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

Официальное название

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

Обзор

The objective of this Master Protocol is to evaluate the efficacy and safety of plixorafenib in participants with BRAF altered (BRAF V600E or BRAF fusions) locally advanced or metastatic solid tumors, or recurrent or progressive primary central nervous system (CNS) tumors, including rare BRAF V600E-mutated solid tumors, including anaplastic thyroid, ovarian, cholangiocarcinoma or other rare cancers.

Вмешательства

• Препарат Plixorafenib
  Oral tablets

Первичные конечные точки

• Objective Response Rate (ORR) (Subprotocols A, B and C) [Срок оценки: Up to approximately 4 years]
• Pharmacokinetics (Subprotocol D) [Срок оценки: Up to approximately 4 years]

Вторичные конечные точки (12)

• Duration of Response (DOR) by BICR (Subprotocols A, B and C) [Срок оценки: Up to approximately 4 years]
• ORR per Investigator Assessment [Срок оценки: Up to approximately 4 years]
• DOR per Investigator Assessment [Срок оценки: Up to approximately 4 years]
• Percentage of Participants with DOR at 6 months, 12 months, and 18 months [Срок оценки: 6 months, 12 months and 18 months]
• Time to Response by BICR (Subprotocols A, B and C) [Срок оценки: Up to approximately 4 years]
• Progression Free Survival (PFS) by BICR (Subprotocols A, B and C) [Срок оценки: Up to approximately 4 years]
• PFS per Investigator's Assessment [Срок оценки: Up to approximately 4 years]
• Overall Survival [Срок оценки: Up to approximately 4 years]
• Percentage of Participants with PFS at 6 months, 12 months and 24 months [Срок оценки: 6 months, 12 months and 24 months]
• Disease Control Rate (DCR) [Срок оценки: Up to approximately 4 years]
• Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs) [Срок оценки: Up to approximately 4 years]
• Plasma Concentrations of Plixorafenib [Срок оценки: Up to approximately 4 years]

Критерии участия

Критерии включения

Subprotocol A:

• Male and female, ≥8 years of age, and weighing ≥25 kg.
• Histologic diagnosis of a solid tumor or primary CNS tumor.
• Documentation of BRAF gene fusion in tumor and/or blood detected by an analytically validated test by DNA sequencing or RNA (transcriptome) sequencing.
• Have an archival tissue sample available meeting protocol requirements.
• Consent to provide scan(s) prior to baseline to assess change in tumor trajectory.
• Received all available standard therapy, is intolerant to available therapies, or the investigator has determined that treatment with standard therapy is not appropriate.
• All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline.

Subprotocol B:

• Male and female, ≥8 years of age, and weighing ≥25 kg.
• Histological diagnosis of a primary CNS tumor, including but not limited to the following:

• 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
• Pediatric patients (8-17 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.
• 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 OR

• 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.

• 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.
• An archival tissue sample available meeting protocol requirements, or fresh biopsy is required if the archival sample is not available for retrospective confirmation test.
• Consent to provide scan(s) prior to baseline to assess change in tumor trajectory.
• Measurable disease based upon specified response criteria, as determined by the radiographic BICR.
• All adverse events related to prior therapies (eg, chemotherapy, radiotherapy, surgery) must have resolved to Grade 1 or baseline.
• 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:

• Male and female, ≥8 years of age, and weighing ≥25 kg.
• Histologic diagnosis of a rare BRAF V600E-mutated solid tumor that is unresectable, locally advanced or metastatic.
• Measurable disease on CT, MRI, or physical exam
• Documented BRAF V600E mutation in tumor and/or liquid biopsy detected by an analytically validated test.
• Have an archival tissue sample available meeting protocol requirements.
• Consent to provide scan(s) prior to baseline to assess change in tumor trajectory
• Received all available standard therapy, is intolerant to available therapies, or the investigator has determined that treatment with standard therapy is not appropriate.

Subprotocol D:

• Male and female, ≥8 years of age, and weighing ≥25 kg.
• Histologic diagnosis of a solid tumor harboring a BRAF V600E mutation and not eligible for other subprotocols.
• Measurable disease on CT, MRI, or physical exam.
• Evidence of BRAF V600E mutation in tumor and/or blood detected by genomic tests.
• Consent to provide a tumor biopsy.
• Willingness to comply with the ECG substudy procedures.
• All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline.

Критерии исключения

Subprotocol A:

• Prior treatment with RAF/BRAF inhibitors active for Class 2 BRAF alterations for advanced unresectable or metastatic disease.
• Prior treatment with a MEK inhibitor.
• 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.
• Malignancy with co-occurring activating RAS mutation(s) at any time.
• Uncontrolled intercurrent illness that would limit compliance with study requirements.
• HIV infection with exceptions; discuss with treating physician.
• 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).
• Grade ≥2 changes in AST, ALT, GGT, or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.

