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Stereotactic Radiosurgery Added to Binimetinib and Encorafenib in Patients With BRAFV600 Melanoma With Brain Metastasis (BECOME-MB)

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: NCT04074096
Recruitment Status : Not yet recruiting
First Posted : August 29, 2019
Last Update Posted : January 30, 2020
Sponsor:
Collaborator:
EADO - European Association of Dermato Oncology
Information provided by (Responsible Party):
UNICANCER

Brief Summary:
This study evaluates the addition of stereotactic radiosurgery (SRS) to the combination of binimetinib plus encorafenib in the treatment of BRAFV600 mutation-positive Melanoma with brain metastases (MBM).

Condition or disease Intervention/treatment Phase
Brain-only Metastased BRAFV600 Melanoma Radiation: Stereotaxic radiosurgery (SRS) Drug: Binimetinib Oral Tablet Drug: Encorafenib Oral Capsule Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2, Randomised Trial Testing the Addition of Stereotactic Radiosurgery to Binimetinib and Encorafenib in Comparison With Binimetinib and Encorafenib Alone in Patients With BRAFV600 Mutation-positive Melanoma With Brain Metastasis
Estimated Study Start Date : September 2020
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : September 2027

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: SRS followed by Encorafenib + binimetinib
Upfront SRS of all lesions ≥5 mm in diameter (or ≥3 mm if other cerebral metastases >5 mm); followed by encorafenib 450 mg PO QD + binimetinib 45 mg PO BID. The treatment should be started more than 2 days and less than 8 days (excluded) after the SRS
Radiation: Stereotaxic radiosurgery (SRS)

Upfront SRS of all lesions ≥5 mm in diameter (or ≥3 mm if other cerebral metastases >5 mm); followed by encorafenib 450 mg PO QD + binimetinib 45 mg PO BID. The treatment should be started more than 2 days and less than 8 days (excluded) after the SRS.

The binimetinib and encorafenib combination will be administered according to a 28-day cycle.


Drug: Binimetinib Oral Tablet

encorafenib 450 mg PO QD + binimetinib 45 mg PO BID.

The binimetinib and encorafenib combination will be administered according to a 28-day cycle.

Other Name: Mektovi

Drug: Encorafenib Oral Capsule
encorafenib 450 mg PO QD + binimetinib 45 mg PO BID. he binimetinib and encorafenib combination will be administered according to a 28-day cycle.
Other Name: Braftovi

Active Comparator: Encorafenib + binimetinib
Encorafenib 450 mg oral route (PO) once daily (QD) + binimetinib 45 mg PO twice daily (BID).
Drug: Binimetinib Oral Tablet

encorafenib 450 mg PO QD + binimetinib 45 mg PO BID.

The binimetinib and encorafenib combination will be administered according to a 28-day cycle.

Other Name: Mektovi

Drug: Encorafenib Oral Capsule
encorafenib 450 mg PO QD + binimetinib 45 mg PO BID. he binimetinib and encorafenib combination will be administered according to a 28-day cycle.
Other Name: Braftovi




Primary Outcome Measures :
  1. intracranial (IC) progression-free survival (PFS) [ Time Frame: From randomisation until IC-PD, or death, whichever occurs first, up to 12 months. ]
    Time from randomisation until IC progression (PD) as evaluated by centralized assessment using modified response evaluation criteria in solid tumours version 1.1 (RECIST v1.1), or death, whichever occurs first.


Secondary Outcome Measures :
  1. Intracranial-response rate (RR) [ Time Frame: From randomisation until IC-CR or IC-PR, up to 60 months. ]
    Percentage of patients with a confirmed IC complete response (CR) or IC partial response (PR) as assessed by the investigator using modified RECIST v1.1.

  2. Intracranial disease control (DC) [ Time Frame: From randomisation until IC-CR or IC-PR or stable intracranial disease, up to 60 months. ]
    Percentage of patients with an IC-CR or IC-PR or stable intracranial disease as assessed by the investigator using modified RECIST v1.1.

