Melanoma
Conditions
Keywords
Metastatic or Unresectable Melanoma, durvalumab (MEDI4736), dafrafenib, trametinib, BRAF-mutation positive, wild-type BRAF, PD-L1, PD-1
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.
Interventions
BIOLOGICALDurvalumab
Intravenous dose of 3 or 10 mg/kg durvalumab.
DRUGDabrafenib
Oral dose of 150 mg dabrafenib capsule.
DRUGTrametinib
Oral dose of 2 mg trametinib tablet.
Sponsors
MedImmune LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) | 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) | 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 | 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 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration after First Dose (Cmax, 1st) of Durvalumab | 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 | 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. |
| Percentage of Participants With Objective Response (OR) | 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. |
| Number of Participants With Postive Anti-Drug Antibodies (ADA) Titer to Durvalumab | 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. |
| Trough Concentration at Steady State (Ctrough) of Durvalumab | 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. |
| Duration of Response (DOR) | 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) | 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 | 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 | 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. |
Countries
Canada, France, Italy, United States
Outcome results
None listed