Last updated: 11/07/2018 05:48:51
This product has been transferred to Novartis. GSK Clinical Study Register is no longer maintained for this study. The most up to date information is available on clinicaltrials.gov.

Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212

GSK study ID
113220
See study documents
Clinicaltrials.gov ID
NCT01072175
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
No longer a GSK study
No longer a GSK study
Overview
Eligibility
Locations
Study documents
Results summary
Plain language summaries
Additional information

Trial overview

Official title: An Open-Label, Dose-Escalation, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the BRAF Inhibitor GSK2118436 in Combination with the MEK Inhibitor GSK1120212 in Subjects with BRAF Mutant Metastatic Melanoma
Trial description: This is an open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2118436 and GSK1120212 in combination. This study is designed in four parts. In Part A, the effect of repeat doses of
GSK1120212 on the pharmacokinetics of single dose GSK2118436, will be investigated prior to evaluating combination regimens. In Part B, the range of tolerated dose combinations will be identified using a dose-escalation procedure. In Part C, different
dose combinations of GSK2118436 and GSK1120212 will be evaluated, based on results from the dose escalation cohorts. In Part D, the pharmacokinetics and safety of GSK2118436 administered as HPMC capsules alone and in combination with GSK1120212 will be evaluated.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
None (Open Label)
Allocation:
Non-randomized
Primary outcomes:

Maximum plasma concentration (Cmax) of a single dose of dabrafenib administered alone and in combination with trametnib in Part A

Timeframe: Day 15

AUC (0-t) and AUC (0-inf) of dabrafenib and its metabolites in Part A

Timeframe: Day 15

Number of participants with any adverse event (AE) or serious adverse event (SAE) in Part B

Timeframe: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks )

Number of participants with the indicated worst-case grade (G) change from Baseline in the indicated clinical chemistry parameters in Part B

Timeframe: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks)

Number of participants with the indicated worst-case grade change from Baseline in the indicated hematology parameters in Part B

Timeframe: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks)

Number of participants with the indicated worst-case change from Baseline in heart rate and blood pressure in Part B

Timeframe: From Baseline (Day 1) until Follow-up visit (up to approximately 103 weeks)

Number of participants with BRAF mutant metastatic melanoma with best overall response as assessed by the investigator in Part C (randomized)

Timeframe: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 47 weeks)

Number of participants with BRAF mutant metastatic melanoma with best overall response assessed by Blinded Independent Central Review (BICR) in Part C (randomized)

Timeframe: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 36 weeks)

Number of participants with BRAF mutant metastatic melanoma with best overall response as assessed by the investigator in Part C (crossover)

Timeframe: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 15 weeks)

Duration of response as assessed by the investigator and Blinded Independent Central Review (BICR) in Part C (randomized)

Timeframe: First documented evidence of PR or CR until the date of the first documented sign of disease progression or the date of death due to any cause (up to approximately 17 months)

Progression-free Survival (PFS) as assessed by the investigator in Part C (randomized)

Timeframe: From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 17 months)

Progression-free Survival (PFS) as assessed by the Blinded Independent Central Review (BICR) in Part C (randomized)

Timeframe: From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 17 months)

Progression-free Survival (PFS) as assessed by the investigator in Part C (crossover)

Timeframe: From the first dose of study medication to the earliest date of disease progression (PD) or death due to any cause (up to approximately 9 months)

Number of participants with any adverse event (AE) or serious adverse event (SAE) in Part C (randomized)

Timeframe: From Baseline (Day 1) until Follow-up visit (up to approximatley 75 weeks)

Number of participants with the indicated worst-case grade (G) change from Baseline in the indicated clinical chemistry parameters in Part C (randomized)

Timeframe: From Baseline (Day 1) until Follow-up visit (up to approximately 75 weeks)

Number of participants with the indicated worst-case grade change from Baseline in the indicated hematology parameters in Part C (randomized)

Timeframe: From Baseline (Day 1) until Follow-up visit (up to approximately 75 weeks)

Number of participants with the indicated worst-case change from Baseline in heart rate and blood pressure in Part C (randomized)

Timeframe: From Baseline (Day 1) until Follow-up visit (up to approximlately 75 weeks)

Maximum plasma concentration (Cmax) of a single and repeat dose of dabrafenib alone and in combination with trametinib in Part D (Analyte=GSK2118436)

Timeframe: Day 1 and Day 21

The tmax of a single and repeat dose of dabrafenib alone and in combination with trametinib in Part D (Analyte=GSK2118436)

Timeframe: Day 1 and Day 21

AUC (0-tau) and AUC (0-inf) of single and repeat doses of dabrafenib alone and in combination with trametinib in Part D (Analyte=GSK2118436)

Timeframe: Day 1 and Day 21

Number of participants with any adverse event (AE) or serious adverse event (SAE) in Part D

Timeframe: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks)

Number of participants with the indicated worst-case grade (G) change from Baseline in the indicated clinical chemistry parameters in Part D

