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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04720768




Registration number
NCT04720768
Ethics application status
Date submitted
15/09/2020
Date registered
22/01/2021
Date last updated
5/01/2024

Titles & IDs
Public title
Encorafenib, Binimetinib and Palbociclib in BRAF-mutant Metastatic Melanoma CELEBRATE
Scientific title
A 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 (The CELEBRATE Study)
Secondary ID [1] 0 0
17/021
Universal Trial Number (UTN)
Trial acronym
CELEBRATE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Melanoma 0 0
Metastasis 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Binimetinib
Treatment: Drugs - Encorafenib
Treatment: Drugs - Palbociclib

Experimental: Dose escalation phase - 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


Treatment: Drugs: Binimetinib
MEK inhibitor

Treatment: Drugs: Encorafenib
BRAF inhibitor

Treatment: Drugs: Palbociclib
CDK4/6 inhibitor
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Dose-limiting toxicity (DLTs)
Timepoint [1] 0 0
The assessment period of DLT for each patient is the first cycle (28 days) of treatment
Secondary outcome [1] 0 0
Adverse events (AEs) of Encorafenib, Binimetinib and Palbociclib
Timepoint [1] 0 0
Trough study completion, up until 12 months after last patient commences treatment
Secondary outcome [2] 0 0
Tolerability as defined 80% compliance with each of Encorafenib, Binimetinib and Palbociclib individually.
Timepoint [2] 0 0
28 days for encorafenib and binimetinib, 21 days for palbociclib
Secondary outcome [3] 0 0
Clinical effficacy defined by response
Timepoint [3] 0 0
8 weeks after commencement of treatment
Secondary outcome [4] 0 0
Clinical efficacy as defined by time to progression
Timepoint [4] 0 0
From the date of registration until the date of disease progression
Secondary outcome [5] 0 0
Clinical efficacy as defined by progression free survival
Timepoint [5] 0 0
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)
Secondary outcome [6] 0 0
Clinical efficacy as defined by overall survival
Timepoint [6] 0 0
From start of treatment until the date of death from any cause, up to approximately 18months)

Eligibility
Key inclusion criteria
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.
Minimum age
18 Years
Maximum age
100 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients with uveal melanoma.

2. 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).

3. Patients receiving enzyme inducing anti-epileptic drugs (as listed in Appendix 5).

4. History of acute or chronic pancreatitis.

5. 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).

6. 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

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1/Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
4/06/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
4/12/2024
Actual
Sample size
Target
78
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Box Hill Hospital - Box Hill
Recruitment hospital [2] 0 0
Austin Hospital - Heidelberg
Recruitment hospital [3] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [4] 0 0
Alfred Health - Melbourne
Recruitment postcode(s) [1] 0 0
3128 - Box Hill
Recruitment postcode(s) [2] 0 0
3084 - Heidelberg
Recruitment postcode(s) [3] 0 0
3000 - Melbourne
Recruitment postcode(s) [4] 0 0
3004 - Melbourne

Funding & Sponsors
Primary sponsor type
Other
Name
Peter MacCallum Cancer Centre, Australia
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04720768
Trial related presentations / publications
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.
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)
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.
Public notes

Contacts
Principal investigator
Name 0 0
Grant McArthur, Prof
Address 0 0
Peter MacCallum Cancer Centre, Australia
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Grant McArthur, Prof
Address 0 0
Country 0 0
Phone 0 0
+61385595000
Fax 0 0
Email 0 0
Grant.McArthur@petermac.org
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04720768