Ignite Creation Date:
2025-12-24 @ 6:37 PM
Ignite Modification Date:
2025-12-28 @ 10:26 AM
Study NCT ID:
NCT04655157
Status:
TERMINATED
Last Update Posted:
2024-05-23
First Post:
2020-12-03
Is NOT Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
Safety and Efficacy in Participants With Metastatic BRAF-mutant Melanoma Treated With Encorafenib With and Without Binimetinib in Combination With Nivolumab and Low-dose Ipilimuma
Sponsor:
Jason J. Luke, MD
Organization:
Study Overview
Official Title:
A Multi-Center Phase I/II Open Label Study to Evaluate Safety and Efficacy in Participants With Metastatic BRAF-mutant Melanoma Treated With Encorafenib With and Without Binimetinib in Combination With Nivolumab and Low-dose Ipilimumab. (QUAD 01: Quadruple Therapy in Melanoma)
Status:
TERMINATED
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Study terminated due to slow enrollment
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
QUAD01
Brief Summary:
Patients with unresectable or metastatic BRAF-mutant melanoma high-risk patients will be given 450 mg orally (PO) daily (QD) plus binimetinib 45 mg PO twice daily (BID) together with nivolumab administered intravenously (IV) at 3mg/kg and ipilimumab administered IV at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab administered IV at 480mg every 4 weeks until progression or discontinuation due to toxicity. Concurrently, a triple therapy arm will be explored with encorafenib 300 mg PO QD together with ipilimumab administered IV at 1mg/kg and nivolumab 3mg/kg IV every 3 weeks for 4 doses, followed by nivolumab administered at 480mg every 4 weeks until progression or discontinuation due to toxicity. Tolerability of the two arms will be compared, and a recommended phase 2 dose (RP2D) will be determined. After determination of treatment schedule, expansion cohorts will further explore the preliminary efficacy and further describe the toxicity profile of the triplet or quadruplet regimen in high-risk cohorts including symptomatic brain metastases or liver metastases with elevated lactate dehydrogenase (LDH) or bulky systemic disease burden.
Detailed Description:
Study participants will consist of metastatic melanoma patients harboring BRAFV600E/K mutation without previous frontline therapy or recently started treatment with up to 6 weeks of targeted therapy (or \> 6 months from adjuvant therapy). Toxicity from prior treatment must have resolved to ≤ Grade 1 and not included previous Grade 3-4 immune-related adverse events (irAEs) that required treatment discontinuation or previous Grade 2 immune-related uveitis or pneumonitis.
Phase I, Cohort 1: Twelve patients will be treated with 300mg encorafenib and 3mg/kg nivolumab and 1 mg/kg ipilimumab. The dose limiting toxicity (DLT) for cohort 1 will be evaluated between weeks 1-6.
Phase I, Cohort 2: Upfront quadruple therapy with 450mg encorafenib, 45mg binimetinib, 3mg/kg nivolumab and 1mg/kg ipilimumab will be investigated with 12 participants. DLT window for phase I, cohort 2 will be evaluated at weeks 1-6.
Upon establishment of RP2R schedule, only participants with advanced melanoma who are treatment naïve in metastatic setting or have had up to 6 weeks of targeted therapy or who have progressed on adjuvant therapy for more than 6 months following completion of adjuvant therapy (either BRAF-MEK or PD1 Ab) will be eligible for participation in high risk disease cohort expansion (Groups 1 or 2).
Phase II will employ the RP2D schedule from Phase I and investigate the early efficacy in participants with high risk features who are less likely to derive benefit from standard treatment approaches and who may benefit from quadruple therapy despite the potential for increased toxicity. These will include: Group 1) symptomatic brain metastases \[up to 30 patients\] and Group 2) Elevated LDH \>1x upper limit of normal (ULN) with: a) liver metastases OR b) bulky visceral disease (sum of longest diameter (SLD) \> 44mm) \[combined with Group 1 up to 60 total patients\].
Following initiation of triple or quadruple therapy, participants will be followed for safety and response. Safety assessments will be a high priority with on-going Bayesian toxicity monitoring and efficacy assessments every 12 weeks. Based on prior targeted, immune, and triplet therapy studies, we anticipate up to 30-50% DLT and will consider temporary suspension of trial enrollment with a DLT \> 75% as determined by CTCAEv5. Treatment efficacy will be documented using RECIST 1.1 and RANO-BM criteria, recorded every 4-12 weeks, and immune-RECIST (iRECIST) and immune-RANO (iRANO) criteria.
Phase I, Cohort 1: Twelve patients will be treated with 300mg encorafenib and 3mg/kg nivolumab and 1 mg/kg ipilimumab. The dose limiting toxicity (DLT) for cohort 1 will be evaluated between weeks 1-6.
Phase I, Cohort 2: Upfront quadruple therapy with 450mg encorafenib, 45mg binimetinib, 3mg/kg nivolumab and 1mg/kg ipilimumab will be investigated with 12 participants. DLT window for phase I, cohort 2 will be evaluated at weeks 1-6.
Upon establishment of RP2R schedule, only participants with advanced melanoma who are treatment naïve in metastatic setting or have had up to 6 weeks of targeted therapy or who have progressed on adjuvant therapy for more than 6 months following completion of adjuvant therapy (either BRAF-MEK or PD1 Ab) will be eligible for participation in high risk disease cohort expansion (Groups 1 or 2).
Phase II will employ the RP2D schedule from Phase I and investigate the early efficacy in participants with high risk features who are less likely to derive benefit from standard treatment approaches and who may benefit from quadruple therapy despite the potential for increased toxicity. These will include: Group 1) symptomatic brain metastases \[up to 30 patients\] and Group 2) Elevated LDH \>1x upper limit of normal (ULN) with: a) liver metastases OR b) bulky visceral disease (sum of longest diameter (SLD) \> 44mm) \[combined with Group 1 up to 60 total patients\].
Following initiation of triple or quadruple therapy, participants will be followed for safety and response. Safety assessments will be a high priority with on-going Bayesian toxicity monitoring and efficacy assessments every 12 weeks. Based on prior targeted, immune, and triplet therapy studies, we anticipate up to 30-50% DLT and will consider temporary suspension of trial enrollment with a DLT \> 75% as determined by CTCAEv5. Treatment efficacy will be documented using RECIST 1.1 and RANO-BM criteria, recorded every 4-12 weeks, and immune-RECIST (iRECIST) and immune-RANO (iRANO) criteria.
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
Secondary ID Infos
| Secondary ID | Type | Domain | Link | View |
|---|---|---|---|---|
| CA209-7Y4 | OTHER | BMS | View |