Encorafenib, Binimetinib and Palbociclib in BRAF-mutant Metastatic Melanoma CELEBRATE

NCT04720768 | Unknown Phase 1 FDA Drug

• 1 other identifier: 17/021
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 4

Brief Summary

This is an open-label, phase IB, non-randomised study consisting of a dose 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 melanoma. 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.

Conditions

Melanoma; Metastasis

Keywords

BRAF-mutant positive

Outcome Measures

Primary Outcomes (1)

• Dose-limiting toxicity (DLTs)

  Dose-Limiting Toxicity is defined as a toxicity that prevents further administration of the trial treatment at that dose level

  The assessment period of DLT for each patient is the first cycle (28 days) of treatment

Secondary Outcomes (6)

• Adverse events (AEs) of Encorafenib, Binimetinib and Palbociclib

  Trough study completion, up until 12 months after last patient commences treatment

• Tolerability as defined 80% compliance with each of Encorafenib, Binimetinib and Palbociclib individually.

  28 days for encorafenib and binimetinib, 21 days for palbociclib

• Clinical effficacy defined by response

  8 weeks after commencement of treatment

• Clinical efficacy as defined by time to progression

  From the date of registration until the date of disease progression

• Clinical efficacy as defined by progression free survival

  From the date of registration until the date of first documented disease progression or date of death due to any cause, whichever occurs first (up to approximately 18 months)

Other Outcomes (4)

• Response rates on Cycle 1 Day 15

  8 weeks after commencement of treatment

• Mutation status of circulating DNA

  From the date of registration to disease progression, up to approximately 18 months

• Genomic alterations in tumour tissue

  From the date of registration to disease progression, up to approximately 18 months

Study Arms (1)

Dose escalation phase

EXPERIMENTAL

Encorafenib (tablet) 450mg PO daily Binimetinib (tablet) 45mg PO BD Palbociclib (tablet) variable dose PO daily for 21 consecutive days on treatment, followed by 7 consecutive days off treatment in a 28 day cycle

Drug: Binimetinib; Drug: Encorafenib; Drug: Palbociclib

Interventions

Binimetinib DRUG

MEK inhibitor

Dose escalation phase

Encorafenib DRUG

BRAF inhibitor

Dose escalation phase

Palbociclib DRUG

CDK4/6 inhibitor

Dose escalation phase

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Dose Escalation Phase only: (Australia only)
• 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)
• 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 consent prior to any screening procedure
• Histologically confirmed diagnosis of unresectable stage III or IV melanoma (stage IIIB to IV per American Joint Committee on Cancer \[AJCC\] 8th edition).
• Documented evidence of BRAF V600 mutation.
• 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.
• 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

You may not qualify if:

• Patients with uveal melanoma.
• Patients with symptomatic or untreated brain metastases or leptomeningeal disease. Patients with previously treated or untreated for brain metastasis that are asymptomatic in the absence of corticosteroid therapy or on a stable dose of steroids for 4 weeks prior to registration are allowed to enroll. Brain metastases must be stable at least 4 weeks prior to registration with verification by imaging (e.g. brain MRI completed at screening demonstrating no current evidence of progressive brain metastases).
• Patients receiving enzyme inducing anti-epileptic drugs (as listed in Appendix 5).
• History of acute or chronic pancreatitis.
• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).
• Impaired cardiovascular function or clinically significant cardiac disease including any of the following:
• CHF requiring treatment (NYHA grade ≥ 2)
• LVEF \< 50% as determined by MUGA scan or ECHO
• History or presence of clinically significant ventricular arrhythmias or uncontrolled atrial fibrillation
• Clinically significant resting bradycardia
• Unstable angina pectoris ≤ 3 months prior to registration
• Acute Myocardial Infarction (AMI) ≤ 3 months prior to registration
• QTcF \> 480 ms
• Any heart disease that requires the use of a cardiac pacemaker or implantable cardioverter defibrillator ≤ 3 months prior to registration
• History of QT syndrome, Brugada syndrome or known

Sponsors & Collaborators

• Peter MacCallum Cancer Centre, Australia: lead

Study Sites (4)

Box Hill Hospital

Box Hill, Victoria, 3128, Australia

RECRUITING

Austin Hospital

Heidelberg, Victoria, 3084, Australia

RECRUITING

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3000, Australia

RECRUITING

Alfred Health

Melbourne, Victoria, 3004, Australia

RECRUITING

Related Publications (3)

• Ascierto PA, Dummer R, Gogas HJ, Flaherty KT, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, de Groot JWB, Loquai C, Gollerkeri A, Pickard MD, Robert C. Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. Eur J Cancer. 2020 Feb;126:33-44. doi: 10.1016/j.ejca.2019.11.016. Epub 2020 Jan 2.

  PMID: 31901705 BACKGROUND

• Ascierto PA, Bechter O, Wolter P. A phase Ib/II dose-escalation study evaluation triple combination therapy with a BRAF (encorafenib), MEK (binimetinib), and CDK4/6 (ribociclib) inhibitor in patients with BRAF V600-mutant solid tumours and melanoma. J Clin Oncol. 2017;35 (suppl; abst 9518)

  BACKGROUND

• Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, Shaik MN, Wilner KD, O'Dwyer PJ, Schwartz GK. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res. 2012 Jan 15;18(2):568-76. doi: 10.1158/1078-0432.CCR-11-0509. Epub 2011 Nov 16.

  PMID: 22090362 BACKGROUND

MeSH Terms

Conditions

Melanoma; Neoplasm Metastasis

Interventions

binimetinib; encorafenib; palbociclib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Grant McArthur, Prof

  Peter MacCallum Cancer Centre, Australia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Grant McArthur, Prof

CONTACT

+61385595000; Grant.McArthur@petermac.org

Joanna Chan, Dr

CONTACT

Joanna.Chan@petermac.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is an open-label, phase IB, non-randomised study consisting of a dose escalation phase and expansion phase

Study Record Dates

• First Submitted: September 15, 2020
• First Posted: January 22, 2021
• Study Start: June 4, 2020
• Primary Completion: December 4, 2024
• Study Completion: December 4, 2024
• Last Updated: January 5, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will share

Locations

AU (4)