Brief Summary
This is an open-label, phase IB, non-randomised study consisting of a dosethe amount of medication taken escalation phase and expansion phase, evaluating the safety, tolerability and preliminary efficacy of the combination of encorafenib, binimetinib and palbociclib in patients with BRAF-mutant metastatic melanomaa type of cancer that develops from melanocytes, which are the cells that produce pigment generally in the skin (but can develop in other areas of the body).
Dose escalation phase: Previously treated or treatment-naïve patients will be evaluated after the first cycle for dose-limiting toxicities to ascertain the recommended phase 2 dose (RP2D) of encorafenib, binimetinib and palbociclib.
Expansion phase: Two cohorts of patients will be further evaluated for the efficacy and safety of the RP2D of palbociclib with encorafenib and binimetinib. Cohort 1 will include patients naïve to both BRAF and MEK inhibitors. Cohort 2 will include patients with either primary or acquired resistance to both BRAF and MEK inhibitors.
Intervention / Treatment
- Drug: Binimetinib
- Drug: Encorafenib
- Drug: Palbociclib
Inclusion Criteria
Dose Escalation Phase only: (Australia only)
- Patients who are naïve to, or have received prior BRAF and MEK inhibitor combination therapy. Prior treatment with chemotherapya cancer treatment that uses drugs to kill or slow the growth of cancer cells, while minimising damage to healthy cells and biological therapy (e.g. checkpoint inhibitor therapy) is permitted.
Dose Expansion Phase only: (All sites)
- 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.
- 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):
- Patients (male and female) age ≥ 18 years
- Has provided written informed consenta process in which a patient receives detailed information about a procedure or treatment, including its potential risks, benefits, and alternatives. The patient then has the opportunity to understand the information and voluntarily agree to the procedure or treatment. prior to any screeningtesting for cancer or conditions that can lead to cancer before symptoms appear, also known as cancer screening procedure
- Histologically confirmed diagnosisthe process of identifying a disease based on signs and symptoms, patient history and medical test results of unresectable stage III or IV melanoma (stage IIIB to IV per American Joint Committee on Cancera disease where abnormal cells split without control and spread to other nearby body tissue and/or organs [AJCC] 8th edition).
- Documented evidence of BRAF V600 mutation.
- Patients must provide either archival or newly obtained tumoura tissue mass that forms from groups of unhealthy cells sample at baseline. In addition, patients must agree to a mandatory biopsyremoval of a section of tissue to analyse for cancer cells during treatment and at the time of progression, if not medically contraindicated.
- 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.
- 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
- ECOG Performance Status ≤ 2
- Able to take oral medications
- Be willing and able to comply with all study requirements, including treatment, attending assessments and follow-up.
- 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.
- 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.