A Phase 2 Master Protocol to assess the efficacy and safety of FORE8394, an inhibitor of BRAF Class 1 and Class 2 alterations, in participants with cancer harboring BRAF alterations

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fore Biotherapeutics Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Mar 2023 → ongoing

Decision date (initial)

2024-09-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Fore Biotherapeutics

External identifiers

EU CT number

2024-513578-23-00

EudraCT number

2022-000627-20

ClinicalTrials.gov

NCT05503797

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenomic, Safety, Pharmacokinetic, Efficacy, Therapy, Pharmacodynamic

The objective of this study is to evaluate the efficacy 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 and/or selected solid tumors, or recurrent primary CNS tumors harboring BRAF V600E mutation.
This will be conducted as four open-label subprotocols (F8394-201A; F8394-201B; F8394-201C; F8394-201D) under one Master Protocol.

Conditions and MedDRA coding

Tumors harboring BRAF alterations

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 27

1. Subprotocol A: 1. Male and female, ≥10 years of age, and weighing ≥30 kg.
2. Subprotocol A: 5. Consent to provide scan(s) prior to baseline to assess change in tumor trajectory.
3. Subprotocol A: 6. Received all available standard therapy, is intolerant to available therapies, or the investigator has determined that treatment with standard therapy is not appropriate.
4. Subprotocol A: 7. All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline
5. Subprotocol B: 1. Male and female, ≥10 years of age, and weighing ≥30 kg.
6. Subprotocol B: 2. Histological diagnosis of a primary CNS tumor, including but not limited to the following: a. Adults (≥18 years) with Grade 1-4 glioma or glioneuronal tumor (including glioblastoma, anaplastic astrocytoma, high grade astrocytoma with piloid features, pilocytic astrocytoma, gliosarcoma, anaplastic pleomorphic xanthoastrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, not otherwise specified [NOS], ganglioglioma, or recurrent LGG), OR b. Pediatric patients (10-17 years of age) with a Grade 3 or 4 glioma or glioneuronal tumor, including those with a prior, histologically confirmed, diagnosis of a low-grade glioma or glioneuronal tumor and now have radiographic or histopathological findings consistent with WHO [2021] Grade 3 or 4 primary CNS tumor. c. Participants must have unresectable, locally advanced or metastatic disease that: i. Had prior treatment with radiotherapy and/or first-line chemotherapy or concurrent chemoradiation therapy (Note: Participants who have a WHO Grade 3 or 4 glioma for whom chemotherapy and/or radiotherapy is not considered standard of care may remain eligible for the study. Consult the Medical Lead to discuss and determine if participant is eligible for enrollment). OR ii. Is intolerant to available therapies OR iii. Treatment with standard therapy is not appropriate.
7. Subprotocol C: 1. Male and female, ≥10 years of age, and weighing ≥30 kg.
8. Subprotocol C: 2. Histologic diagnosis of a rare BRAF V600E-mutated solid tumor that is unresectable, locally advanced or metastatic.
9. Subprotocol C: 3. Documented BRAF V600E mutation in tumor and/or blood detected by an analytically validated test at CLIA or CLIA-equivalent laboratory approved by sponsor or sponsor-designated central test.
10. Subprotocol C: 4. Have an archival tissue sample available meeting protocol requirements. If an archival tissue sample is not available, a newly obtained (before treatment) tumor biopsy may be submitted instead.
11. Subprotocol C: 5. Consent to provide scan(s) prior to baseline to assess change in tumor trajectory.
12. Subprotocol B: 3.Documented BRAF V600E mutation in tumor and/or blood detected by an analytically validated test at CLIA or CLIA-equivalent laboratory approved by sponsor or sponsor-designated central test.
13. Subprotocol C: 6. Received all available standard therapy, is intolerant to available therapies, or treatment with standard therapy is not appropriate.
14. Subprotocol D: 1. Male and female, 16-65 years of age.
15. Subprotocol D: 2. Histologic diagnosis of a solid tumor harboring a BRAFV600E mutation and not elegible for other subprotocols.
16. Subprotocol D: 3. Measurable disease on CT, MRI or physical exam
17. Subprotocol D: 4. Evidence of BRAF V600E mutation in tumor and/or blood detected by genomic tests
18. Subprotocol B: 4. An archival tissue sample available meeting protocol requirements, or fresh biopsy is required if the archival sample is not available for retrospective confirmation test. Tissue obtained most proximal to initiating this subprotocol is preferred.
19. Subprotocol B: 5. Measurable disease based upon specified response criteria, as determined by the radiographic BICR.
20. Subprotocol B: 6. All adverse events related to prior therapies (eg, chemotherapy, radiotherapy, surgery) must have resolved to Grade 1 or baseline except for: a. Alopecia (Grade ≤2) b. Sensory neuropathy (Grade ≤2) c. Other adverse events that have resolved to Grade ≤2 that, according to the clinical judgment of the investigator, do not constitute a safety risk to the participant
21. Subprotocol B: 7. Participants who are receiving corticosteroid treatment must be on a stable or decreasing dose of ≤8 mg/day of dexamethasone or equivalent corticosteroid treatment for 7 days prior to first dose of study treatments.
22. Subprotocol A: 2. Histologic diagnosis of a solid tumor or primary CNS tumor.
23. Subprotocol A: 3. Documentation of BRAF gene fusion in tumor and/or blood detected by an analytically validated test by DNA sequencing or RNA (transcriptome) sequencing at CLIA or CLIA-equivalent laboratory or sponsor-designated central laboratory.
24. Subprotocol A: 4. Have an archival tissue sample available meeting protocol requirements. If an archival tissue sample is not available, a newly obtained (before treatment) tumor biopsy may be submitted instead.
25. Subprotocol D: 5. Consent to provide a tumor biopsy.
26. Subprotocol D: 6. Willingness to comply with the ECG substudy procedures
27. Subprotocol D: 7. All AEs related to prior therapies must have resolved to grade 1 or baseline.

