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

Phase 1

Active, not recruiting

• Conditions: Melanoma; Colorectal Carcinoma; Metastatic Lung Non-Small Cell Carcinoma; Metastatic Melanoma; Metastatic Lung Cancer; NSCLC; Solid Carcinoma; KRAS G12R; Non-small Cell Lung Cancer; BRAF Gene Mutation
• Interventions: Drug: BDTX-4933

• Registration Number: NCT05786924
• Lead Sponsor: Black Diamond Therapeutics, Inc.

Brief Summary

BDTX-4933-101 is a first-in-human, open-label, Phase 1 dose escalation and an expansion cohort study designed to evaluate the safety and tolerability, maximum tolerated dose (MTD) and the preliminary recommended Phase 2 dose (RP2D), and antitumor activity of BDTX-4933. The study population for the Dose Escalation part of the study comprises adults with recurrent advanced/metastatic non-small cell lung cancer (NSCLC) harboring KRAS non-G12C mutations, BRAF, or CRAF (RAF1) mutations, advanced/metastatic melanoma harboring BRAF or NRAS mutations, histiocytic neoplasms harboring BRAF, CRAF, or NRAS mutations, and other solid tumors harboring BRAF mutations. The study population for the Dose Expansion part of the study comprises adults with recurrent advanced/metastatic NSCLC harboring KRAS non-G12C mutations. All patients will self-administer BDTX-4933 orally in 28-day cycles until disease progression, toxicity, withdrawal of consent, or termination of the study.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-03-06
• Study First Submitted QC: 2023-03-15
• Study First Posted: 2023-03-28
• Study Start: 2023-04-18
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-24
• Last Update Posted: 2025-03-25
• Primary Completion: 2026-06
• Study Completion: 2026-12

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

1. Disease criteria:

   1. Histologically or cytologically confirmed recurrent/advanced (unresectable) or metastatic solid tumors or histiocytic neoplasms with documented RAS or BRAF mutations.

      Note: Patients may have stable central nervous system (CNS) metastases. Patients with 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.

   2. Dose Escalation cohorts:

      • NSCLC with KRAS non-G12C mutations, including other mutations at KRAS-G12 (eg, G12V/G12D) and other oncogenic variants of KRAS mutations on G13 and Q61 amino acid residues, BRAF, or CRAF mutations.
      • Melanoma with BRAF, CRAF, or NRAS mutations.
      • Histiocytic neoplasms with BRAF or NRAS mutations.
      • Thyroid carcinoma with BRAF 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 or local standard-of-care with Sponsor approval.

   3. Dose Expansion cohort:

   Recurrent advanced/metastatic NSCLC with KRAS non-G12C mutations without small cell lung cancer transformation with progressive disease confirmed by radiographic assessment.

2. Prior standard-of-care

   For dose levels <200 mg once daily and/or not at preliminary RP2D(s):

   1. Exhausted all available standard-of-care therapies or, in the opinion of the Investigator, would be unlikely to tolerate or derive clinically meaningful benefit from available standard-of-care therapy.
   2. Patients with eligible tumors harboring BRAF V600E mutations must have received FDA approved BRAF targeted therapy, BRAF/MEK inhibitors combination, or BRAF inhibitors combination.

   For dose levels ≥200 mg once daily or at preliminary RP2D(s):

   a. Patients must have received at least 1 but no more than 2 prior lines of systemic therapy for metastatic/advanced disease (adjuvant and maintenance therapy do not count towards the limit).

3. Evaluable or measurable disease in dose escalation and measurable disease only for dose expansion cohorts.

4. Adequate bone marrow and organ function.

5. Recovered from toxicity to prior anti-cancer therapy.

6. Appropriate candidate for BDTX-4933 monotherapy.

7. Life expectancy of >=12 weeks in the opinion of the Investigator.

Key

Exclusion Criteria

1. Cancer that has a known MEK1/2 mutation.
2. Major surgery within 4 weeks of study entry or planned during study.
3. Ongoing anticancer therapy.
4. Ongoing radiation therapy.
5. Uncontrolled or active clinically relevant bacterial, fungal, or specific viral infection requiring systemic therapy.
6. Symptomatic spinal cord compression.
7. Evidence of active malignancy (other than study-specific malignancies) requiring systemic therapy within the next 2 years.
8. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO.
9. Females who are pregnant or breastfeeding.
10. Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.
11. Prior use of experimental agents that target the KRAS/BRAF/MEK/ERK pathway.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1 Dose Escalation	BDTX-4933	BDTX-4933 will be administered at escalating dose levels until the maximum tolerated dose (MTD) is reached and the preliminary recommended Phase 2 dose (RP2D) is determined.
Phase 1 Dose Expansion	BDTX-4933	BDTX-4933 will be administered at the RP2D.

Primary Outcome Measures

Name	Time	Method
Dose Escalation: Incidence of dose-limiting toxicities (DLTs) to estimate the preliminary RP2D and/or MTD of BDTX-4933	The first 28-day cycle (Cycle 1)	A DLT is defined as any event meeting the DLT criteria occurring within the first 28-day cycle
Dose 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 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 Expansion: Time-to-response (TTR)	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 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)

Secondary Outcome Measures

Name	Time	Method
Dose Escalation: 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: 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
Dose Escalation: 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: 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: 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: 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: 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)

Trial Locations

Locations (10)

Banner Health- MD Anderson Cancer Center; 🇺🇸 Gilbert, Arizona, United States

University of Colorado - Aurora Cancer Center; 🇺🇸 Aurora, Colorado, United States

Georgetown University Lombardi Cancer Center; 🇺🇸 Washington, District of Columbia, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

South Texas Accelerated Research Therapeutics (START) Midwest; 🇺🇸 Grand Rapids, Michigan, United States

Masonic Cancer Center University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

Washington University; 🇺🇸 Saint Louis, Missouri, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

NEXT Virginia; 🇺🇸 Fairfax, Virginia, United States

Fred Hutchinson Cancer Research Center; 🇺🇸 Seattle, Washington, United States