This is an open-label, multi-center, dose-finding Phase 1 study that will enroll subjects at least 18 years old with unresectable or metastatic melanoma and BRAF V600 mutations. The primary objective of the study is to describe the safety for the doublet therapy (dabrafenib and ipilimumab) and the triplet therapy (dabrafenib/trametinib and ipilimumab). Preliminary efficacy data will also be collected. Subjects will be assigned to receive either the doublet combination (dabrafenib and ipilimumab) or the triplet combination (dabrafenib, trametinib, and ipilimumab). Subjects will be enrolled to dose-finding cohorts in the doublet combination (dabrafenib + ipilimumab) in a sequential 3+3 fashion. Following establishment of a dose for the doublet combination, an expansion cohort will be opened. At the same time, enrollment to dose finding cohorts for the triplet combination (dabrafenib + trametinib + ipilimumab) will begin in a sequential 6+6 fashion. Enrollment into triplet cohorts will take priority when both the doublet expansion arm and the triplet dose-finding arm are open for enrollment at the same time. Approximately 9-24 subjects will be enrolled to the dose finding portion of the study. Approximately 30 subjects will be enrolled to doublet expansion cohort and 30 subjects will be enrolled in the triplet expansion cohort. A two-week run-in period without ipilimumab will be followed by 4 intravenous doses of ipilimumab at the recommended dose and schedule. Oral daily dosing of dabrafenib or dabrafenib + trametinib will continue from the two-week run-in, through combination with ipilimumab, and post-ipilimumab until no longer of clinical benefit, in the opinion of the treating physician, or until unacceptable AE or death
Name: Dabrafenib
Description: Dabrafenib 100 mg or 150 mg BID orally will be administered. Capsules with unit dose strengths of 50 mg or 75 mgType: DrugTriplet arm Doublet arm
Name: Trametinib
Description: Trametinib 1 mg or 2 mg once daily will be administered. Tablets with unit dose strengths of 0.5 mg or 2 mgType: DrugTriplet arm
Name: Ipilimumab
Description: Ipilimumab 3 mg/kg intravenously over 90 minutes Q3W for a total of 4 doses will be administered. Supplied as Vials of 50 mg/10 mL (5 mg/mL) and 200 mg/40 mL (5 mg/mL)Type: DrugTriplet arm Doublet arm
Description: AEs will be collected from the time the first dose of study treatment is administered until 30 days following discontinuation of study treatment
Measure: Number of subjects with Adverse Events (AEs) to assess the safety of dabrafenib +/- trametinib when administered in combination with ipilimumab Time: Follow-up up to 6 months after last subject last doseDescription: Hematology, clinical chemistry, and urinalysis parameters to be tested. Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate. A complete physical examination will be performed at screening and every 12 months thereafter, as well as whenever clinically indicated.A brief physical examination will be performed every 3 or 4 weeks
Measure: Changes in laboratory values, vital signs, and physical examinations as a measure of safety of dabrafenib +/- trametinib when administered in combination with ipilimumab Time: Follow-up up to 6 months after last subject last doseDescription: All subjects will be evaluated for dose-limiting toxicity (DLT) from the first dose of ipilimumab until 1 week after the third dose of ipilimumab to determine a recommended dose for dabrafenib +/- trametinib when administered in combination with ipilimumab
Measure: Number of subjects with AEs and changes in laboratory values, vital signs, and physical examinations to determine a recommended dose for dabrafenib +/- trametinib when administered in combination with ipilimumab Time: Up to approximately Week 9 in doublet and triplet armDescription: Overall Response will be determined using Modified immune-related response criteria (irRC)
Measure: Overall response rate Time: Follow-up up to 6 months after last subject last doseDescription: Four blood samples will be collected on the day of first dose of ipilimumab (Cycle 1) - Study Day 15. One blood sample will be obtained on the day of the second and third dose of ipilimumab (Cycles 2 and 3) - Study Days 36 and 57. Subjects will be instructed to withhold their morning dose until after they arrive at the clinic. Ipilimumab infusion should start as soon as possible after oral dosing of dabrafenib/trametinib. PK samples have a +/-30 minute window for collection.
Measure: Concentrations of trametinib, dabrafenib and its metabolites (GSK2285403, GSK2298683, and GSK2167542) in the triplet arm and dabrafenib and its metabolites in the doublet arm Time: Day 15 (pre-dose,1, 2, and 4 hours post-dose); Day 36 and Day 57 (pre-dose only) for doublet and triplet armsAllocation: Randomized
Single Group Assignment
There are 2 SNPs
Study of Dabrafenib +/- Trametinib in Combination With Ipilimumab for V600E/K Mutation Positive Metastatic or Unresectable Melanoma This is an open-label, multi-center, dose-finding Phase 1 study that will enroll subjects at least 18 years old with unresectable or metastatic melanoma and BRAF V600 mutations. --- V600E ---
PK samples have a +/-30 minute window for collection.. Inclusion Criteria: - Signed written informed consent - Males and females >= 18 years of age - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E or V600K mutation-positive by the local laboratory. --- V600E ---
Patients with active autoimmune disease or a history of autoimmune disease other than those mentioned above must be approved by the GSK medical monitor - Active pneumonitis or interstitial lung disease - Lactating female - History of another malignancy (Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible) - Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures - Any prohibited medication - Administration of an investigational study treatment within 28 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment(s) in this study - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Unwillingness or inability to follow the procedures outlined in the protocol Inclusion Criteria: - Signed written informed consent - Males and females >= 18 years of age - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E or V600K mutation-positive by the local laboratory. --- V600E ---
PK samples have a +/-30 minute window for collection.. Inclusion Criteria: - Signed written informed consent - Males and females >= 18 years of age - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E or V600K mutation-positive by the local laboratory. --- V600E --- --- V600K ---
Patients with active autoimmune disease or a history of autoimmune disease other than those mentioned above must be approved by the GSK medical monitor - Active pneumonitis or interstitial lung disease - Lactating female - History of another malignancy (Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible) - Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures - Any prohibited medication - Administration of an investigational study treatment within 28 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment(s) in this study - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Unwillingness or inability to follow the procedures outlined in the protocol Inclusion Criteria: - Signed written informed consent - Males and females >= 18 years of age - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E or V600K mutation-positive by the local laboratory. --- V600E --- --- V600K ---