Exclusion criteria 32

1. Subprotocol A:3. Prior treatment with MAPK inhibitors active for Class 2 BRAF alterations for advanced unresectable or metastatic disease (including but not limited to tovorafenib [formerly known as DAY 101, TAK 580, and MLN 2480], KIN-2787, BGB-3245, andCFT1946). Note: Participants with pediatric-type LGGs (molecular classification byWHO2021; diagnosed at ≤25 years of age) who had received prior treatment(s)with RAF/BRAF inhibitors are eligible for enrollment, provided there was no evidence of tumor progression on that therapy or within 4 weeks of discontinuation, based upon radiographic assessment.
2. Subprotocol C: 3. Participant has CNS metastases.
3. Subprotocol C: 5. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.
4. Subprotocol C: 6. Uncontrolled intercurrent illness that would limit compliance with study requirements.
5. Subprotocol C: 7. Active infection requiring systemic therapy.
6. Subprotocol C: 8. Current or planned participation in a study of an investigational agent or device.
7. Subprotocol C: 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, small bowel resection).
8. Subprotocol C: 10. Grade ≥ 2 changes in AST, ALT, gamma-glutamyl transaminase (GGT), or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.
9. Subprotocol D: 1. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.
10. Subprotocol D: 2. Participant has CNS metastases.
11. Subprotocol B: 2. Known or suspected neurofibromatosis-1 (NF-1) and/or Ras related gene alterations.
12. Subprotocol A: 4. 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. NOTE: There is no restriction on the number of lines of chemotherapy or immunotherapy.
13. Subprotocol D: 3. Uncontrolled intercurrent illness that would limit compliance with study requirements.
14. Subprotocol D: 4. Active infection requiring systemic therapy.
15. Subprotocol D: 5. Current or planned participation in a study of an investigational agent or device.
16. Subprotocol D: 6. 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, small bowel resection).
17. Subprotocol D: 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.
18. Subprotocol D: 8. Use or anticipate the need for medications with known risk for QT-prolonging potential and Torsades de Pointes.
19. Subprotocol B: 3. Uncontrolled intercurrent illness that would limit compliance with study requirements.
20. Subprotocol B: 4. Active infection requiring systemic therapy.
21. Subprotocol B: 5. Current or planned participation in a study of an investigational agent or device.
22. Subprotocol B: 6. Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral plixorafenib (such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
23. Subprotocol A: 5. Malignancy with co-occurring activating RAS mutation(s) at any time.
24. Subprotocol B: 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.
25. Subprotocol D: 9. History of acute or chronic cardiovascular disease or surgery, hypertension, with systolic blood pressure > 160 mm Hg, history of QTc abnormalities, or clinical significant ECG abnormalities.
26. Subprotocol A: 6. Uncontrolled intercurrent illness that would limit compliance with study requirements.
27. Subprotocol A: 7. Current or planned participation in a study of an investigational agent or device.
28. Subprotocol A: 8. Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral plixorafenib (such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, and small bowel resection).
29. Subprotocol C: 1. Diagnosis of colorectal adenocarcinoma or pancreatic ductal adenocarcinoma (neuroendocrine or acinar tumors are eligible).
30. Subprotocol C: 2. Diagnosis of BRAF V600E mutated melanoma, papillary thyroid cancer or NSCLC.
31. Subprotocol B: 1. Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).
32. Subprotocol C: 4. Prior treatment with BRAF, ERK, and/or MEK inhibitor(s), unless otherwise specified for specific tumor types (i.e. low grade serios or borderline ovarian cancer)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 1. Objective Response Rate (ORR) (Subprotocol A, B and C): ORR will be determined by standard tumor response criteria by blinded independent central review (BICR)
2. 2. Pharmacokinetics (Subprotocol D): Systemic exposure of plixorafenib measured by Cmax and AUC.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fore Biotherapeutics Inc.

Sponsor organisation

Fore Biotherapeutics Inc.

Address

3675 Market Street

City

Philadelphia

Postcode

19104-2897

Country

United States

Scientific contact point

Organisation

Fore Biotherapeutics Inc.

Contact name

Fore Biotherapeutics, Director of Clinical Operations

Public contact point

Organisation

Fore Biotherapeutics Inc.

Contact name

Fore Biotherapeutics, Director of Clinical Operations

Third parties 12

Locations

7 EU/EEA countries · 25 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 127 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications