Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212
NCT ID: NCT01072175
(View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 10-056
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 three 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.
Dana-Farber Cancer Institute, Brigham and Women's Hospital, Beth-Israel Deaconess Medical Center, Massachusetts General Hospital
Keith Flaherty, MD,
Massachusetts General Hospital
Daniel Cho, MD,
Beth Israel Deaconess Medical Center
Geoffrey Shapiro, MD, PhD,
Dana-Farber Cancer Institute
Beth-Israel Deaconess Medical Center:
Cancer Trials Call Center, 617-667-3060
Massachusetts General Hospital:
Cancer Trials Call Center, 877-789-6100
- 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; other BRAF mutation positive tumor types may be
- 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.
- Subjects who test positive for Human Papilloma Virus may be enrolled after informed
consent regarding discussion of risk of papilloma virus infection. If enrolled these
subjects must use condoms for sexual activity, regardless of the use of other
- Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy,
or biologic therapy).
- Prior exposure to BRAF or MEK inhibitors unless approved by the medical monitor.
- 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 within 7 days prior to the first dose of
- 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
- 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.
- 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.
- 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.