Timeframe: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks)

Number of participants with the indicated worst-case grade change from Baseline in the indicated hematology parameters in Part D

Timeframe: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks)

Number of participants with the indicated worst-case change from Baseline in heart rate and blood pressure in Part D

Timeframe: From Baseline (Day 1) until Follow-up visit (up to approximately 61 weeks)

Secondary outcomes:

Steady state concentration of trametinib with concomitant administration of dabrafenib in Part A

Timeframe: Day 15 and Day 16

The AUC [0-tau] of dabrafenib (DAB) and its metabolite in combination with trametinib (T) in Part B

Timeframe: Day 15 and Day 21

Pre-dose (trough) concentration at the end of the dosing interval (Ctau) and maximum plasma concentration (Cmax) of dabrafenib and its metabolite in combination with trametinib in Part B

Timeframe: Day 15 and Day 21

The tmax of dabrafenib and its metabolite in combination with trametinib in Part B

Timeframe: Day 15 and Day 21

The AUC (0-tau) assessment of trametinib in combination with dabrafenib in Part B (Analyte=GSK1120212)

Timeframe: Day 15 and Day 21

The Ctau and Cmax assessments of trametinib in combination with dabrafenib in Part B (Analyte=GSK1120212)

Timeframe: Day 15 and Day 21

The tmax assessment of trametinib in combination with dabrafenib in Part B (Analyte=GSK1120212)

Timeframe: Day 15 and Day 21

Number of participants with BRAFi-naïve mutant metastatic melanoma with the best overall response as assessed by investigator in Part B

Timeframe: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to 103 weeks)

Duration of response as assessed by the investigator in participants with BRAFi-naïve mutant metastatic melanoma in Part B

Timeframe: First documented evidence of PR or CR until the earlier of date of disease progression or date of death due to any cause (up to approximately 22 months)

Progression-free Survival (PFS) as assessed by the investigator in participants with BRAFi-naïve mutant metastatic melanoma in Part B

Timeframe: From the date of first dose to the earliest date of disease progression (PD) or death due to any cause (up to approximately 22 months)

Overall survival (OS) in Part B BRAFi Naïve Melanoma participants

Timeframe: From the date of first dose until date of death due to any cause (up to approximately 22 months)

Pre- and post-dose H-scores for individual participants in Part B

Timeframe: Screening and at disease progression (up to approximately 8 months)

Overall survival (OS) in Part C

Timeframe: From the date of randomization until date of death due to any cause (up to approximately 17 months)

Plasma concentrations of dabrafenib and its metabolites in Part C

Timeframe: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56

Plasma concentrations of trametinib in Part C

Timeframe: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56

Oral clearance (CL/F) of dabrafenib and trametinib

Timeframe: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48

Oral volume of distribution (V/F) of dabrafenib and trametinib

Timeframe: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48

Cmax of dabrafenib metabolites in Part D

Timeframe: Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose

The tmax of dabrafenib metabolites in Part D

Timeframe: Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose

Area under the concentration-time curve (AUC) of dabrafenib metabolites in Part D

Timeframe: Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose

The Cmax assessment of trametinib in Part D

Timeframe: Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose

The tmax assessment of trametinib in Part D

Timeframe: Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose

Area under the concentration-time curve assessment of trametinib in Part D

Timeframe: Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose. Day 21: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours post-dose

Number of participants with the best overall response as assessed by the investigator in participants in Part D

Timeframe: From the date of first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 280 days )

Duration of response as assessed by the investigator in Part D

Timeframe: First documented evidence of PR or CR until the earlier of date of disease progression or date of death due to any cause (up to approximately 13 months)

Progression-free Survival (PFS) as assessed by the investigator in Part D

Timeframe: From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 13 months)

Overall survival in Part D

Timeframe: From the date of first dose until date of death due to any cause (up to approximately 14 months)

Interventions:
  • Drug: GSK1120212
  • Drug: GSK2118436
    • Enrollment:
    430
    Primary completion date:
    2012-31-05
    Observational study model:
    Not applicable
    Time perspective:
    Not applicable
    Clinical publications:
    KT Flaherty, JR Infante, Al Daud, R Gonzalez, RF Kefford, J Sosman, O Hamid, L Schuchter, J Cebon, N Ibrahim, R Kudchadkar, HA Burris III,G Falchook, A Algazi, K Lewis, GV Long, I Puzanov, P Lebowitz, A Singh, S Little, P Sun, A Allred, D Ouellet, K Kim,. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations . N Engl J Med. 2012;367:1694-1703.
    Medical condition
    Cancer, Neoplasms
    Product
    dabrafenib, dabrafenib/trametinib, trametinib
    Collaborators
    Not applicable
    Study date(s)
    March 2010 to April 2018
    Type
    Interventional
    Phase
    2/3

