Clinical trial NCT01072175: Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cancer
Keywords: drug-drug interaction
BRAF inhibitor
expansion cohorts
melanoma
dose escalation
MEK inhibitor
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2010-02-19
Enrollment: 430
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Primary purpose: TREATMENT

Brief summary: This was an open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2118436 and GSK1120212 in combination. This study was designed in four parts. In Part A, the effect of repeat doses of GSK1120212 on the pharmacokinetics of single dose GSK2118436 was investigated prior to evaluating combination regimens. In Part B, the range of tolerated dose combinations was identified using a dose-escalation procedure. In Part C, different dose combinations of GSK2118436 and GSK1120212 were 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 was evaluated.

Detailed description: During Part A, a cohort of subjects received a single dose of GSK2118436 alone (Day 1) and then repeat doses of GSK1120212 for (Day 2 through Day 15). The dose regimen of GSK1120212 were continuous dosing. A second single dose of GSK2118436 was administered on Day 15 concomitantly with GSK1120212. Day 16 through Day 28 was a washout period, during which no study medication was administered. Starting on Day 29, subjects who elected to continue participation in the study were doses with GSK2118436. The dose of GSK2118436 after Day 29 might be altered based on emerging data from the first-time-in human study BRF112680. The dose might be increased to a dose level that has been completed and determined to be less than or equal to the maximum tolerated dose in that study.

Part B of the study enrolled cohorts in escalating doses to identify a set of allowable doses to be expanded in Part C. Subjects were enrolled in a 3+3 cohort design, with provisional dose levels of both drugs. The decision regarding escalation to the next dose levels of GSK1120212 and GSK2118436 was further guided by a Bayesian logistic regression model. The first cohort started at low doses for both drugs. Doses up to 300 mg/day for GSK2118436 and up to 3 mg QD for GSK1120212 were studied. The starting dose might be lowered based on emerging data from other studies and from Part A.

Expansion cohorts enrolled in Part C at dose levels of GSK2118436 and GSK1120212 as defined in Part B. One of the selected doses might include GSK2118436 administered as monotherapy at a tolerable dose (less than or equal to the maximum tolerated dose) determined in BRF112680. Part C was a randomized open-label Phase II portion of the study, and consisted of expansion cohorts investigating 2 to 3 dose levels of GSK2118436 and GSK1120212 dosing in combination, and GSK2118436 administered as monotherapy. Subjects were assigned to treatment arms in a randomized fashion to compare tolerability and safety. Population PK parameters, clinical activity, durability of response and safety of GSK2118436 and GSK1120212 dosed orally in combination and GSK2118436 as monotherapy were evaluated.

Part D consisted of evaluation of the pharmacokinetics of GSK2118436 HPMC capsules administered as monotherapy and in combination with GSK1120212. Pharmacokinetics of GSK2118436 was assessed following a single dose on Day 1 and after repeat dosing (Day 21) and compared between combination and monotherapy. The pharmacokinetics of GSK1120212 was also be assessed. Safety, tolerability and clinical activity were evaluated in 4 dosing cohorts. These cohorts might be expanded for additional safety data. Subjects were randomized to different cohorts.

Eligibility criteria: Key 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.

Key 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.

