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

May 15, 2019 updated by: MedImmune LLC

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

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
68

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5G 2M9
        • Research Site
    • Quebec
      • Montreal, Quebec, Canada, H3A 1A1
        • Research Site
  • France
      • Villejuif, France, 94805
        • Research Site
  • Italy
      • Napoli, Italy, 80131
        • Research Site
  • United States
    • Arizona
      • Scottsdale, Arizona, United States, 85258
        • Research Site
    • California
      • Los Angeles, California, United States, 90095
        • Research Site
      • San Francisco, California, United States, 94115
        • Research Site
    • Florida
      • Miami Beach, Florida, United States, 33140
        • Research Site
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Research Site
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Research Site
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Research Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Cohort A1: Durvalumab (3 mg/kg) + Dabrafenib +Trametinib
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.
Biological: Durvalumab
Intravenous dose of 3 or 10 mg/kg durvalumab.
Drug: Dabrafenib
Oral dose of 150 mg dabrafenib capsule.
Drug: Trametinib
Oral dose of 2 mg trametinib tablet.
Experimental: Cohort A2: Durvalumab (10 mg/kg) + Dabrafenib +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.
Biological: Durvalumab
Intravenous dose of 3 or 10 mg/kg durvalumab.
Drug: Dabrafenib
Oral dose of 150 mg dabrafenib capsule.
Drug: Trametinib
Oral dose of 2 mg trametinib tablet.
Experimental: Cohort B: Durvalumab (10 mg/kg) +Trametinib (Concurrent)
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.
Biological: Durvalumab
Intravenous dose of 3 or 10 mg/kg durvalumab.
Drug: Trametinib
Oral dose of 2 mg trametinib tablet.
Experimental: Cohort C: Durvalumab (10 mg/kg) +Trametinib (Sequential)
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.
Biological: Durvalumab
Intravenous dose of 3 or 10 mg/kg durvalumab.
Drug: Trametinib
Oral dose of 2 mg trametinib tablet.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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)
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)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Time Frame: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)
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)
Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAEs
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 are reported.
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
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 are reported.
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
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 are reported.
From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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
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
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
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
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
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
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
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
MedImmune LLC

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 20, 2013

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
April 24, 2018

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 24, 2018

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
November 20, 2013

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 2, 2014

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 6, 2014

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 17, 2019

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 15, 2019

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • CD-ON-MEDI4736-1161

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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