Clinical trial NCT05786924: A Study of BDTX-4933 in Patients With KRAS, BRAF and Select RAS/MAPK Mutation-Positive Cancers
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Non-small Cell Lung Cancer
Histiocytic Neoplasm
Histiocytosis
Melanoma
Melanoma (Skin)
BRAF Gene Mutation
BRAF V600E
BRAF V600 Mutation
BRAF Mutation-Related Tumors
BRAF
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 G12D
KRAS G12V
KRAS Mutation-Related Tumors
NRAS Gene Mutation
Thyroid Cancer
Thyroid Carcinoma
Colorectal Cancer
Colorectal Carcinoma
Recurrent Histiocytic and Dendritic Cell Neoplasm
Brain Metastases
Recurrent NSCLC
KRAS G13C
Acquired Resistance to KRAS G12C Inhibitor
KRAS G12A
KRAS G12F
KRAS G12R
KRAS G13D
Keywords: BRAF Class I
BRAF Class II
BRAF Class III
KRAS
Intolerant histiocytic neoplasm
BDTX-4933
Phase 1
dose escalation
dose expansion
MAPK
mitogen-activated protein kinase
RAS
RAF
Upstream oncogenic alterations
RAF inhibitor
intracranial disease
CRAF
NRAS
RAF fusions
Lead sponsor: Servier
Sponsor class: INDUSTRY
First posted: 2023-03-28
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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) 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.

Primary outcomes:
measure: Dose Escalation: Incidence of dose-limiting toxicities (DLTs) to estimate the preliminary RP2D and/or MTD of BDTX-4933
timeFrame: The first 28-day cycle (Cycle 1)
measure: Dose Expansion: Objective response rate (ORR) including extracranial and intracranial
timeFrame: 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)
measure: Dose Expansion: Duration of response (DOR)
timeFrame: 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)
measure: Dose Expansion: Time-to-response (TTR)
timeFrame: 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)
measure: Dose Expansion: Progression-free survival (PFS)
timeFrame: 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 outcomes:
measure: Dose Escalation/Expansion: Incidence and severity of treatment-emergent adverse events (TEAEs)
timeFrame: Through study completion, approximately 1 year
measure: Dose Escalation/Expansion: Maximum plasma concentration (Cmax) of BDTX-4933 and its metabolite
timeFrame: 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)
measure: Dose Escalation/Expansion: Time of maximum plasma concentration (Tmax) of BDTX-4933 and its metabolite
timeFrame: 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)
measure: Dose Escalation/Expansion: Area under the plasma drug concentration-time curve (AUC) of BDTX-4933 and its metabolite
timeFrame: 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)
measure: Dose Escalation/Expansion: Half-life (t1/2) of BDTX-4933 and its metabolite
timeFrame: 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)
measure: Dose Escalation: Objective response rate (ORR) including extracranial and intracranial
timeFrame: 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)
measure: Dose Escalation: Duration of response (DOR)
timeFrame: 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)
measure: Dose Escalation: Time to response
timeFrame: 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)
measure: Dose Escalation: PFS
timeFrame: 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)
measure: Dose Escalation/Expansion: Overall survival
timeFrame: First dose of study drug to death due to any cause or for 12 months from last dose
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner Health- MD Anderson Cancer Center
state: Arizona
city: Aurora
country: United States
facility: University of Colorado - Aurora Cancer Center
state: Colorado
city: Washington
country: United States
facility: Georgetown University Lombardi Cancer Center
state: District of Columbia
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Grand Rapids
country: United States
facility: South Texas Accelerated Research Therapeutics (START) Midwest
state: Michigan
city: Minneapolis
country: United States
facility: Masonic Cancer Center University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Fairfax
country: United States
facility: NEXT Virginia
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
References: