Drug Combination for Brain Metastases from Melanoma
(DETERMINE Trial)
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: University of Utah
Must not be taking: Strong CYP3A4, CYP2C9 inhibitors
Disqualifiers: Symptomatic brain metastasis, Uveal melanoma, others
No Placebo Group
Trial Summary
What is the purpose of this trial?The goal of this interventional clinical trial is to provide proof-of-principle data for the biologic activity of defactinib in combination with avutometinib in brain metastases from melanoma, and to define the potential role of the combination with mutant BRAF inhibitors or after BRAF/MEK inhibitors in BRAF V600E/K mutant tumors, in individuals with advanced melanoma who experience the development or progression of brain metastases after treatment with immune checkpoint inhibitors.
The main questions it aims to answer are:
* What is the preliminary response rate of defactinib and avutometinib in patients with RAS mutant, BRAF mutant, NF1 mutant, triple RAS/BRAF/NF1 wild type (wt) melanoma (including RAF fusions)?
* What is the safety and tolerability of the combination of defactinib, avutometinib, and encorafenib in patients with BRAF V600E/K mutant melanoma with at least one untreated brain metastases?
* What is the preliminary response rate of the three drug combination of defactinib, avutometinib, and encorafenib in patients with BRAF V600E/K mutant melanoma.
Will I have to stop taking my current medications?
The trial requires participants to stop taking certain medications that could interact with the study drugs, such as strong CYP3A4, CYP2C9, P-glycoprotein, and BCRP inhibitors or inducers, as well as warfarin. A washout period (time without taking certain medications) of at least five half-lives or as clinically indicated is required before starting the study treatment.
What data supports the effectiveness of the drug combination for brain metastases from melanoma?
Research shows that combinations of BRAF and MEK inhibitors, like dabrafenib and trametinib, have improved outcomes for patients with melanoma that has spread to the brain. These combinations have been effective in increasing survival and reducing symptoms in patients with BRAF-mutant melanoma.
12345Is the drug combination for brain metastases from melanoma generally safe in humans?
The combination of BRAF and MEK inhibitors, including encorafenib and binimetinib, has been used in treating melanoma with brain metastases, and studies have not shown any unexpected safety issues. Common side effects include diarrhea and fatigue, but no new safety concerns have been identified in recent studies.
23678How is the drug combination of Avutometinib, Defactinib, and Encorafenib unique for treating brain metastases from melanoma?
This drug combination is unique because it includes Avutometinib and Defactinib, which are not typically used in standard BRAF/MEK inhibitor treatments for melanoma with brain metastases. Encorafenib, part of this combination, has shown improved efficacy and tolerability due to its distinct pharmacokinetics, offering a potentially more effective and better-tolerated option compared to other BRAF/MEK inhibitor combinations.
23569Eligibility Criteria
This trial is for advanced melanoma patients with brain metastases who didn't respond to immune checkpoint inhibitors. It's specifically for those with certain genetic mutations (RAS, BRAF V600E/K, NF1) or without these mutations (triple wild type). Patients must have at least one untreated brain metastasis to qualify.Inclusion Criteria
I can give written consent and follow the study rules, or someone can do it for me if I'm unable.
I am fully active or able to carry out light work.
My blood tests show my organs and bone marrow are working well.
+9 more
Exclusion Criteria
I have an eye condition.
I have HIV with a detectable viral load in the last 6 months.
I do not have an active infection like TB, hepatitis B, or C.
+21 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive defactinib and avutometinib, with or without encorafenib, in 4-week cycles with 3 weeks of treatment followed by a 1-week rest period
6 months
Biweekly visits for drug administration
Follow-up
Participants are monitored for safety and effectiveness after treatment
up to 5 years
Participant Groups
The study tests defactinib and avutometinib's effectiveness on various melanoma genetic types in the brain. For BRAF V600E/K mutants, it also adds encorafenib. The goal is to see how well these drugs work alone or combined and assess their safety.
3Treatment groups
Experimental Treatment
Group I: Phase Ib, Defactinib, Avutometinib, and Encorafenib (Cohort B)Experimental Treatment3 Interventions
Avutometinib will be administered at 3.2 mg biweekly orally (e.g., Monday/Thursday, Tuesday/Friday, or Wednesday/Saturday) for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle.
Defactinib will be administered at 200 mg twice a day orally for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle.
Encorafenib will be administered orally to a small cohort to a limited dose escalation cohort using a Bayesian optimal interval (BOIN) design to evaluate safety, toxicity, and recommended phase II dose for dosage of encorafenib when combined with avutometinib and defactinib.
Dose escalation levels for Encorafenib:
Dose Level -1: 225 mg Daily (three 75mg capsules) Dose Level 0: 300 mg Daily (four 75mg capsules) Dose Level 1: 450 mg Daily (six 75mg capsules)
Group II: Phase II, Defactinib, Avutometinib, and Encorafenib (Cohort B)Experimental Treatment3 Interventions
Avutometinib will be administered at 3.2 mg biweekly orally (e.g., Monday/Thursday, Tuesday/Friday, or Wednesday/Saturday) for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle.
