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

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Servier Protocol Code: BDTX-4933-101 Sponsor: Institut de Recherches Internationales Servier Clinicaltrials.gov Identifier: NCT05786924

Find a recruiting site

How to participate to the study?
If you think you are eligible for this study (see
eligibility criteria
below), you can identify the location closest to you and contact them directly. If you don’t find a location close to you, please contact Institut de Recherches Internationales Servier (I.R.I.S.)
Name: Institut de Recherches Internationales Servier, Département des études cliniques
Phone number: +33 1 55 72 60 00
The study has 10 locations

Study description

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.
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
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
Interventions / Treatments
  • BDTX-4933
Other study id numbers
  • BDTX-4933-101

Eligibility Criteria

Eligible age for the study

18 years and older (Adult, Older Adult)

Sexes

Male/Female

Accepts Healthy Volunteers

No

  • 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.

  • 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.

How is the study designed?

Allocation
Non-randomized
Interventional study model
Sequential
Participant Group / Arm
Experimental: Phase 1 Dose Escalation
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.
Intervention / Treatment
Drug: BDTX-4933
RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations
Participant Group / Arm
Experimental: Phase 1 Dose Expansion
BDTX-4933 will be administered at the RP2D.
Intervention / Treatment
Drug: BDTX-4933
RAF inhibitor targeting all classes of oncogenic BRAF alterations (Classes I, II, and III) and constitutively active CRAF, KRAS or NRAS mutations

Keywords

Provided by Servier
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
Additional Relevant MeSH Terms Glioma
Carcinoma, Non-Small-Cell Lung Histiocytosis Melanoma Lung Neoplasms Thyroid Neoplasms Colorectal Neoplasms Brain Neoplasms