Subprotocol B:

• Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).
• Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.
• Uncontrolled intercurrent illness that would limit compliance with study requirements.
• Active infection requiring systemic therapy.
• HIV infection with exceptions; discuss with treating physician.
• Have impairment of 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).
• 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:

• Diagnosis of colorectal adenocarcinoma or pancreatic ductal adenocarcinoma (neuroendocrine or acinar tumors are eligible).
• Diagnosis of BRAF V600E-mutated cutaneous melanoma, papillary thyroid cancer, or NSCLC.
• Participant has CNS metastases.
• Prior treatment with BRAF, ERK, and/or MEK inhibitor(s), unless otherwise specified for specific tumor types (i.e. low grade serous or borderline ovarian cancer).
• Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.
• Participants with prostate, breast, or gynecologic cancers with known activating mutations that lead to constitutive hormone receptor activation (AR-V7, ESR1).
• Uncontrolled intercurrent illness that would limit compliance with study requirements.
• Active infection requiring systemic therapy.
• HIV infection with exceptions; discuss with treating physician.

Subprotocol D:

• Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations or other co-occurring driver mutations.
• Participant has a non-CNS solid tumor with CNS metastases.
• Uncontrolled intercurrent illness that would limit compliance with study requirements.
• Active infection requiring systemic therapy.
• HIV infection with exceptions; discuss with treating physician.
• Use or anticipate the need for medications with known risk for QT-prolonging potential and Torsades de Pointes.
• History of acute or chronic cardiovascular disease or surgery, hypertension, with systolic blood pressure >160mm HG, history of QTc abnormalities, or clinical significantly ECG abnormalities (for participants in the ECG substudy).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 30 центров

• Precision NextGen Oncology & Research Center — Beverly Hills
• UCSF Helen Diller Family Comprehensive Cancer Center — San Francisco
• University of California Los Angeles Rheumatology — Westwood, Los Angeles
• Norwalk Hospital — Norwalk
• University of Miami Hospital and Clinics — Miami
• The John Hopkins Hospital — Baltimore
• Maryland Oncology Hematology- Columbia — Rockville
• Tufts Medical Center — Boston
• … и ещё 22 центра

Франция · 7 центров

• Institut Bergonie — Bordeaux
• Hôpital Nord de Marseille — Marseille
• Hôpital Morvan — Brest
• Institut de Cancerologie de l'Ouest- Angers — Angers
• Gustave Roussy — Villejuif
• Institut Universitaire du Cancer de Toulouse Oncopole — Toulouse
• Hôpital Universitaire Pitié Salpêtrière — Paris

South Korea · 6 центров

• Catholic University of Korea Saint Vincent's Hospital — Suwon
• Seoul National University Hospital — Suwon
• Dong-A University Hospital — Pusan
• Chonnam National University Hwasun Hospital — Hwasun
• Seoul National University Hospital — Seoul
• Severance Hospital — Seoul

Испания · 6 центров

• Hospital Clinico Universitarlo de Santiago — Santiago de Compostela
• Hospital Universitari Vall d'Hebron — Barcelona
• Hospital Infantil Universitario Niño Jesús — Madrid
• Hospital Universitario 12 de Octubre — Madrid
• Hospital Universitario Virgen del Rocío — Seville
• Hospital Clinico Universitarlo de Valencia — Valencia

Австралия · 5 центров

• Newcastle Private Hospital — New Lambton Heights
• Orange Health Service — Orange
• Sydney Children's Hospital Network - Randwick — Randwick
• Flinders Medical Centre — Bedford Park
• The Alfred — Melbourne

Италия · 4 центра

• Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST — Meldola
• Istituto Nazionale Tumori IRCCS Fondazione G. Pascale — Naples
• Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale San Raffaele — Milan
• Istituto Europeo di Oncologia — Milan

Германия · 3 центра

• Universitätsklinikum Heidelberg — Heidelberg
• Krankenhaus Nordwest — Frankfurt am Main
• Charité - Universitätsmedizin Berlin — Berlin

Канада · 2 центра

• Sunny brook Health Sciences Centre- Bayview Campus — Toronto
• Centre Hospitalier Universitaire Sainte-Justine — Montreal

Норвегия · 2 центра

• Haukeland Univeritetssjukehus — Bergen
• Oslo Universitetssykehus-Radiumhospitalet — Oslo

Швеция · 2 центра

• Skånes Universitetssjukhus — Lund
• Karolinska Universitetssjukhuset — Solna

Великобритания · 2 центра

• The Christie NHS Foundation Trust — Manchester
• Sarah Cannon Research Institute — London

Нидерланды · 1 центр

• Erasmus Medisch Centrum — Rotterdam

Идентификаторы

NCT: NCT05503797 · F8394-201 · 2024-513578-23-00 · 2022-000627-20

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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