NCT05503797招募中2 期
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
Fore Biotherapeutics115 个研究点 分布在 11 个国家目标入组 254 人开始时间: 2023年2月21日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 254
- 试验地点
- 115
- 主要终点
- Objective Response Rate (ORR) (Subprotocols A, B and C)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 8 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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).
研究组 & 干预措施
Subprotocol D
Experimental
Participants with BRAF V600E-mutated advanced solid tumors will receive plixorafenib until disease progression, unacceptable toxicity, or other reason for withdrawal.
干预措施: Plixorafenib (Drug)
Subprotocol C
Experimental
Participants with advanced, rare, non-CNS solid tumors harboring BRAF V600E mutations will receive plixorafenib, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal.
干预措施: Plixorafenib (Drug)
Subprotocol B
Experimental
Participants with recurrent primary CNS tumors harboring BRAF V600E mutations will receive plixorafenib, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal.
干预措施: Plixorafenib (Drug)
Subprotocol A
Experimental
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.
干预措施: Plixorafenib (Drug)
结局指标
主要结局
Objective Response Rate (ORR) (Subprotocols A, B and C)
时间窗: Up to approximately 4 years
ORR will be determined by standard tumor response criteria by blinded independent central review (BICR).
Pharmacokinetics (Subprotocol D)
时间窗: Up to approximately 4 years
Systemic exposure of plixorafenib measured by Cmax and AUC
次要结局
- ORR per Investigator Assessment(Up to approximately 4 years)
- Percentage of Participants with DOR at 6 months, 12 months, and 18 months(6 months, 12 months and 18 months)
- 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)
- Plasma Concentrations of Plixorafenib(Up to approximately 4 years)
- Duration of Response (DOR) by BICR (Subprotocols A, B and C)(Up to approximately 4 years)
- ORR per Investigator Assessment(Up to approximately 4 years)
- DOR per Investigator Assessment(Up to approximately 4 years)
- 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)
- 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)
研究者
研究点 (115)
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