Study of an Oral Cdk Inhibitor Administered With an Oral BRAF Inhibitor in Patients With Advanced or Inoperable Malignant Melanoma With BRAF Mutation

Exclusion Criteria

• •1. Prior malignancy (within the last 2 years) except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, in situ breast cancer, in situ prostate cancer or any other cancer for which the patient has been disease-free for at least 2 years
• •2. Patients who have received any prior chemotherapy, radiotherapy, biologic/targeted anti-cancer therapy (one week for BRAF inhibitor for melanoma) or surgery within 4 weeks (6 weeks for monoclonal antibodies, radioactive monoclonal antibodies or any radio-or toxin-immunoconjugates) before Day 1 of Investigational product administration and have not recovered (to \< Grade 1) from the toxic effects from any prior therapy
• •3. Patients having received any other investigational agents within 4 weeks prior to Day 1 of Investigational product administration and have not recovered completely (to \< Grade 1) from the side effects of the earlier investigational agent
• •4. Anticipated administration of any anti-cancer therapies (chemotherapy, radiation therapy, immunotherapy, biological therapy, hormonal therapy, surgery, and/or tumor embolisation) other than those administered in this study such as BRAF inhibitor
• •5. Patients with symptomatic or untreated leptomeningeal or brain metastases, or spinal cord compression \[patients with previous brain metastases will be allowed to enter the trial if metastases have been surgically removed or all known sites of metastases have been treated with stereotactic high dose radiosurgery. Patients must be off corticosteroids for at least one month and have a stable lesion with verification by imaging (CT/MRI) within 28 days prior to Day 1 of Investigational product administration\]
• •6. Patients with clinically significant medical condition of malabsorption, inflammatory bowel disease, chronic diarrheal condition, refractory nausea, vomiting or any other condition that will interfere significantly with the absorption of study drugs
• •7. Patients with mean QTc interval \>480 msec at screening
• •8. Treatment with drugs with potential to cause dysrhythmias including but not limited to terfenadine, quinidine, procainamide, diisopyramide, sotalol, probucol, bepridil, haloperidol, risperidone and/or indapamide
• •9. Patients on warfarin treatment
• •10. Any condition for which participation in this study as judged by the Investigator to be detrimental to the patient with (such as) inter-current illness including, but not limited to ongoing or active infection, New York Heart Association functional classification class III, or IV heart failure; unstable angina pectoris; cardiac arrhythmia; history of myocardial infarction; uncontrolled hypertension (blood pressure above 160/100 mm Hg despite antihypertensive treatment); coronary artery bypass graft; cerebrovascular accident; transient ischemic attack or pulmonary embolism during the previous 6 months or psychiatric illness/social situations that would jeopardize compliance with study requirements
• •11. Patients with a known immediate or delayed hypersensitivity reaction or idiosyncrasy to any other medication chemically related to P1446A-05 or vemurafenib, or excipients considered to be clinically significant by the investigator
• •12. Nursing woman
• •13. Patients with known HIV positivity or AIDS- related illness, or active Hepatitis B virus, and active Hepatitis C virus
• •14. Patients taking drugs known to prolong the QTc interval who cannot be switched to an alternative drug.
• •For Extension phase-
• •1. Patients with active second malignancy will be eligible as long as they do not need systemic therapy for the second malignancy
• •2. Patients with active brain metastases will be included in the study as long as the tumor size is less than 1 cm without the requirement of steroid use for neurological symptoms
• •3. Patients with evaluable metastatic disease will be allowed even if there is no measurable disease per RECIST 1.1. In this case patients with many sub centimeter in-transit skin/SQ nodules will be eligible for the biopsy cohort.