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

Inclusion Criteria: 1. Patients having histologically confirmed unresectable (Stage III) or metastatic (Stage IV) malignant melanoma with a positive BRAF mutation result determined by Roche CoDx or local CLIA-certified analysis 2. Patients naïve to a selective BRAF inhibitor therapy or must have progressed after therapy on a selective BRAF inhibitor. For patients entering the protocol progressing on vemurafenib therapy, they must be tolerant of the 960 mg po bid dose. 3. Tumor biopsies are optional in this study except for patients entering the mandatory biopsy cohorts. Nevertheless tumor biopsies are encouraged, especially in patients with accessible tumors for biopsy to include the collection of formalin-fixed, paraffin-embedded (FFPE) and fresh- frozen tissue (FF) as outlined in the biomarker sections of the protocol. Willingness of patient to give consent of biopsy, should be ascertained 4. Patients of ≥ 18 years of age 5. Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0 or1 6. Patients with measurable disease per 'Response Evaluation Criteria In Solid Tumors' (RECIST version 1.1) 7. Patients must have normal organ and adequate marrow function 8. Patients with ability to swallow and retain oral medication 9. Women of childbearing potential and men willing to agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the duration of study participation and for at least 4 weeks after withdrawal from the study, unless they are surgically sterilized. 10. Negative serum pregnancy test within 10 days prior to commencement of therapy dosing in premenopausal women. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year. 11. Ability to understand and the willingness to offer a written Informed Consent document prior to the screening procedures for participation into the study * For Extension phase- * For patients entering the protocol progressing on vemurafenib therapy, they must be tolerant of the vemurafenib dose selected for the extension phase 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.