An Open-Label Phase II Study of the Combination of GSK2118436 and GSK1120212 in Patients With Metastatic Melanoma Which is Refractory or Resistant to BRAF Inhibitor
Condition: Melanoma
MeSH terms: Melanoma
Intervention: GSK2118436; GSK1120212
Intervention description: Starting dose 150 mg by mouth twice a day.; 2 mg by mouth daily.
Intervention MeSH terms: Trametinib; Dabrafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 28.0
Sex: All
Minimum age: 16 Years
Healthy volunteers: No
Keywords: Melanoma; Metastatic melanoma; Refractory or Resistant to BRAF Inhibitor; Advanced melanoma; GSK2118436; GSK1120212

Summary:

      The goal of this clinical research study is to learn if the combination of 2 drugs dabrafenib
      and trametinib can help to control melanoma that has or has not spread to the brain. The
      safety of this drug combination will also be studied.

      Dabrafenib is designed to block the mutated BRAF protein. This mutation is only found in
      moles of the skin and in melanoma cells. By blocking the protein, the drug may slow the
      growth of or kill cancer cells that have the protein.

      Trametinib is designed to block certain proteins that cause cancer cells to grow and
      multiply. This may cause the cancer cells to die.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form.

          2. Patients must have histologically or cytologically confirmed Stage IV or recurrent or
             unresectable Stage III melanoma.

          3. BRAF mutation-positive melanoma (i.e., V600E, V600K or V600D)

          4. For Cohort A, patients must have easily accessible tumor for a mandatory biopsy. This
             is not required for patients enrolled on Cohort B.

          5. Patients must have measurable disease, defined by RECIST 1.1

          6. Patients must have tumor lesions which is refractory or resistant to a selective BRAF
             inhibitor (RO5185426 or GSK2118436).

          7. Age >/= 16 years.

          8. Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          9. Patients must have organ and marrow function as defined below: · absolute neutrophil
             count >/= 1,500/mcL · platelets >/= 75,000/mcL · total bilirubin </= 1.5 ×
             institutional upper limit of normal: no restriction to serum bilirubin level if
             Gilbert's syndrome is diagnosed or suspected · AST(SGOT)/ALT(SGPT) </= 2.5 ×
             institutional upper limit of normal, (</= 3x upper limit of normal for AST and ALT for
             those subjects with liver metastasis) · creatinine </= 1.3 × institutional upper limit
             of normal OR · creatinine clearance >/= 60 mL/min/1.73 m2 for patients with creatinine
             levels above 1.3 X institutional upper limit of normal.

         10. Ability to understand and the willingness to sign a written informed consent document.

         11. For Cohort B, patients must have at least 1 measureable parenchymal brain metastasis
             of at least 10 mm in the greatest diameter and no greater than 40 mm diameter. There
             must be at least one parenchymal brain metastasis that has not received any previous
             locally-directed treatment (i.e. surgery or radiation), or that has progressed after
             prior treatment for the brain metastases (i.e. surgery or radiation).

         12. Male subjects must agree to use contraception, this criterion must be followed from
             the time of the first dose of study medication until 4 weeks after the last dose of
             study medication. However, it is advised that contraception be used for a total of 16
             weeks following the last dose (based on the lifecycle of sperm).

         13. A female subject is eligible to participate if she is of: Non-childbearing potential
             defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or
             postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a
             blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/mL and
             estradiol < 40 pg/mL (<140 pmol/L) is confirmatory]. Females on hormone replacement
             therapy (HRT) and whose menopausal status is in doubt will be required to use
             contraception if they wish to continue their HRT during the study. Following
             confirmation of their post-menopausal status, they can resume use of HRT during the
             study without use of a contraceptive method.

         14. (cont' from Inclusion #12) • Child-bearing potential and agrees to use one of the
             contraception methods listed in Section 7.1.1 for an appropriate period of time (as
             determined by the product label or investigator) prior to the start of dosing to
             sufficiently minimize the risk of pregnancy at that point. Female subjects must agree
             to use contraception until 4 weeks after the last dose of study medication, and must
             have a negative serum pregnancy test within 14 days prior to the start of dosing.
             Note: Oral contraceptives are not reliable due to potential drug-drug interaction.

        Exclusion Criteria:

          1. Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or
             biologic therapy) except a selective RAF inhibitor.

          2. Patients must not have previously received a selective BRAF inhibitor (RO5185426,
             GSK2118436) and a selective MEK inhibitor (AZD6244, GSK1120212) concurrently.

          3. Received an investigational anti-cancer drug within four weeks or five half-lives
             (whichever is shorter) of study drug administration, other than BRAF inhibitor--at
             least 14 days must have passed between the last dose of the prior investigational
             anti-cancer drug and the first dose of study drug. However, there is no required
             washout period for any BRAF inhibitors at least until the baseline biopsy is
             performed.

          4. Current use of a prohibited medication or requires any of these medications during
             treatment with study drug.

          5. Any major surgery, within the last 3 weeks. Radiotherapy, or immunotherapy within the
             last 2 weeks.

          6. Unresolved toxicity greater than NCI-Common Toxicity Criteria for Adverse Effects
             (CTCAE) v4 Grade 1 from previous anti-cancer therapy except alopecia and peripheral
             neuropathy, for which </= grade 2 toxicity is allowed to participate.

          7. Presence of rheumatoid arthritis.

          8. History of retinal vein occlusion or central serous retinopathy, or predisposing
             factors to retinal vein occlusion or central serous retinopathy (e.g. uncontrolled
             glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension,
             diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes).

          9. Presence of active gastrointestinal disease or other condition that will interfere
             significantly with the absorption, distribution, metabolism, or excretion of drugs.

         10. Brain Metastases a. For cohort A, patients will be excluded if they have brain
             metastases, unless they have been previously treated brain metastases with surgery or
             stereotactic radiosurgery and the disease has been confirmed stable (i.e., no increase
             in lesion size) for at least 4 weeks with MRI scans using contrast prior to Day 1.
             Subjects are not permitted to receive enzyme-inducing anti-epileptic drugs and/or
             steroids to control symptoms/signs of brain metastases. Patients previously treated
             with whole brain radiation therapy must have confirmed stable disease for at least 12
             weeks prior to starting treatment. However, untreated asymptomatic brain metastasis
             less than 10 mm will be allowed if no steroid and anti-epileptic drugs are used.

         11. 10 (con't) b. For cohort B, patients may not have any evidence of leptomeningeal
             disease. Use of corticosteroids is permitted as long as the dose of steroids required
             for symptom control has been stable or decreasing for at least 3 weeks prior to the
             first dose of study treatment.

         12. History of acute coronary syndromes (including myocardial infarction and unstable
             angina), coronary angioplasty, or stenting within the past 6 months.

         13. Corrected QT interval (QTc) >/= 480 msec (>/= 500 msec for subjects with Bundle Branch
             Block).

         14. Uncontrolled arrhythmias. • Subjects with controlled atrial fibrillation for >1 month
             prior to study Day 1 are eligible.

         15. Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA)
             functional classification system.

         16. Abnormal cardiac valve morphology (subjects with minimal abnormalities can be entered
             on study if deemed not clinically significant)

         17. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to the study drugs, or excipients. NOTE: To date there are no known
             FDA approved drugs chemically related to GSK2118436 or GSK1120212.

         18. Pregnant or lactating female.

         19. Unwillingness or inability to follow the procedures required in the protocol.

         20. Uncontrolled diabetes, hypertension or other medical conditions that may interfere
             with assessment of toxicity

         21. Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency.