Clinical Drug Experience Knowledgebase

Criteria

Inclusion Criteria:

Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
Patients must have histologically or cytologically confirmed Stage IV or recurrent or unresectable Stage III melanoma.
BRAF mutation-positive melanoma (i.e., V600E, V600K or V600D)
For Cohort A, patients must have easily accessible tumor for a mandatory biopsy. This is not required for patients enrolled on Cohort B.
Patients must have measurable disease, defined by RECIST 1.1
Patients must have tumor lesions which is refractory or resistant to a selective BRAF inhibitor (RO5185426 or GSK2118436).
Age >/= 16 years.
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
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.
Ability to understand and the willingness to sign a written informed consent document.
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).
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).
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.
(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:

Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) except a selective RAF inhibitor.
Patients must not have previously received a selective BRAF inhibitor (RO5185426, GSK2118436) and a selective MEK inhibitor (AZD6244, GSK1120212) concurrently.
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.
Current use of a prohibited medication or requires any of these medications during treatment with study drug.
Any major surgery, within the last 3 weeks. Radiotherapy, or immunotherapy within the last 2 weeks.
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.
Presence of rheumatoid arthritis.
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).
Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs.
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.
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.
History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within the past 6 months.
Corrected QT interval (QTc) >/= 480 msec (>/= 500 msec for subjects with Bundle Branch Block).
Uncontrolled arrhythmias. • Subjects with controlled atrial fibrillation for >1 month prior to study Day 1 are eligible.
Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
Abnormal cardiac valve morphology (subjects with minimal abnormalities can be entered on study if deemed not clinically significant)
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.
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 (G6PD) deficiency.