  3. Extracranial (EC) response rate [ Time Frame: From randomisation until confirmed EC-CR or EC-PR, up to 60 months. ]
    Percentage of patients with a confirmed EC-CR or EC-PR

  4. Overall response rate (ORR) [ Time Frame: From randomisation until confirmed CR or PR, up to 60 months. ]
    Percentage of patients with a confirmed CR or PR

  5. Duration of intracranial, extracranial, and overall response [ Time Frame: Time from first observation of, IC-, EC-, or overall response respectively (i.e. CR or PR), until disease progression (PD), up to 60 months. ]
    Time from first observation of, IC-, EC-, or overall response respectively (i.e. CR or PR), until disease progression (PD) according to modified RECIST v1.1 (intracranial disease) or RECIST v1.1 (extracranial disease) or death, whichever occurs first.

  6. Duration of response of treated target lesions [ Time Frame: From first documented response (i.e. CR or PR) until PD of treated target lesions or death, whichever occurs first, up to 60 months. ]
    Time from first documented response (i.e. CR or PR) until PD of treated target lesions or death, whichever occurs first.

  7. Progression-free survival (PFS) [ Time Frame: From randomisation until IC-PD, or death, whichever occurs first, up to 60 months. ]
    Time from randomisation until IC-PD according to modified RECIST v1.1, EC-PD according to RECIST v1.1, or death, whichever occurs first.

  8. Overall survival (OS) [ Time Frame: From randomisation until death due to any cause, up to 60 months. ]
    Time from randomisation until death due to any cause.

  9. Global Quality of Life (HRQOL) - QLQ-C30 [ Time Frame: From randomisation until end of treatment, up to 60 months. ]

    This self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials.

    The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease.

    All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.


  10. Quality of Life (HRQOL) in patients with brain mestastis - QLQ-BN20 [ Time Frame: From randomisation until end of treatment, up to 60 months. ]

    This EORTC brain cancer specific questionnaire is intended to supplement the QLQ-C30 questionaire.

    The QLQ-BN20 contains 20 items organized into four scales (three items each: future uncertainty, visual disorder, motor dysfunction, and communication deficit), and seven single items (headaches, seizures, drowsiness, hair loss, itchy skin, weakness of legs, and bladder control). All items are rated on a four-point Likert-type scale (1 = "not at all," 2 = "a little," 3 = "quite a bit," and 4 = "very much"), and are linearly transformed to a 0-100 scale, with higher scores indicating more severe symptoms.


  11. Cognitive performance [ Time Frame: From randomisation until end of treatment, up to 60 months. ]
    Assessed using the Montreal Cognitive Assessment (MoCA).

  12. Frequency and severity of adverse events [ Time Frame: From randomisation until end of treatment, up to 60 months. ]
    Assessed according to National Cancer Institute - Common terminology criteria for adverse events version 5.0 (NCI-CTCAE v5.0).

  13. Safety assessment [ Time Frame: From randomisation until end of treatment, up to 60 months. ]
    Other skin, laboratory, vital-sign, cardiac function, and neurological assessment data will be assessed according to National Cancer Institute - Common terminology criteria for adverse events version 5.0 (NCI-CTCAE v5.0). The assesment will be showed according to the different grades.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  1. Provided written informed consent prior to any trial specific procedures.
  2. Aged ≥18 years.
  3. An Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
  4. Histologically confirmed Stage IV cutaneous melanoma that is metastatic to the brain.
  5. Presence of BRAFV600E/K/D/R mutation according to a locally validated BRAF Assay.
  6. Candidacy for SRS therapy validated by the radiation oncologist and/or neurosurgeon at the investigative centre. This should be documented in the patient file.
  7. No more than one previous systemic treatment regimen for distant metastatic melanoma including chemo-, cytokine-, immune-, biological- and vaccine therapy.

    Note: Prior systemic treatment in the adjuvant setting is permitted and does not count as a previous line of metastatic treatment. Any prior, anti-CTLA4 or anti-PD-1 treatment must have ended ≥8 weeks prior to treatment initiation.

  8. No more than one previous local intracranial therapy (e.g. craniotomy, SRS). Note: Treatment with stereotactic radiosurgery must have been completed ≥14 days prior to randomisation and this lesion cannot be target lesion for radiosurgery.
  9. Able to undergo gadolinium-enhanced magnetic resonance imaging (MRI).
  10. At least one measurable intracranial lesion for which all of the following criteria have to be met:

