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

Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05786924
• Other study ID #: BDTX-4933-101
• Status: Recruiting
• Phase: Phase 1
• Start date: April 18, 2023
• Est. completion date: December 2026

Study information

• Verified date: April 2024
• Source: Black Diamond Therapeutics, Inc.
• Contact: BDTX Clinical Trial Navigation Service
• Phone: (866) 955-4397
• Email: blackdiamondtx[@]careboxhealth.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 or BRAF mutations, advanced/metastatic melanoma harboring BRAF or NRAS mutations, histiocytic neoplasms harboring BRAF 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: December 2026
• Est. primary completion date: June 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key 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) or BRAF (Class I, II, or III) (with Sponsor approval).

• Melanoma with BRAF (Class I, II, or III) or NRAS 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 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. Received prior standard-of-care:

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 that have received FDA approved BRAF targeted therapy, BRAF/MEK inhibitors combination, or BRAF inhibitors combination.

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.

Related Conditions & MeSH terms

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

Intervention

Drug:
• BDTX-4933
RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active KRAS or NRAS mutations

Locations

Country	Name	City	State
United States	University of Colorado - Aurora Cancer Center	Aurora	Colorado
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	NEXT Virginia	Fairfax	Virginia
United States	Banner Health- MD Anderson Cancer Center	Gilbert	Arizona
United States	South Texas Accelerated Research Therapeutics (START) Midwest	Grand Rapids	Michigan
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Huntsman Cancer Institute (University of Utah)	Salt Lake City	Utah
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Georgetown University Lombardi Cancer Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Black Diamond Therapeutics, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose Escalation: Incidence of dose-limiting toxicities (DLTs) to estimate the preliminary RP2D and/or 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)
Primary	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)
Primary	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)
Primary	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)
Primary	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	Dose Escalation/Expansion: Incidence and severity of treatment-emergent adverse events (TEAEs)		Through study completion, approximately 1 year
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Dose Escalation/Expansion: Overall survival		First dose of study drug to death due to any cause or for 12 months from last dose