A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations

Phase 2

Recruiting

• Conditions: Cancer Harboring BRAF Alterations; HGG; LGG; Solid Tumors; Melanoma BRAF V600E/K Mutated; Thyroid Cancer
• Interventions: Drug: Plixorafenib; Drug: Cobicistat

• Registration Number: NCT05503797
• Lead Sponsor: Fore Biotherapeutics

Brief Summary

The objective of this Master Protocol is to evaluate the efficacy and safety of plixorafenib in participants with locally advanced or metastatic solid tumors, or recurrent or progressive primary central nervous system (CNS) tumors harboring BRAF fusions, or in participants with rare BRAF V600-mutated solid tumors, melanoma, thyroid, or recurrent primary CNS tumors.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2022-08-15
• Study First Submitted QC: 2022-08-15
• Study First Posted: 2022-08-17
• Study Start: 2023-02-21
• Status Verified: 2024-09
• Last Update Submitted: 2025-05-13
• Last Update Posted: 2025-05-14
• Primary Completion: 2026-06-27
• Study Completion: 2026-12-28

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 135

Inclusion Criteria

Not provided

Exclusion Criteria

Subprotocol A:

1. Participants with known co-occurring NF1 alteration and/or RAS-related mutations.
2. Participants with evidence of subclonal mutations or heterogeneity that are indicative of a prior treatment effect instead of a driver mutation.
3. Prior treatment with RAF/BRAF inhibitors active for Class 2 BRAF alterations for advanced unresectable or metastatic disease.
4. Prior treatment with a MEK inhibitor.
5. Tyrosine kinase inhibitor(s) and/or targeted therapies are allowed (other than BRAF/MAPK pathway inhibitors per Exclusion Criteria 3 and 4) and will be restricted to no more than the number of lines of therapy that are consistent with standard treatment guidelines.
6. Malignancy with co-occurring activating RAS mutation(s) at any time.
7. Uncontrolled intercurrent illness that would limit compliance with study requirements.
8. HIV infection with exceptions; discuss with treating physician.
9. Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral plixorafenib or cobicistat (such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, and small bowel resection).
10. Current active liver disease from any cause, including a positive test at screening for HBV (HBsAg), or HCV (HCV antibody, confirmed by HCV RNA PCR).
11. Grade ≥2 changes in AST, ALT, GGT, or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.

Subprotocol B:

1. Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).
2. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.
3. Uncontrolled intercurrent illness that would limit compliance with study requirements.
4. Active infection requiring systemic therapy.
5. HIV infection with exceptions; discuss with treating physician.
6. Have impairment of GI function or GI disease that may significantly alter the absorption of oral plixorafenib or cobicistat (such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
7. Grade ≥ 2 changes in AST, ALT, gamma-glutamyl transaminase (GGT), or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.

Subprotocol C:

1. Diagnosis of colorectal adenocarcinoma or pancreatic ductal adenocarcinoma (neuroendocrine or acinar tumors are eligible).
2. Diagnosis of BRAF V600E-mutated cutaneous melanoma, thyroid cancer (ATC and PTC), or NSCLC.
3. Participant has CNS metastases.
4. Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).
5. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.
6. Participants with prostate, breast, or gynecologic cancers with known activating mutations that lead to constitutive hormone receptor activation (AR-V7, ESR1).
7. Uncontrolled intercurrent illness that would limit compliance with study requirements.
8. Active infection requiring systemic therapy.
9. HIV infection with exceptions; discuss with treating physician.

