CELEBRATE: This phase I/II trial will begin to understand how safe, well tolerated and effective a combination therapy is for the treatment of BRAF-mutant melanoma that has spread to other parts of the bodyA Phase 1B Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of the Combination of Encorafenib, Binimetinib and Palbociclib in Patients With BRAF-mutant Metastatic Melanoma

Inclusion

Dose Escalation Phase only: (Australia only)

1. Patients who are naïve to, or have received prior BRAF and MEK inhibitor combination therapy. Prior treatment with chemotherapy and biological therapy (e.g. checkpoint inhibitor therapy) is permitted.

   Dose Expansion Phase only: (All sites)

2. Cohort 1: Patients who are naïve to BRAF and MEK inhibitor therapy. Prior treatment with chemotherapy and biological therapy (e.g. checkpoint inhibitor therapy) is permitted.

3. Cohort 2: Patients who have progressed on prior BRAF and MEK inhibitor combination therapy. Prior treatment with chemotherapy and biological therapy (e.g. checkpoint inhibitor therapy) is permitted.

   For both phases (All sites):

4. Patients (male and female) age ≥ 18 years
5. Has provided written informed consent prior to any screening procedure
6. Histologically confirmed diagnosis of unresectable stage III or IV melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC] 8th edition).
7. Documented evidence of BRAF V600 mutation.
8. Patients must provide either archival or newly obtained tumour sample at baseline. In addition, patients must agree to a mandatory biopsy during treatment and at the time of progression, if not medically contraindicated.
9. Evidence of measurable disease, as determined by RECIST v1.1. Note: Lesions in areas of prior radiotherapy or other locoregional therapies (e.g., percutaneous ablation) should not be considered measurable, unless lesion progression has been documented since the therapy.

10. Patients must have adequate haematological, coagulation, renal and hepatic functions as defined by:

    Absolute neutrophil count ≥ 1.5 x 109/L Haemoglobin ≥ 10 g/L without transfusions Platelet count ≥ 100 x 109/L without transfusions Total serum creatinine ≤ 1.5 x ULN or calculated or directly measured CrCl < 50% LLN (lower limit of normal) Serum total bilirubin ≤ 1.5 x ULN ( 3 x ULN in cases of known Gilbert's syndrome) AST/SGOT or ALT/SGPT ˂ 3 x ULN, or ˂ 5 x ULN if liver metastases are present PT/INR or aPTT < 1.5xULN

11. ECOG Performance Status ≤ 2
12. Able to take oral medications
13. Be willing and able to comply with all study requirements, including treatment, attending assessments and follow-up.
14. Female patients of childbearing potential must have a negative serum pregnancy test at screening: and be willing to use two methods of birth control or be surgically sterile: or abstain from heterosexual activity for the course of the study through to 3 months after the last dose of study medication. Patients of childbearing potential are those who have not been surgically sterilised or have not been free from menses for > 1 year.
15. Sexually active males must use a condom during intercourse while taking the study drugs and for 3 months after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomised men in order to prevent delivery of the drug via seminal fluid.