Defactinib will be administered at 200 mg twice a day orally for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle.
Encorafinib will be administered orally at doses defined in the dose escalation portion (225mg - 450mg) Daily continuously (days 1-28 of a 28 day cycle) for Cohort B.
Group III: Phase II, Defactinib and Avutometinib (Cohort A)Experimental Treatment2 Interventions
Avutometinib will be administered at 3.2 mg biweekly orally (e.g., Monday/Thursday, Tuesday/Friday, or Wednesday/Saturday) for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle.
Defactinib will be administered at 200 mg twice a day orally for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of IowaIowa City, IA
Huntsman Cancer InstituteSalt Lake City, UT
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Who Is Running the Clinical Trial?
University of UtahLead Sponsor
Verastem, Inc.Industry Sponsor
References
Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. [2022]Label="BACKGROUND">Dabrafenib plus trametinib improves clinical outcomes in BRAFV600-mutant metastatic melanoma without brain metastases; however, the activity of dabrafenib plus trametinib has not been studied in active melanoma brain metastases. Here, we report results from the phase 2 COMBI-MB trial. Our aim was to build on the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases.
Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib. [2021]BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups.
Clinical experience with combination BRAF/MEK inhibitors for melanoma with brain metastases: a real-life multicenter study. [2019]BRAF and MEK kinase inhibitors can be highly effective in treating BRAF-mutant melanomas, but their safety and activity in patients with active/symptomatic brain metastases are unclear. We sought to shed light on this open clinical question. We conducted a multicenter retrospective study on real-life patients with melanoma and active brain metastases treated with combination BRAF/MEK inhibitors. A total of 65 patients were included (38 men and 27 women; median age: 49 years). Of them, 53 patients received dabrafenib/trametinib, 10 received vemurafenib/cobimetinib, one received encorafenib/binimetinib, and one received vemurafenib/trametinib. We did not observe any unexpected treatment-related safety signals in our cohort. Overall, 17 patients continued on therapy through the cutoff date. After initiation of therapy, steroid dose could be decreased in 22 of 33 patients (11 tapered off entirely), anticonvulsants were stopped in four of 21, and narcotics were stopped in four of 12. Median progression-free survival from the start of therapy was 5.3 months (95% confidence interval: 3.6-6.1), and median overall survival was 9.5 months (95% confidence interval: 7.7-13.5). A total of 20 patients were surviving at the cutoff date. Univariate analysis of age, sex, ulceration status, thickness, stage, location, or lactate dehydrogenase did not reveal significant predictors of progression-free survival or overall survival within our cohort, but multivariate analysis suggested that older age, lower risk location of original lesion, and nodular melanoma are poor prognostic indicators. Combination therapy with BRAF/MEK inhibitors is a viable treatment option for patients with BRAF-mutant melanoma and brain metastases, but further studies should help to define the optimal treatment approach in this population.
How I treat brain metastases of melanoma. [2023]Brain metastases are common in advanced melanoma and cause death in >50% of patients. Until recently, median survival was only ∼4 months. Improved systemic treatment including immune checkpoint inhibitors and combinations of BRAF/MEK inhibitors, however, has significantly improved intracranial tumor response and survival. In addition, advances in radiation therapy have also improved the intracranial outcomes for advanced melanoma patients with brain metastases (MBM). There has long been concern that systemic treatment of the central nervous metastases would be ineffective due to inability of active agents to cross an intact blood-brain barrier. Recent studies have shown, however, that highly active systemic therapy can have significant benefit in these patients. When determining a patient's treatment, the important factors in predicting the likelihood of benefit including the presence of neurologic symptoms, the number and size of brain metastases, performance status/status of extracranial disease, and BRAF mutation status should all be considered. In this review, we will discuss the challenges and treatment options for patients with advanced melanoma and brain metastases.
Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. [2022]Brain metastases are common in patients with metastatic melanoma and median overall survival from their diagnosis is typically 17-22 weeks. We assessed dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain.
Encorafenib and Binimetinib Combination Therapy in Metastatic Melanoma. [2022]The treatment landscape for metastatic melanoma has changed dramatically over the past few years as new medications have been developed. Encorafenib, a B-Raf protein kinase inhibitor, and binimetinib, a MEK inhibitor, were approved by the U.S. Food and Drug Administration in 2018 for the treatment of patients with unresectable or metastatic melanoma which harbor a BRAF V600E or V600K mutation. These approvals were based on findings from the COLUMBUS trial, which demonstrated improvement in progression-free survival and overall survival with the combination of encorafenib plus binimetinib compared with vemurafenib alone. Encorafenib plus binimetinib is the third BRAF plus MEK inhibitor combination to be approved, and there are clinical and practical differences between the combination regimens that should be considered when selecting an appropriate treatment regimen for patients.
Intracranial Control With Combination BRAF and MEK Inhibitor Therapy in Patients With Metastatic Melanoma. [2023]Purpose/Objectives Combination BRAF (vemurafenib, dabrafenib, or encorafenib) plus MEK (trametinib, cobimetinib, or binimetinib) inhibitor therapy is now widely used in the treatment of metastatic melanoma. However, data for intracranial response to these drugs are limited. We aimed to evaluate the intracranial efficacy of BRAF plus MEK inhibitors in patients with BRAF-mutant melanoma with brain metastases (BM) and to determine patterns of failure of these new agents to inform optimal integration of local intracranial therapy. Materials and methods We retrospectively reviewed charts of patients with BRAF-mutant melanoma with metastasis to the brain with at least one untreated brain metastasis at the time of initiation of BRAF plus MEK inhibitors at our institution from 2006 to 2020. We collected per-patient and per-lesion data on demographics, treatment modality, and outcomes. The cumulative incidence of local (LF), distant intracranial (DF), and extracranial failure (EF) were calculated with competing risk analysis with death as a competing risk and censored at the last brain MRI follow-up. LF was calculated on a per-lesion basis while DF and EF were calculated on a per-patient basis. DF was defined as any new intracranial lesions. Overall survival (OS) was analyzed using Kaplan-Meier. Logistic regression was used to identify predictors for LF. Results We identified 10 patients with 63 untreated brain metastases. The median age was 50.5 years. The median sum of the diameters of the five largest untreated brain metastases per patient was 20 mm (interquartile range 15-39 mm) and the median diameter for all measurable lesions was 4 mm. Median follow-up time was 9.0 months (range 1.4 months-46.2 months). Median OS was 13.6 months. The one-year cumulative incidence of LF, DF, and EF was 17.1%, 88.6, and 71.4%, respectively. The median time to LF, DF, and EF from the start of BRAF plus MEK inhibitors was 9.0 months, 4.7 months, and 7.0 months, respectively. The larger size of the BM was associated with LF on univariate analysis (odds ratio 1.13 per 1 mm increase in diameter, 95% confidence interval 1.019 to 1.308, p
Effectiveness, safety and utilization of cobimetinib and vemurafenib in patients with BRAF V600 mutant melanoma with and without cerebral metastasis under real-world conditions in Germany: the non-interventional study coveNIS. [2023]Cobimetinib/vemurafenib combination therapy is approved for treatment of adults with unresectable or metastatic BRAF V600 mutated malignant melanoma (mM). The non-interventional post-authorisation safety study coveNIS collected real-world data on cobimetinib/vemurafenib treatment focussing on overall survival (OS), safety and utilization. MM patients with brain metastases are usually excluded from clinical studies. coveNIS observed 2 cohorts: mM patients without (Cohort A) and with cerebral metastases (Cohort B), aiming to close the data gap for the latter population. A direct comparison of the 2 cohorts was not intended. The primary effectiveness objective was OS; the safety objective was the incidence of all and of serious adverse events (AEs). Secondary objectives included progression-free survival (PFS), time to development of cerebral metastasis (Cohort A) and time to central nervous system relapse (Cohort B). All statistical analyses were descriptive. Between 2017 and 2021, 95 patients were included (Cohort A: 54, Cohort B: 41 patients) at 32 sites in Germany. Median OS was 21.6 months in Cohort A, 7.4 months in Cohort B. Median PFS was 6.9 months in Cohort A, 5.2 months in Cohort B. The proportion of patients experiencing any AEs was 83.3% (Cohort A) and 87.8% (Cohort B). The two most common AEs in Cohort A were 'diarrhoea' (37%), 'vomiting' (20.4%) and 'pyrexia' (20.4%); in Cohort B 'diarrhoea' (36.6%) and 'fatigue' (22%). In conclusion, the OS rates in Cohort A and Cohort B of coveNIS are in line with the OS data from other trials with BRAF/MEK inhibitors for mM. No new safety signals were observed.
Encorafenib in combination with binimetinib for unresectable or metastatic melanoma with BRAF mutations. [2019]Label="INTRODUCTION" NlmCategory="BACKGROUND">Combination treatment with a BRAF inhibitor and MEK inhibitor is the standard of care for patients with advanced BRAFV600 mutation-positive melanoma. With the currently available combinations of dabrafenib plus trametinib and vemurafenib plus cobimetinib, median progression-free survival (PFS) of over 12 months has been achieved. However, treatment resistance and disease recurrence remain a clinical challenge. Areas covered: Encorafenib in combination with bimetinib offers a new approach that may offer benefits over existing BRAF/MEK inhibitor combinations. Expert opinion: While other BRAF/MEK inhibitor combinations have achieved a median overall survival (OS) of 22 months, patients with advanced BRAF mutation-positive melanoma treated with encorafenib plus binimetinib achieved a median OS of 33.6 months in the phase III COLUMBUS trial. PFS also appears to be improved with encorafenib plus binimetinib. This improved efficacy may be related to the distinct pharmacokinetics of encorafenib, with prolonged binding to the target molecule providing greater BRAF inhibition and increased potency compared with other drugs in the same class. Increased specificity of encorafenib may also result in better tolerability with less off-target effects, including reduced occurrence of pyrexia and photosensitivity. Encorafenib plus binimetinib seems likely to emerge as a valuable therapeutic alternative to established BRAF/MEK inhibitor combinations.