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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04720768
Recruitment Status : Recruiting
First Posted : January 22, 2021
Last Update Posted : January 22, 2021
Sponsor:
Information provided by (Responsible Party):
Peter MacCallum Cancer Centre, Australia

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.


Condition or disease Intervention/treatment Phase
Melanoma Metastasis Drug: Binimetinib Drug: Encorafenib Drug: Palbociclib Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 78 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description: This is an open-label, phase IB, non-randomised study consisting of a dose escalation phase and expansion phase
Masking: None (Open Label)
Primary Purpose: Treatment
Official 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)
Actual Study Start Date : June 4, 2020
Estimated Primary Completion Date : December 4, 2022
Estimated Study Completion Date : December 4, 2023

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
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

Drug: Binimetinib
MEK inhibitor

Drug: Encorafenib
BRAF inhibitor

Drug: Palbociclib
CDK4/6 inhibitor




Primary Outcome Measures :
  1. Dose-limiting toxicity (DLTs) [ Time Frame: The assessment period of DLT for each patient is the first cycle (28 days) of treatment ]
    Dose-Limiting Toxicity is defined as a toxicity that prevents further administration of the trial treatment at that dose level


Secondary Outcome Measures :
  1. Adverse events (AEs) of Encorafenib, Binimetinib and Palbociclib [ Time Frame: Trough study completion, up until 12 months after last patient commences treatment ]
    Adverse events including type, grade and relationship to study treatment according to CTCAE v5.0

  2. Tolerability as defined 80% compliance with each of Encorafenib, Binimetinib and Palbociclib individually. [ Time Frame: 28 days for encorafenib and binimetinib, 21 days for palbociclib ]
    Tolerability: defined as ability to complete (with 80% compliance) cycle 1 of combination therapy. Compliance is defined as the percentage of days of treatment given at the assigned dose relative to the total number of days that treatment was intended to be given at the assigned dose (i.e. 28 days for encorafenib and binimetinib, 21 days for palbociclib). Eighty percent compliance must be achieved for each of the drugs considered separately for tolerability to be achieved.

  3. Clinical effficacy defined by response [ Time Frame: 8 weeks after commencement of treatment ]

    Clinical efficacy as defined by:

    o Best response at 8 weeks from start of treatment using RECIST v1.1 criteria


  4. Clinical efficacy as defined by time to progression [ Time Frame: From the date of registration until the date of disease progression ]

    Clinical efficacy as defined by:

    - Time to progression measured from the date of registration until the date of disease progression. Death, loss to follow up and follow up to the close out date without disease progression will be censoring events.


  5. Clinical efficacy as defined by progression free survival [ Time Frame: 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) ]

    Clinical efficacy as defined by:

    - Progression-free survival measured from the date of registration until the date of disease progression or the date of death from any cause. . Loss to follow up and follow up to the close out date without progression or death will be censoring events.


  6. Clinical efficacy as defined by overall survival [ Time Frame: From start of treatment until the date of death from any cause, up to approximately 18months) ]

    Clinical efficacy as defined by:

    - Overall survival measured from the date of registration until the date of death from any cause. Loss to follow up and follow up to the close out date without death will be censoring events.



Other Outcome Measures:
  1. Response rates on Cycle 1 Day 15 [ Time Frame: 8 weeks after commencement of treatment ]
    FDG-PET response rates on Cycle 1 Day 15

  2. Mutation status of circulating DNA [ Time Frame: From the date of registration to disease progression, up to approximately 18 months ]
    Mutational status of circulating tumour DNA at baseline, during treatment and at progression. Circulating tumour DNA will extracted and anakysed for BRAF V600E and V600K mutation status.

  3. Genomic alterations in tumour tissue [ Time Frame: From the date of registration to disease progression, up to approximately 18 months ]
    Genomic alterations in tumour tissue at baseline, on treatment and progression.Biomaker analyses to be performed include immunochemistry for molecules known to be relevant of the MAPK and CDK4 pathways, for molecules that are potential PD biomarkers for the trail drugs, potentially related to response/resistance, evaluation of the tumour microenvironment and BRAF mutations and other somatic mutations

  4. Presence of biomarkers [ Time Frame: From the time of screening, during treatment and 30 days after treatment ]
    Biomarkers in tumour tissue, blood and faecal microbiome for response/resistance



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04720768


Contacts
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Contact: Grant McArthur, Prof +61385595000 Grant.McArthur@petermac.org
Contact: Jennifer Soon, Dr Jennifer.Soon@petermac.org

Locations
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Australia, Victoria
Peter MacCallum Cancer Centre Recruiting
Melbourne, Victoria, Australia, 3000
Contact: Grant A McArthur, MBBS, PhD    +61 3 8559 5000    Grant.McArthur@petermac.org   
Contact: Jennifer A Soon, MBBS (Hons)    +61 3 8559 5000    Jennifer.Soon@petermac.org   
Sponsors and Collaborators
Peter MacCallum Cancer Centre, Australia
Investigators
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Principal Investigator: Grant McArthur, Prof Peter MacCallum Cancer Centre, Australia
Publications:
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Responsible Party: Peter MacCallum Cancer Centre, Australia
ClinicalTrials.gov Identifier: NCT04720768    
Other Study ID Numbers: 17/021
First Posted: January 22, 2021    Key Record Dates
Last Update Posted: January 22, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified patient data may be shared with external collaborators at other institutions. Any future data sharing agreement for future research will ensure data security and patient confidentiality in maintained.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Peter MacCallum Cancer Centre, Australia:
BRAF-mutant positive
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Palbociclib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action