Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212
NCT ID: NCT01072175
Last Updated: 2019-07-05
Study Results
Results available
Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.
View full resultsBasic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE2
Total Enrollment
430 participants
Study Classification
INTERVENTIONAL
Study Start Date
2010-03-26
Study Completion Date
2018-02-27
Brief Summary
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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.
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Detailed Description
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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.
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.
Conditions
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Cancer
Study Design
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Allocation Method
NON_RANDOMIZED
Primary Study Purpose
TREATMENT
Blinding Strategy
NONE
Study Groups
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Arm Part A
Day 1: GSK2118436 75mg; Day 2 through Day 16: GSK1120212 2mg; Day 15: GSK2118436 75mg +GSK1120212 2mg Drug-drug interaction
Group Type
EXPERIMENTAL
GSK2118436
Intervention Type
DRUG
GSK2118436 is a potent and selective inhibitor of BRAF kinase activity with a mode of action consistent with adenosine triphosphate-competitive inhibition.
GSK1120212
Intervention Type
DRUG
GSK1120212 is a potent and highly selective inhibitor of MEK1/2 activation and kinase activity.
Arm Part B
GSK2118436 + GSK1120212 Dose escalation to a maximum tolerated combination dose
Group Type
EXPERIMENTAL
GSK2118436
Intervention Type
DRUG
GSK2118436 is a potent and selective inhibitor of BRAF kinase activity with a mode of action consistent with adenosine triphosphate-competitive inhibition.
Arm Part C
GSK2118436 + GSK1120212 cohort expansion for safety and efficacy
Group Type
EXPERIMENTAL
GSK2118436
Intervention Type
DRUG
GSK2118436 is a potent and selective inhibitor of BRAF kinase activity with a mode of action consistent with adenosine triphosphate-competitive inhibition.
GSK1120212
Intervention Type
DRUG
GSK1120212 is a potent and highly selective inhibitor of MEK1/2 activation and kinase activity.
Interventions
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GSK2118436
GSK2118436 is a potent and selective inhibitor of BRAF kinase activity with a mode of action consistent with adenosine triphosphate-competitive inhibition.
Intervention Type
DRUG
GSK1120212
GSK1120212 is a potent and highly selective inhibitor of MEK1/2 activation and kinase activity.
Intervention Type
DRUG
Eligibility Criteria
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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.
* 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.
* 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.
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Novartis Pharmaceuticals
INDUSTRY
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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Novartis Pharmaceuticals
Role: STUDY_DIRECTOR
Novartis Pharmaceuticals
Locations
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Novartis Investigative Site
Los Angeles, California, United States
Site Status
Novartis Investigative Site
San Francisco, California, United States
Site Status
Novartis Investigative Site
Aurora, Colorado, United States
Site Status
Novartis Investigative Site
New Haven, Connecticut, United States
Site Status
Novartis Investigative Site
Tampa, Florida, United States
Site Status
Novartis Investigative Site
Lutherville-Timonium, Maryland, United States
Site Status
Novartis Investigative Site
Boston, Massachusetts, United States
Site Status
Novartis Investigative Site
Boston, Massachusetts, United States
Site Status
Novartis Investigative Site
Rochester, Minnesota, United States
Site Status
Novartis Investigative Site
Philadelphia, Pennsylvania, United States
Site Status
Novartis Investigative Site
Nashville, Tennessee, United States
Site Status
Novartis Investigative Site
Nashville, Tennessee, United States
Site Status
Novartis Investigative Site
Houston, Texas, United States
Site Status
Novartis Investigative Site
Westmead, New South Wales, Australia
Site Status
Novartis Investigative Site
Heidelberg, Victoria, Australia
Site Status
Countries
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United States
Australia
References
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Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov 1;367(18):1694-703. doi: 10.1056/NEJMoa1210093. Epub 2012 Sep 29.
Reference Type
BACKGROUND
Long GV, Eroglu Z, Infante J, Patel S, Daud A, Johnson DB, Gonzalez R, Kefford R, Hamid O, Schuchter L, Cebon J, Sharfman W, McWilliams R, Sznol M, Redhu S, Gasal E, Mookerjee B, Weber J, Flaherty KT. Long-Term Outcomes in Patients With BRAF V600-Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib. J Clin Oncol. 2018 Mar 1;36(7):667-673. doi: 10.1200/JCO.2017.74.1025. Epub 2017 Oct 9.
Reference Type
DERIVED
Long GV, Grob JJ, Nathan P, Ribas A, Robert C, Schadendorf D, Lane SR, Mak C, Legenne P, Flaherty KT, Davies MA. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016 Dec;17(12):1743-1754. doi: 10.1016/S1470-2045(16)30578-2. Epub 2016 Nov 16.
Reference Type
DERIVED
Long GV, Weber JS, Infante JR, Kim KB, Daud A, Gonzalez R, Sosman JA, Hamid O, Schuchter L, Cebon J, Kefford RF, Lawrence D, Kudchadkar R, Burris HA 3rd, Falchook GS, Algazi A, Lewis K, Puzanov I, Ibrahim N, Sun P, Cunningham E, Kline AS, Del Buono H, McDowell DO, Patel K, Flaherty KT. Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. J Clin Oncol. 2016 Mar 10;34(8):871-8. doi: 10.1200/JCO.2015.62.9345. Epub 2016 Jan 25.
Reference Type
DERIVED
Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, Hamid O, Messersmith WA, Daud A, Kurzrock R, Pierobon M, Sun P, Cunningham E, Little S, Orford K, Motwani M, Bai Y, Patel K, Venook AP, Kopetz S. Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer. J Clin Oncol. 2015 Dec 1;33(34):4023-31. doi: 10.1200/JCO.2015.63.2471. Epub 2015 Sep 21.
Reference Type
DERIVED
Latimer NR, Amonkar MM, Stapelkamp C, Sun P. Adjusting for confounding effects of treatment switching in a randomized phase II study of dabrafenib plus trametinib in BRAF V600+ metastatic melanoma. Melanoma Res. 2015 Dec;25(6):528-36. doi: 10.1097/CMR.0000000000000193.
Reference Type
DERIVED
Johnson DB, Flaherty KT, Weber JS, Infante JR, Kim KB, Kefford RF, Hamid O, Schuchter L, Cebon J, Sharfman WH, McWilliams RR, Sznol M, Lawrence DP, Gibney GT, Burris HA 3rd, Falchook GS, Algazi A, Lewis K, Long GV, Patel K, Ibrahim N, Sun P, Little S, Cunningham E, Sosman JA, Daud A, Gonzalez R. Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. J Clin Oncol. 2014 Nov 20;32(33):3697-704. doi: 10.1200/JCO.2014.57.3535. Epub 2014 Oct 6.
Reference Type
DERIVED
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.
Reference Type
DERIVED
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.
Reference Type
DERIVED
Other Identifiers
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113220
Identifier Type: -
Identifier Source: org_study_id
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