Primary outcomes:
measure: Part A: Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib
timeFrame: Day 15
measure: Part A: AUC (0-t) and AUC (0-inf) of Dabrafenib and Its Metabolites
timeFrame: Day 15
measure: Part B: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
measure: Part B: Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
measure: Part B: Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
measure: Part B: Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
measure: Part B: Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
measure: Part B: Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 8 years)
measure: Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator
timeFrame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 7 years)
measure: Part C (Randomized): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response Assessed by Blinded Independent Central Review (BICR)
timeFrame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 19 months)
measure: Part C (Crossover): Number of Participants With BRAF Mutant Metastatic Melanoma With Best Overall Response as Assessed by the Investigator
timeFrame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 7 years)
measure: Part C (Randomized): Progression-free Survival (PFS) as Assessed by the Investigator
timeFrame: From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 7 years)
measure: Part C (Crossover): Progression-free Survival (PFS) as Assessed by the Investigator
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 7 years)
measure: Part C (Randomized): Progression-free Survival (PFS) as Assessed by the Blinded Independent Central Review (BICR)
timeFrame: From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 19 months)
measure: Part C (Randomized): Duration of Response as Assessed by the Investigator and Blinded Independent Central Review (BICR)
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 19 months)
measure: Part C (Randomized): Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
measure: Part C (Randomized): Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
measure: Part C (Randomized): Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
measure: Part C (Randomized): Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
measure: Part C (Randomized): Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
measure: Part C (Randomized): Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
measure: Part D (Analyte=GSK2118436): Maximum Plasma Concentration (Cmax) of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib
timeFrame: Day 1 and Day 21
measure: Part D (Analyte=GSK2118436): Tmax of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib
timeFrame: Day 1 and Day 21
measure: Part D (Analyte=GSK2118436): AUC (0-tau) and AUC (0-inf) of Single and Repeat Doses of Dabrafenib Alone and in Combination With Trametinib
timeFrame: Day 1 and Day 21
measure: Part D: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
measure: Part D: Number of Participants With Worst-case Chemistry Toxicity Grade Change From Baseline
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
measure: Part D: Number of Participants With Worst-case Chemistry Change From Baseline With Respect to Normal Range
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
measure: Part D: Number of Participants With Worst-case Hematology Toxicity Grade Change From Baseline
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
measure: Part D: Number of Participants With Worst-case Hematology Change From Baseline With Respect to Normal Range
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
measure: Part D: Number of Participants With the Indicated Worst-case Change From Baseline in Heart Rate and Blood Pressure
timeFrame: From Baseline (Day 1) until Follow-up visit (up to approximately 7 years)
Secondary outcomes:
measure: Part A: Steady State Concentration of Trametinib With Concomitant Administration of Dabrafenib
timeFrame: Day 15 and Day 16
measure: Part B: AUC [0-tau] of Dabrafenib (DAB) and Its Metabolite in Combination With Trametinib
timeFrame: Day 15 and Day 21
measure: Part B: 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
timeFrame: Day 15 and Day 21
measure: Part B: Tmax of Dabrafenib and Its Metabolite in Combination With Trametinib
timeFrame: Day 15 and Day 21
measure: Part B (Analyte=GSK1120212): AUC (0-tau) Assessment of Trametinib in Combination With Dabrafenib
timeFrame: Day 15 and Day 21
measure: Part B (Analyte=GSK1120212): Ctau and Cmax Assessments of Trametinib in Combination With Dabrafenib
timeFrame: Day 15 and Day 21
measure: Part B (Analyte=GSK1120212): Tmax Assessment of Trametinib in Combination With Dabrafenib
timeFrame: Day 15 and Day 21
measure: Part B: Number of Participants With BRAFi-naïve Mutant Metastatic Melanoma With the Best Overall Response as Assessed by Investigator
timeFrame: From the first dose of study medication to the first documented evidence of a confirmed complete response or partial response (up to approximately 8 years)
measure: Part B: Duration of Response as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma
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 8 years)
measure: Part B: Progression-free Survival (PFS) as Assessed by the Investigator in Participants With BRAFi-naïve Mutant Metastatic Melanoma
timeFrame: From the date of first dose to the earliest date of disease progression (PD) or death due to any cause (up to approximately 8 years)
measure: Part B: Overall Survival (OS) in BRAFi Naïve Melanoma Participants
timeFrame: From the date of first dose until date of death due to any cause (up to approximately 8 years)
measure: Part B: Pre- and Post-dose H-scores for Individual Participants
timeFrame: Screening and at disease progression (up to approximately 8 years)
measure: Part C (Randomized): Overall Survival (OS)
timeFrame: From the date of randomization until date of death due to any cause (up to approximately 7 years)
measure: Part C: Plasma Concentrations of Dabrafenib and Its Metabolites
timeFrame: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56
measure: Part C: Plasma Concentrations of Trametinib
timeFrame: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, and Week 56
measure: Part C: Oral Clearance (CL/F) of Dabrafenib and Trametinib
timeFrame: Day 15, Week 8, Week 16, Week 24, Week 32, Week 40, and Week 48
measure: Part C: 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
measure: Part D: Cmax of Dabrafenib Metabolites
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
measure: Part D: Tmax of Dabrafenib Metabolites
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
measure: Part D: Area Under the Concentration-time Curve (AUC) of Dabrafenib Metabolites
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
measure: Part D: Cmax Assessment of Trametinib
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
measure: Part D: Tmax Assessment of Trametinib
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
measure: Part D: Area Under the Concentration-time Curve Assessment of Trametinib
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
measure: Part D: Number of Participants With the Best Overall Response as Assessed by the Investigator in Participants
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 7 years)
measure: Part D: Duration of Response as Assessed by the Investigator
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 7 years)
measure: Part D: Progression-free Survival (PFS) as Assessed by the Investigator
timeFrame: From the date of randomization to the earliest date of disease progression (PD) or death due to any cause (up to approximately 7 years)
measure: Part D: Overall Survival (OS)
timeFrame: From the date of first dose until date of death due to any cause (up to approximately 7 years)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: San Francisco
country: United States
facility: Novartis Investigative Site
state: California
city: Aurora
country: United States
facility: Novartis Investigative Site
state: Colorado
city: New Haven
country: United States
facility: Novartis Investigative Site
state: Connecticut
city: Tampa
country: United States
facility: Novartis Investigative Site
state: Florida
city: Lutherville-Timonium
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Rochester
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Philadelphia
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Nashville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Nashville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: Westmead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Heidelberg
country: Australia
facility: Novartis Investigative Site
state: Victoria
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
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citation: Frederick DT, Salas Fragomeni RA, Schalck A, Ferreiro-Neira I, Hoff T, Cooper ZA, Haq R, Panka DJ, Kwong LN, Davies MA, Cusack JC, Flaherty KT, Fisher DE, Mier JW, Wargo JA, Sullivan RJ. Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics. PLoS One. 2014 Jul 1;9(7):e101286. doi: 10.1371/journal.pone.0101286. eCollection 2014.
citation: Carlino MS, Gowrishankar K, Saunders CA, Pupo GM, Snoyman S, Zhang XD, Saw R, Becker TM, Kefford RF, Long GV, Rizos H. Antiproliferative effects of continued mitogen-activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma. Mol Cancer Ther. 2013 Jul;12(7):1332-42. doi: 10.1158/1535-7163.MCT-13-0011. Epub 2013 May 3.