    Participation criteria

    Sex
    Female & Male
    Age
    18+ years
    Accepts healthy volunteers
    none
    • Capable of given written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
    • Male or female age 18 years or greater; able to swallow and retain oral medication.
    • Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy).
    • Part A and Part B: Prior exposure to BRAF or MEK inhibitors unless approved by the GSK Medical Monitor.
    Inclusion and exclusion criteria
    Inclusion criteria:
    • Capable of given written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
    • Male or female age 18 years or greater; able to swallow and retain oral medication.
    • BRAF mutation positive melanoma or colorectal cancer; other BRAF mutation positive tumor types may be considered.
    • Measurable disease according to RECIST version 1.1.
    • Eastern Cooperative Oncology Group Performance Status of 0 or 1 for Parts A and B. Subjects with Eastern Cooperative Oncology Group Performance Status of 2 or less may be entered into Part C with approval of medical monitor.
    • Agree to contraception requirements.
    • Calcium phosphorus product less than 4.0mmol2/L2.
    • Adequate organ system function.
    Exclusion criteria:
    • Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy).
    • Part A and Part B: Prior exposure to BRAF or MEK inhibitors unless approved by the GSK Medical Monitor.
    • Part C: Prior exposure to BRAF or MEK inhibitors. Prior anti-cancer therapy in the metastatic setting, with the exception of up to one regimen of chemotherapy and/or interleukin-2 (IL-2).
    • Part D: Prior exposure to BRAF inhibitors. A washout period of 6 weeks is required for ipilimumab.
    • Received an investigational anti-cancer drug within 4 weeks or 5 half-lives (whichever is shorter) of study drug administration--- at least 14 days must have passed between the last dose of prior investigational anti-cancer drug and the first dose of study drug.
    • Current use of a prohibited medication or requires any of these medications during treatment with study drug.
    • Current use of therapeutic warfarin.
    • Any major surgery, radiotherapy, or immunotherapy within the last 4 weeks. Limited radiotherapy within the last 2 weeks.
    • Chemotherapy regimens with delayed toxicity within the last 4 weeks. Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last 2 weeks.
    • Unresolved toxicity greater than National Cancer Institute-Common Terminology Criteria for Adverse Events version 4 Grade 1 from previous anti-cancer therapy except alopecia.
    • History of retinal vein occlusion, central serous retinopathy or glaucoma.
    • Predisposing factors to retinal vein occlusion including uncontrolled hypertension, uncontrolled diabetes, uncontrolled hyperlipidemia, and coagulopathy.
    • Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for retinal vein occlusion or central serous retinopathy.
    • Intraocular pressure greater than 21mm Hg as measured by tonography.
    • Glaucoma diagnosed within one month prior to study Day 1.
    • Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism or excretion of drugs.
    • Known human immunodeficiency virus, Hepatitis B or Hepatitis C infection.
    • Primary malignancy of the central nervous system.
    • Untreated or symptomatic brain metastasis, leptomeningeal disease or spinal cord compression. Subjects who are on a stable dose of corticosteroids for more than 1 month or off corticosteroids for 2 weeks can be enrolled with approval of medical monitor. Subjects are not permitted to receive enzyme-inducing anti-epileptic drugs.
    • Subjects with brain metastases are excluded, unless a. All known lesions must be previously treated with surgery or stereotactic radiosurgery, and- b. Brain lesion(s), if still present, must be confirmed stable (i.e. no increase in lesion size) for ≥90 days prior to first dose on study (must be documented with two consecutive MRI or CT scans using contrast), and c. Asymptomatic with no corticosteroids requirement for ≥ 30 days prior to first dose on study, and d. No enzyme-inducing anticonvulsants for ≥ 30 days prior to first dose on study.
    • History of alcohol or drug abuse within 6 months prior to screening.
    • Psychological, familial, sociological or geographical conditions that do not permit compliance with the protocol.
    • QTc interval greater than or equal to 480msecs.
    • History of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks.
    • Class II, III, or IV heart failure as defined by the New York Heart Association functional classification system.
    • Abnormal cardiac valve morphology (subjects with minimal abnormalities can be entered on study with approval from the medical monitor.
    • Treatment refractory hypertension defined as a blood pressure of systolic> 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy
    • Patients with intra-cardiac defibrillators or permanent pacemakers.
    • Cardiac metastases
    • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs or excipients.
    • Pregnant or lactating female.
    • Unwillingness or inability to follow the procedures required in the protocol.
    • Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity.
    • Subjects with known glucose 6 phosphate dehydrogenase deficiency.

    Trial location(s)

    This study does not involve prospective enrollment of participants.

    Study documents

    Clinical study report
    Available language(s): English
    Download document(s)
    Scientific result summary
    Available language(s): English
    Download document(s)

    If you wish to request for full study report, please contact - [email protected]

    Results overview

    Refer to study documents

    Recruitment status
    No longer a GSK study
    Actual primary completion date
    2012-31-05
    Actual study completion date
    Not applicable

    Plain language summaries

    Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.

    Additional information about the trial

    Additional information
    Not applicable
    Participate in clinical trial
    Access to clinical trial data by researchers
    Visit website