Summary

Eligibility
for people ages 10 years and up (full criteria)
Location
at Westwood, California and other locations
Dates
study started
completion around
Principal Investigator
by Noah C. Federman, MD
Headshot of Noah C. Federman
Noah C. Federman

Description

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.

Official Title

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

Keywords

Cancer Harboring BRAF Alterations, HGG, LGG, Solid Tumors, Melanoma BRAF V600E/K Mutated, Thyroid Cancer, BRAF alterations, BRAF Fusions, BRAF V600E, BRAF Class 1, BRAF Class 2, High grade glioma, low grade glioma, Thyroid Neoplasms, Cobicistat, Plixorafenib

Eligibility

You can join if…

Open to people ages 10 years and up

Subprotocol A:

  1. Male and female, ≥10 years of age, and weighing ≥30 kg.
  2. Histologic diagnosis of a solid tumor or primary CNS tumor.
  3. Documentation of BRAF gene fusion in tumor and/or blood detected by an analytically validated test by DNA sequencing or RNA (transcriptome) sequencing.
  4. Have an archival tissue sample available meeting protocol requirements.
  5. Consent to provide scan(s) prior to baseline to assess change in tumor trajectory.
  6. Received all available standard therapy, is intolerant to available therapies, or the investigator has determined that treatment with standard therapy is not appropriate.
  7. All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline.

Subprotocol B:

  1. Male and female, ≥10 years of age, and weighing ≥30 kg.
  2. Histological diagnosis of a primary CNS tumor, including but not limited to the following:
    1. 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
    2. 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.
    3. Participants must have unresectable, locally advanced or metastatic disease that:
    4. Had prior treatment with radiotherapy and/or first-line chemotherapy or concurrent chemoradiation therapy OR
    5. 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.

    ii. Is intolerant to available therapies OR iii. The investigator has determined that treatment with standard therapy is not appropriate.

  3. Documented BRAF V600E mutation in tumor and/or liquid biopsy detected by an analytically validated test at CLIA or CLIA-equivalent laboratory approved by sponsor or sponsor-designated central test.
  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.
  5. Consent to provide scan(s) prior to baseline to assess change in tumor trajectory.
  6. Measurable disease based upon specified response criteria, as determined by the radiographic BICR.
  7. All adverse events related to prior therapies (eg, chemotherapy, radiotherapy, surgery) must have resolved to Grade 1 or baseline.
  8. 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.

Subprotocol C:

  1. Male and female, ≥10 years of age, and weighing ≥30 kg.
  2. Histologic diagnosis of a rare BRAF V600E-mutated solid tumor that is unresectable, locally advanced or metastatic.
  3. Measurable disease on CT, MRI, or physical exam
  4. Documented BRAF V600E mutation in tumor and/or liquid biopsy detected by an analytically validated test.
  5. Have an archival tissue sample available meeting protocol requirements.
  6. Consent to provide scan(s) prior to baseline to assess change in tumor trajectory
  7. Received all available standard therapy, is intolerant to available therapies, or the investigator has determined that treatment with standard therapy is not appropriate.
  8. All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline.

Subprotocol D:

  1. Male and female, ≥10 years of age, and weighing ≥30 kg.
  2. Histologic diagnosis of a metastatic melanoma or thyroid cancer harboring a BRAF V600E mutation.
  3. Participants with cutaneous melanoma have previously received and not tolerated a BRAF inhibitor, while participants with thyroid cancer are MAPK inhibitor naïve.
  4. Measurable disease on CT, MRI, or physical exam.
  5. Evidence of BRAF V600E mutation in tumor and/or blood detected by genomic tests.
  6. Consent to provide a tumor biopsy.
  7. All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline.

You CAN'T join if...

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.

Locations

  • University of California Los Angeles Rheumatology accepting new patients
    Westwood California 90095-6984 United States
  • UCSF Helen Diller Family Comprehensive Cancer Center accepting new patients
    San Francisco California 94143 United States

Lead Scientist at UCLA

  • Noah C. Federman, MD
    Dr. Noah Federman is the Director of the Pediatric Bone and Soft Tissue Sarcoma Program at UCLA, part of the UCLA Sarcoma Program and UCLA's Jonsson Comprehensive Cancer Center. Dr. Federman specializes in treating children, adolescents and young adults with these aggressive cancers.

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Fore Biotherapeutics
Links
Sign up for this study
ID
NCT05503797
Phase
Phase 2 research study
Study Type
Interventional
Participants
Expecting 250 study participants
Last Updated