A Study of BDTX-4933 in Patients With BRAF and Select RAS/MAPK Mutation-Positive Cancers

Study Overview
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Brief Summary
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BDTX-4933-101 is a first-in-human, open-label, Phase 1 dose escalation and multiple expansion cohort study designed to evaluate the safety and antitumor activity of BDTX-4933. The study population comprises adults with recurrent advanced/metastatic cancers harboring BRAF (Class I, II, and III), KRAS (other than G12C such as G12D, G12V), or NRAS mutations including non-small cell lung cancer (NSCLC), melanoma, histiocytic neoplasms, thyroid cancer, colorectal cancer, and other solid tumor cancers with or without brain metastases. All patients will self-administer BDTX-4933 orally in 28-day cycles until disease progression, toxicity, withdrawal of consent, or termination of the study.

Official Title
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A Phase 1, Open-label Study of BDTX-4933 in Patients With BRAF and Other Select RAS/MAPK Mutation-Positive Neoplasms

Conditions
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KRAS G12D, Non-small Cell Lung Cancer, Non-small Cell Carcinoma, Histiocytic Neoplasm, Histiocytosis, Melanoma, Melanoma (Skin), BRAF Gene Mutation, BRAF V600E, BRAF V600 Mutation, BRAF Mutation-Related Tumors, BRAF, Metastatic Cancer, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Melanoma, Metastatic Lung Cancer, Recurrent Melanoma, Recurrent Lung Cancer, Recurrent Lung Non-Small Cell Carcinoma, NSCLC, Solid Tumor, Solid Carcinoma, KRAS G12V, KRAS Mutation-Related Tumors, NRAS Gene Mutation, Thyroid Cancer, Thyroid Carcinoma, Colorectal Cancer, Colorectal Carcinoma, Recurrent Histiocytic and Dendritic Cell Neoplasm, Brain Tumor, Brain Metastases, Recurrent NSCLC

Intervention / Treatment
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* Drug: BDTX-4933


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Disease criteria: Histologically or cytologically confirmed recurrent/advanced metastatic solid tumors or histiocytic neoplasms with documented BRAF or RAS (NRAS or KRAS) mutations. Note: Patients may have stable central nervous system (CNS) metastases. Patients with CNS gliomas or active CNS metastases or primary CNS tumors associated with progressive neurological symptoms or needing increased doses of corticosteroids to control the CNS disease are excluded from the study. Dose Escalation cohorts: Melanoma with BRAF (Class I, II, or III) or NRAS mutations. NSCLC with BRAF (Class II or III) or KRAS mutations other than G12C (ie, G12D, G12V) mutations (with Sponsor approval for KRAS mutations). Histiocytic neoplasms with BRAF (Class I, II, or III) or NRAS mutations. Thyroid carcinoma with BRAF (Class I, II, or III) mutations. Colorectal carcinoma with BRAF (Class II or III) mutations with Sponsor approval. Other solid tumors with BRAF Class I mutations after prior treatment with a BRAF/MEK inhibitor with Sponsor approval. Dose Expansion cohorts: Cohort 1: Recurrent NSCLC with BRAF Class II alterations or KRAS mutations other than G12C (ie, G12D, G12V) mutations (with Sponsor approval for KRAS mutations) without small cell lung cancer transformation with progressive disease confirmed by radiographic assessment. Cohort 2: Recurrent histiocytic or intolerant neoplasms with BRAF or NRAS alterations with progressive disease confirmed by radiographic assessment or intolerance of standard of care. Cohort 3: Recurrent NSCLC (without small cell lung cancer transformation) or melanoma with BRAF Class I mutations with progressive disease after prior standard of care therapy. Cohort 4: Recurrent melanoma with NRAS mutations with progressive disease confirmed by radiographic assessment. Received prior systemic therapy (must have received 1 but no more than 2 prior lines of therapy; patients with melanoma may have up to 3 prior lines of therapy). Evaluable or measurable disease in dose escalation and measurable disease only for dose expansion cohorts. Adequate bone marrow and organ function. Recovered from toxicity to prior anti-cancer therapy. Appropriate candidate for BDTX-4933 monotherapy. Life expectancy of >=12 weeks in the opinion of the Investigator. Key Exclusion Criteria: Cancer that has a known MEK1/2 mutation. Major surgery within 4 weeks of study entry or planned during study. Ongoing or recent anticancer therapy. Ongoing or recent radiation therapy. Uncontrolled or active clinically relevant bacterial, fungal, or specific viral infection requiring systemic therapy. Symptomatic spinal cord compression. Evidence of active malignancy (other than study-specific malignancies) requiring systemic therapy within the next 2 years. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO. Females who are pregnant or breastfeeding. Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Escalation<br>BDTX-4933 will be administered at escalating dose levels until the maximum tolerated dose (MTD) is reached. | Drug: BDTX-4933<br>* RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active KRAS or NRAS mutations<br>|
| Experimental: Phase 1 Dose Expansion<br>BDTX-4933 will be administered at the recommended Phase 2 dose (RP2D). | Drug: BDTX-4933<br>* RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active KRAS or NRAS mutations<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation: Incidence of dose-limiting toxicities (DLTs) to estimate the recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD) of BDTX-4933 | A DLT is defined as any event meeting the DLT criteria occurring within the first 28-day cycle | The first 28-day cycle (Cycle 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation/Expansion: Incidence and severity of treatment-emergent adverse events (TEAEs) |  | Through study completion, approximately 1 year | 
| Dose Escalation/Expansion: Maximum plasma concentration (Cmax) of BDTX-4933 and its metabolite |  | Cycle 1 Days 1 and 15, Day 1 of Cycle 2 through Cycle 5, and Day 1 of every other cycle thereafter to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Expansion: Time of maximum plasma concentration (Tmax) of BDTX-4933 and its metabolite |  | Cycle 1 Days 1 and 15, Day 1 of Cycle 2 through Cycle 5, and Day 1 of every other cycle thereafter to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Expansion: Area under the plasma drug concentration-time curve (AUC) of BDTX-4933 and its metabolite |  | Cycle 1 Days 1 and 15, Day 1 of Cycle 2 through Cycle 5, and Day 1 of every other cycle thereafter to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Expansion: Half-life (t1/2) of BDTX-4933 and its metabolite |  | Cycle 1 Days 1 and 15, Day 1 of Cycle 2 through Cycle 5, and Day 1 of every other cycle thereafter to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Expansion: Objective response rate (ORR) including extracranial and intracranial |  | Day 1 of every 2 cycles to Cycle 13 Day 1, then Day 1 of every 3 cycles thereafter to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Expansion: Duration of response (DOR) |  | Day 1 of every 2 cycles to Cycle 13 Day 1, then Day 1 of every 3 cycles thereafter to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Expansion: Time to response |  | Day 1 of every 2 cycles to Cycle 13 Day 1, then Day 1 of every 3 cycles thereafter to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Expansion: Progression-free survival (PFS) |  | Day 1 of every 2 cycles to Cycle 13 Day 1, then Day 1 of every 3 cycles thereafter to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Expansion: Overall survival |  | First dose of study drug to death due to any cause or for 12 months from last dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BDTX-4933, Phase 1, dose escalation, dose expansion, MAPK, mitogen-activated protein kinase, RAS, RAF, Upstream oncogenic alterations, RAF inhibitor, intracranial disease, BRAF Class I, BRAF Class II, BRAF Class III, KRAS, Intolerant histiocytic neoplasm