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

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ClinicalTrials.gov Identifier: NCT02027961
Recruitment Status : Completed
First Posted : January 6, 2014
Last Update Posted : May 17, 2019
Sponsor:
Information provided by (Responsible Party):
MedImmune LLC

Tracking Information
First Submitted Date  ICMJE November 20, 2013
First Posted Date  ICMJE January 6, 2014
Last Update Posted Date May 17, 2019
Actual Study Start Date  ICMJE December 20, 2013
Actual Primary Completion Date April 24, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 15, 2019)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 2, 2014)
Maximum Tolerated Dose/Safety [ Time Frame: 90 days after the last dose of MEDI4736 ]
The primary endpoint for determining maximum tolerated dose includes dose limiting toxicities. The primary endpoint for safety assessment include adverse events, serious adverse events, laboratory evaluations, vitial signs, physical examination, and echocardiogram/elecrocardiogram results.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 15, 2019)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 2, 2014)
  • Antitumor Activity [ Time Frame: 90 days after the last dose of investigational product ]
    The endpoints for assessment of antitumor activity include objective response based on revised RECIST criteria Version 1.1, duration of response, progression-free survival, and overall survival.
  • Antitumor Activity [ Time Frame: 90 days after the last dose of investigational product ]
    The endpoints for assessment of antitumor activity include disease control, based on revised RECIST criteria Version 1.1, duration of response, progression-free survival, and overall survival.
  • Pharmacokinetic of MEDI4736 [ Time Frame: 90 days after the last dose of MEDI4736 ]
    PK of MEDI4736 includes individual MEDI4736 concentrations in serum.
  • Pharmacokinetic of MEDI4736 [ Time Frame: 90 days after the last dose of MEDI4736 ]
    PK parameters of MEDI4736 including peak concentration, area under the concentration-time curve clearance and half-life.
  • Immunogenicity of MEDI4736 [ Time Frame: 90 days after the last dose of MEDI4736 ]
    Immunogenicity of MEDI4736 include the number and percentage of subjects who develop detectable anti-drug antibodies.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 1 Safety and Tolerability of MEDI4736 in Combination With Dabrafenib and Trametinib or With Trametinib Alone
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Melanoma
Intervention  ICMJE
  • 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.
Study Arms  ICMJE
  • 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.
    Interventions:
    • Biological: Durvalumab
    • Drug: Dabrafenib
    • Drug: Trametinib
  • 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.
    Interventions:
    • Biological: Durvalumab
    • Drug: Dabrafenib
    • Drug: Trametinib
  • 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.
    Interventions:
    • Biological: Durvalumab
    • Drug: Trametinib
  • 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.
    Interventions:
    • Biological: Durvalumab
    • Drug: Trametinib
Publications *
  • 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).

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 23, 2017)
68
Original Estimated Enrollment  ICMJE
 (submitted: January 2, 2014)
69
Actual Study Completion Date  ICMJE April 24, 2018
Actual Primary Completion Date April 24, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   France,   Italy,   United States
Removed Location Countries United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT02027961
Other Study ID Numbers  ICMJE CD-ON-MEDI4736-1161
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party MedImmune LLC
Study Sponsor  ICMJE MedImmune LLC
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: MedImmune LLC MedImmune LLC
PRS Account MedImmune LLC
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP