Binimetinib and Encorafenib for the Treatment of Metastatic Melanoma and Central Nervous System Metastases
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|ClinicalTrials.gov Identifier: NCT05026983|
Recruitment Status : Recruiting
First Posted : August 30, 2021
Last Update Posted : February 27, 2023
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|Condition or disease||Intervention/treatment||Phase|
|Clinical Stage IV Cutaneous Melanoma AJCC v8 Metastatic Melanoma Pathologic Stage IV Cutaneous Melanoma AJCC v8||Drug: Binimetinib Drug: Encorafenib Other: Questionnaire Administration||Phase 2|
I. To evaluate antitumor activity of high dosing regimen of encorafenib + binimetinib combination therapy for patients with BRAFV600-mutant melanoma brain metastases and/or leptomeningeal disease (LMD) as measured by progression free survival (PFS).
II. To evaluate the safety/tolerability of high dosing regimen of encorafenib + binimetinib combination therapy for patients with BRAFV600-mutant melanoma brain metastases and/or LMD.
I. To further evaluate antitumor activity of high dosing regimen of encorafenib + binimetinib combination therapy for patients with BRAFV600-mutant melanoma and/or LMD, as measured by brain metastasis response rate (BMRR), extracranial response rate, global response rate, brain metastases disease control rate (DCR), overall survival (OS), and duration of response (DOR).
I. To compare the immunological effects of this treatment on immune cells in the cerebrospinal fluid (CSF) to those observed in the peripheral blood.
II. To compare levels of encorafenib and binimetinib in the CSF and peripheral blood.
III. To assess neurocognitive function as measured by the Montreal Cognitive Assessment (MoCA) and MD Anderson Symptom Inventory brain tumor module (MDASI-BT).
Patients receive encorafenib orally (PO) once daily (QD) and binimetinib PO twice daily (BID) on day 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 12 weeks thereafter.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||35 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase II Study of Binimetinib With Encorafenib in Patients With Metastatic Melanoma and CNS Metastases|
|Actual Study Start Date :||December 27, 2021|
|Estimated Primary Completion Date :||May 1, 2025|
|Estimated Study Completion Date :||May 1, 2025|
Experimental: Treatment (encorafenib, binimetinib)
Patients receive encorafenib PO QD and binimetinib PO BID on day 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Questionnaire Administration
- Progression free survival (PFS) (Cohort A) [ Time Frame: At 3 months ]
- Incidence of dose-limiting toxicities (DLTs) [ Time Frame: Up to 28 days ]
- Incidence of adverse events (AEs) [ Time Frame: Up to 30 days after last dose ]Graded according to the NCI CTCAE version 4.03 and changes in clinical laboratory parameters, vital signs, ECGs, ECHO/MUGA scans and ophthalmic examinations.
- Incidence of dose interruptions, dose modifications and discontinuations due to AEs [ Time Frame: Up to 3 years ]
- Progression free survival [ Time Frame: From the date of first dose of study drug to the time of the first documented progression or death, whichever occurs first, assessed up to 3 years ]
- Extracranial response rate [ Time Frame: Up to 3 years ]Extracranial response rate is defined as the proportion of patients with a best overall extracranial response of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 per investigator assessment.
- Intracranial response rate [ Time Frame: Up to 3 years ]Intracranial response rate is defined as the proportion of patients with a best overall Intracranial response of CR or PR according to modified (m)RECIST v1.1 per Investigator assessment. In addition, as part of our secondary endpoint, we will use Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria for response assessment.
- Disease control rate [ Time Frame: Up to 3 years ]Defined as the proportion of patients with a best overall response of CR, PR or stable disease (SD) per Investigator assessment.
- Duration of response (DOR) [ Time Frame: From first documented response of CR or PR per Investigator assessment until first documented progression or death due to any cause, whichever occurs first, assessed up to 3 years ]DOR will be estimated using the Kaplan-Meier method. DOR estimates along with two-sided 95% confidence interval is will be presented.
- Overall survival (OS) [ Time Frame: From the date of first dose of study drug to the date of death due to any cause, assessed up to 3 years ]The survival distribution function for OS will be estimated using the Kaplan-Meier method. OS estimates along with two-sided 95% Cis will be presented. Associations between OS and demographic/clinical measures may be evaluated using Cox proportional hazards regression models.
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- Able to provide written informed consent. Adult patients under guardianship may participate if permitted by local regulations with the consent of their legally authorized guardian. All local regulations concerning patients under guardianship must be followed
- Age >= 18 years at the time of informed consent
- Histologically confirmed diagnosis of melanoma
- Presence of BRAFV600 mutation in tumor tissue previously determined by a local assay (including immunohistochemistry [IHC]) at any time prior to Screening or during Screening
- Cohort A: BRAF V600 mutant melanoma patients with progressive central nervous system (CNS) metastases. This includes patients with parenchymal brain metastases and/or LMD
Cohort A: Prior therapy with Food and Drug Administration (FDA)-approved BRAF inhibitors (+/- MEK inhibitors) is required
- No washout period is required
- Cohort B: BRAF V600 mutant melanoma patients who are treatment naive to BRAF/MEK inhibitors with CNS metastases, including LMD. Prior treatment with immunotherapy is permitted
For patients with parenchymal brain metastases (mets) without LMD
- Metastatic disease to the brain with at least 1 progressing parenchymal brain lesion >= 0.5 cm and =< 3 cm, defined as a magnetic resonance imaging (MRI) contrast-enhancing lesion that may be accurately measured in at least 1 dimension
For patients with LMD
- Patients must have radiographic and/or CSF cytological evidence of LMD
- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of =< 2
Patients may receive steroids to control symptoms related to CNS involvement
- For patients with parenchymal brain metastases the dose must be =< 2 mg per 24 hours of dexamethasone (or the equivalent). Patient's symptoms should experience stability of neurological symptoms for at least 7 days, or on tapering dose of steroids. Physiologic replacement doses for adrenal insufficiency is allowed on this protocol
- For patients with LMD: the dose must be =< 4 mg per 24 hours of dexamethasone (or the equivalent). Physiologic replacement doses for adrenal insufficiency is allowed on this protocol
- For patients with parenchymal brain mets: prior radiation therapy is allowed, but patient must be progressing in or having at least 1 new CNS lesion. Washout to prior radiation 14 days
- For patients with LMD: Patients who have received radiation to brain and/or spine, including whole brain radiation, stereotactic radiosurgery, or stereotactic body radiation therapy (SBRT), are eligible, but must have completed radiation treatment at least 7 days prior to the start of treatment
Other cancer directed treatment:
Concurrent treatment with other anti-cancer systemic therapies is not allowed. No other concomitant intrathecal therapy with another agent will be allowed. For patients that have received other systemic therapies, the minimum wash out period is as follows:
- Patients that received previous intrathecal (IT) therapy must have received their last treatment >= 7 days prior to the start of treatment
- Patients who have received systemic chemotherapy must have received their last treatment >= 21 days prior to the start of treatment
- Patients who have received an approved biologic therapy (e.g. anti-PD-1, anti-CTLA4, IL2, interferon) must have received their last treatment >= 2 weeks prior to the start of treatment
- Patients who have received any other investigational agents must have received their last treatment >= 14 days prior to the start of treatment
- Absolute neutrophil count (ANC) 1.5 X 10^9/L
- Hemoglobin 9.0 g/dL
- Platelets 75 X 10^9/L
- Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 X upper limit of normal (ULN)
Total bilirubin =< 1.5 X ULN (isolated bilirubin > 1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%)
- NOTE: Patients with documented Gilbert syndrome or hyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled following discussion and agreement with the primary investigator
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 2.5 X ULN, in patients with liver metastases 5 X ULN
- Albumin 2.5 g/dL
- Creatinine =< 1.5 X ULN OR calculated creatinine clearance >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min
- Female patients of childbearing potential must have a negative serum beta-human chorionic gonadotropin (HCG) test result
- Female patients of childbearing potential must agree to protocol-approved methods of contraception and to not donate ova from Screening until 30 days after the last dose of study drug. Male patients must agree to use methods of contraception that are highly effective or acceptable and to not donate sperm from Screening until 90 days after the last dose of study drug
- The patient is deemed by the Investigator to have the initiative and means to comply with scheduled visits, treatment plan and study procedures
- Evidence of active infection =< 7 days prior to initiation of study drug therapy (does not apply to viral infections that are presumed to be associated with the underlying tumor type required for study entry)
- Use of non-oncology vaccines containing live virus for prevention of infectious diseases within 30 days of prior to study drug. Dead virus vaccines (e.g Flu) are allowed, even during treatment with study drug
- Inability to swallow and retain study treatment
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on antiretroviral therapy (ART)
Impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, the following:
- History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6 months prior to screening
- Congestive heart failure requiring treatment (New York Heart Association grade >= 2)
- A left ventricular ejection fraction (LVEF) < 50% as determined by multigated acquisition (MUGA) or echocardiogram (ECHO)
- History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia)
- Baseline Fridericia's correction formula (QTcF) interval >= 480 msec. Can be repeated up to three times to confirm
- Concurrent neuromuscular disorder (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
- Impairment of gastrointestinal function or disease which may significantly alter the absorption of study treatment (e.g., active ulcerative disease; uncontrolled nausea, vomiting or diarrhea; malabsorption syndrome; small bowel resection). Known 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); history of retinal degenerative disease
- Use of herbal supplements, medications or foods that are moderate or strong inhibitors or inducers of cytochrome P450 (CYP) 3A4/5 =< 1 week prior to the start of study treatment
- History of a thromboembolic event < 12 weeks prior to starting study treatment. Examples of thromboembolic events include transient ischemia attack, cerebrovascular accident, deep vein thrombosis or pulmonary embolism. Catheter-related venous thrombosis is not considered a thromboembolic event for this trial even if < 12 weeks prior to starting study treatment. Note: Patients with either deep vein thrombosis or pulmonary emboli that do not result in hemodynamic instability are allowed to enroll as long as they are stable, asymptomatic and on stable anticoagulants for at least 2 weeks. Additionally, patients with thromboembolic events related to indwelling catheters or other procedures may be enrolled
Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
- NOTE: Patients with laboratory evidence of cleared HBV or HCV infection may be enrolled
- NOTE: Patients with no prior history of HBV infection who have been vaccinated against HBV and who have a positive antibody against hepatitis B surface antigen as the only evidence of prior exposure may enroll
- Pregnancy or breastfeeding or patients who plan to become pregnant during the duration of the study
- Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient an inappropriate candidate for the study
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): NCT05026983
|United States, Texas|
|M D Anderson Cancer Center||Recruiting|
|Houston, Texas, United States, 77030|
|Contact: Isabella C. Glitza 713-792-2921 email@example.com|
|Principal Investigator: Isabella C. Glitza, MD|
|Principal Investigator:||Isabella C Glitza||M.D. Anderson Cancer Center|
|Responsible Party:||M.D. Anderson Cancer Center|
|Other Study ID Numbers:||
NCI-2021-08716 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2021-0205 ( Other Identifier: M D Anderson Cancer Center )
|First Posted:||August 30, 2021 Key Record Dates|
|Last Update Posted:||February 27, 2023|
|Last Verified:||February 2023|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms by Site