    1. Previously untreated (no local therapy including local radiotherapy, resection, radiosurgery) or progressive after previous local therapy.
    2. Longest diameter ≥5 mm as determined by contrast-enhanced MRI. Longest diameter ≥3 mm is acceptable for other IC lesions provided there is at least one lesion ≥5 mm.
    3. Cumulative Intracranial Target Volume (CITV) ≤12 cm³ as determined by contrast-enhanced MRI.
  11. All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values) must be resolved or Grade 1 according to National Cancer Institute - Common terminology criteria for adverse events version 5 (NCI-CTCAE v5.0).
  12. Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption (malabsorption syndrome, major resection of the stomach or bowels).
  13. Adequate bone marrow, organ function, and laboratory parameters; defined as the following (all criteria must be met):

    1. Absolute neutrophil count ≥1.5 x 10⁹/L;
    2. Haemoglobin ≥9 g/dL without transfusions;
    3. Platelets ≥100 x 10⁹/L without transfusions;
    4. Aspartate aminotransferase and alanine aminotransferase ≤2.5 × upper limit of normal (ULN); ≤5 x ULN is acceptable for patient with liver metastases;
    5. Total bilirubin ≤2 x ULN;
    6. Creatinine ≤1.5 mg/dL, or calculated creatinine clearance ≥50 mL/min (as determined using the modification of diet in renal disease (MDRD) method).
  14. Adequate cardiac function, defined as the following (all criteria must be met):

    1. Left ventricular ejection fraction (LVEF) ≥ local lower normal limit (LLN) as determined by a multigated acquisition (MUGA) scan or echocardiogram;
    2. Baseline QT interval corrected for heart rate QTc ≤480 ms using standard formula.
  15. Women of childbearing potential (WOCBP) or men must agree to refrain from sexual activity or use adequate contraception for the duration of study treatment and for 30 days after completing treatment.
  16. Affiliated to or a beneficiary of the local social security system or equivalent.

Exclusion Criteria:

NON-INCLUSION CRITERIA:

Patients are not eligible to participate in the trial if they meet any of the following criteria:

  1. More than 10 intracranial metastases.
  2. Presence of neurological symptoms related to intracranial metastases which induce alteration of the ECOG performance status to 2 or more or require immediate radiation treatment.
  3. Prior treatment with a BRAF inhibitor or a MEK inhibitor.
  4. Ocular melanoma.
  5. Brain metastases that necessitate immediate neurosurgery. Postoperative SRS is not allowed.
  6. Any previous treatment with whole-brain radiation.
  7. Presence of leptomeningeal disease or any parenchymal brain metastasis >30 mm in longest diameter.
  8. Current or expected use of a strong inhibitor of CYP3A4.
  9. History of malignancy other than disease under study occurring within 3 years of study enrolment with the exception of completely resected non-melanoma skin cancer or indolent second malignancies.
  10. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that, in the opinion of the investigator, could interfere with the patient's safety, obtaining informed consent, or compliance with study procedures.
  11. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (patients with laboratory evidence of cured HBV and/or HCV will be permitted).
  12. A history or evidence of cardiovascular risk including any of the following:

    1. Current LVEF < LLN;
    2. A QTc >480 msec;
    3. A history or evidence of current clinically significant uncontrolled arrhythmias; Note: Patients with atrial fibrillation controlled for >30 days prior to randomisation are eligible.
    4. A history or evidence of current >Class II congestive heart failure as defined by the New York Heart Association guidelines;
    5. Treatment refractory hypertension defined as a systolic blood pressure of >140 mmHg and/ or diastolic blood pressure >90 mmHg, which cannot be controlled by antihypertensive therapy;
    6. Patients with intra-cardiac defibrillators;
    7. A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting less than 6 months prior to enrolment.
  13. A history or current evidence of retinal vein occlusion.
  14. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, and their excipients.
  15. Hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption
  16. Participation in another therapeutic trial within the 30 days prior to randomization
  17. Pregnant or nursing female. Note: WOCBP must have a negative urine or serum pregnancy test within 14 days prior to enrolment.
  18. History of interstitial lung disease or pneumonitis.

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): NCT04074096


Contacts
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Contact: geraldine martineau +33144235575 g-martineau@unicancer.fr

Sponsors and Collaborators
UNICANCER
EADO - European Association of Dermato Oncology
Investigators
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Principal Investigator: Philippe Saiag, Prof Ambroise Paré Hospital
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Responsible Party: UNICANCER
ClinicalTrials.gov Identifier: NCT04074096    
Other Study ID Numbers: RAD06 - UC-0107/1810
First Posted: August 29, 2019    Key Record Dates
Last Update Posted: January 30, 2020
Last Verified: January 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
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