (3 mg/kg) + Dabrafenib +Trametinib
DabrafenibCohort A1: Durvalumab (3 mg/kg) + Dabrafenib +Trametinib
TrametinibCohort A1: Durvalumab (3 mg/kg) + Dabrafenib +Trametinib

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Cohort A1: Durvalumab (3 mg/kg) + Dabrafenib +TrametinibExperimentalParticipants 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.
  • Durvalumab
  • Dabrafenib
  • Trametinib
Cohort A2: Durvalumab (10 mg/kg) + Dabrafenib +TrametinibExperimentalParticipants 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.
  • Durvalumab
  • Dabrafenib
  • Trametinib
Cohort B: Durvalumab (10 mg/kg) +Trametinib (Concurrent)ExperimentalParticipants 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.
  • Durvalumab
  • Trametinib
Cohort C: Durvalumab (10 mg/kg) +Trametinib (Sequential)ExperimentalParticipants 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.
  • Durvalumab
  • Trametinib

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
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants With Dose Limiting Toxicities (DLTs)
Time Frame:From first dose of study drug (Day 1) until the planned 3rd dose of durvalumab (Day 29)
Safety Issue:
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.

Secondary Outcome Measures

Measure:Percentage of Participants With Objective Response (OR)
Time Frame:From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
Safety Issue:
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.
Measure:Duration of Response (DOR)
Time Frame:From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
Safety Issue:
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.
Measure:Progression-free Survival (PFS)
Time Frame:From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
Safety Issue:
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.
Measure:Overall Survival
Time Frame:From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
Safety Issue:
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.
Measure:Percentage of Participants With Disease Control
Time Frame:From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)
Safety Issue:
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.
Measure:Maximum Observed Plasma Concentration after First Dose (Cmax, 1st) of Durvalumab
Time Frame:Cohorts A and B: End of infusion on Day 1; Cohort C: End of infusion on Day 29
Safety Issue:
Description:Maximum observed plasma concentration of durvalumab after first dose is reported.
Measure:Maximum Observed Plasma Concentration at Steady State (Cmax, ss) of Durvalumab
Time Frame:Cohorts A and B: end of infusion on Day 141; Cohort C: end of infusion on Day 169
Safety Issue:
Description:Maximum observed plasma concentration of durvalumab at steady state is reported.
Measure:Trough Concentration at Steady State (Ctrough) of Durvalumab
Time Frame:Cohorts A and B: Pre-dose on Day 141; Cohort C: Pre-dose on Day 169
Safety Issue:
Description:Trough concentration of durvalumab pre-dose at steady state is reported.
Measure:Number of Participants With Postive Anti-Drug Antibodies (ADA) Titer to Durvalumab
Time Frame:Cohorts A and B: Days 1 and 29; Cohort C: Days 29 and 57
Safety Issue:
Description:The number of participants with positive serum antibodies to durvalumab post dosing are reported.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:MedImmune LLC

Trial Keywords

  • Metastatic or Unresectable Melanoma, durvalumab (MEDI4736), dafrafenib, trametinib, BRAF-mutation positive, wild-type BRAF, PD-L1, PD-1

Last Updated

May 17, 2019