Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212
Condition: Cancer
Intervention: GSK2118436; GSK1120212
Intervention description: GSK2118436 is a potent and selective inhibitor of BRAF kinase activity with a mode of action consistent with adenosine triphosphate-competitive inhibition.; GSK1120212 is a potent and highly selective inhibitor of MEK1/2 activation and kinase activity.
Intervention MeSH terms: Trametinib; Dabrafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Masking: None (Open Label)
Enrollment: 430.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: drug-drug interaction; BRAF inhibitor; expansion cohorts; melanoma; dose escalation; MEK inhibitor

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.
    

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.