Subprotocol D:

1. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.
2. Participants with known acquired driver mutations, including from prior MAPK pathway targeted therapies.
3. Participant has CNS metastases.
4. Uncontrolled intercurrent illness that would limit compliance with study requirements.
5. Active infection requiring systemic therapy.
6. HIV infection with exceptions; discuss with treating physician.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Subprotocol A	Plixorafenib	Participants with unresectable, locally advanced or metastatic solid tumors or primary CNS tumors harboring BRAF fusions will receive plixorafenib which will be increased as tolerated, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal.
Subprotocol B	Plixorafenib	Participants with recurrent primary CNS tumors harboring BRAF V600E mutations will receive plixorafenib administered with cobicistat, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal.
Subprotocol B	Cobicistat	Participants with recurrent primary CNS tumors harboring BRAF V600E mutations will receive plixorafenib administered with cobicistat, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal.
Subprotocol C	Plixorafenib	Participants with advanced, rare, non-CNS solid tumors harboring BRAF V600E mutations will receive plixorafenib administered with cobicistat, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal.
Subprotocol C	Cobicistat	Participants with advanced, rare, non-CNS solid tumors harboring BRAF V600E mutations will receive plixorafenib administered with cobicistat, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal.
Subprotocol D	Plixorafenib	Participants with BRAF V600E-mutated cutaneous melanoma and BRAF V600E-mutated thyroid cancer (MAPK inhibitor naïve) will be randomized to receive plixorafenib with or without cobicistat.
Subprotocol D	Cobicistat	Participants with BRAF V600E-mutated cutaneous melanoma and BRAF V600E-mutated thyroid cancer (MAPK inhibitor naïve) will be randomized to receive plixorafenib with or without cobicistat.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR) (Subprotocols A, B and C)	Up to approximately 4 years	ORR will be determined by standard tumor response criteria by blinded independent central review (BICR).
Pharmacokinetics (Subprotocol D)	Up to approximately 4 years	Systemic exposure of plixorafenib measured by Cmax and AUC

Secondary Outcome Measures

Name	Time	Method
Duration of Response (DOR) by BICR (Subprotocols A, B and C)	Up to approximately 4 years	DOR will be determined by standard tumor response criteria per BICR (subprotocols A-C)
ORR per Investigator Assessment	Up to approximately 4 years	ORR will be determined by standard tumor response criteria by Investigator Assessment.
DOR per Investigator Assessment	Up to approximately 4 years	DOR will be determined by standard tumor response criteria.
Percentage of Participants with DOR at 6 months, 12 months, and 18 months	6 months, 12 months and 18 months
Time to Response by BICR (Subprotocols A, B and C)	Up to approximately 4 years
Progression Free Survival (PFS) by BICR (Subprotocols A, B and C)	Up to approximately 4 years
PFS per Investigator's Assessment	Up to approximately 4 years
Overall Survival	Up to approximately 4 years
Percentage of Participants with PFS at 6 months, 12 months and 24 months	6 months, 12 months and 24 months	BICR (Subprotocols A, B and C) Investigator Assessment (Subprotocols A, B, C and D)
Disease Control Rate (DCR)	Up to approximately 4 years
Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs)	Up to approximately 4 years
Plasma Concentrations of Plixorafenib	Up to approximately 4 years
Plasma Concentrations of Plixorafenib Metabolites	Up to approximately 4 years
Subprotocol A: CNS-DOR by BICR	Up to approximately 4 years
Subprotocol A: CNS-ORR by BICR	Up to approximately 4 years
Subgroup analyses for efficacy endpoints in low-grade and high-grade primary CNS tumors will be reported.	Up to approximately 4 years

Trial Locations

Locations (55)

UCSF Helen Diller Family Comprehensive Cancer Center; 🇺🇸 San Francisco, California, United States

University of California Los Angeles Rheumatology; 🇺🇸 Westwood, California, United States

University of Miami Hospital and Clinics; 🇺🇸 Miami, Florida, United States

The John Hopkins Hospital; 🇺🇸 Baltimore, Maryland, United States

Maryland Oncology Hematology- Columbia; 🇺🇸 Rockville, Maryland, United States

Tufts Medical Center; 🇺🇸 Boston, Massachusetts, United States

St. Luke's Hospital; 🇺🇸 Duluth, Minnesota, United States

Mosaic Life Care at Saint Joseph - Medical Center; 🇺🇸 Saint Joseph, Missouri, United States

Nebraska Cancer Specialists - Midwest Cancer Center - Legacy; 🇺🇸 Omaha, Nebraska, United States

Overlook Medical Center; 🇺🇸 Summit, New Jersey, United States

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