Phase 1/2 Study of Silevertinib (BDTX-1535) in Patients With Glioblastoma or Non-Small Cell Lung Cancer With EGFR Mutations

NCT05256290 | Active Not Recruiting Phase 1 FDA Drug

• 1 other identifier: BDTX-1535-101
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 25

Brief Summary

BDTX-1535-101 is an open-label, Phase 1 dose escalation and Phase 2 multiple cohort study designed to evaluate the safety, pharmacokinetics (PK), optimal dosage, central nervous system (CNS) activity, and antitumor activity of silevertinib (BDTX-1535). The study population comprises adults with either advanced/metastatic non-small cell lung cancer (NSCLC) with non-classical or acquired epidermal growth factor receptor (EGFR) resistance (EGFR C797S) mutations with or without CNS disease (in Phase 1 and Phase 2), or glioblastoma (GBM) expressing EGFR alterations (Phase 1 only). All patients will self-administer silevertinib (BDTX-1535) monotherapy by mouth in 21-day cycles. Phase 1 enrollment is now complete. Phase 2 is currently ongoing.

Conditions

Metastatic Lung Non-Small Cell Carcinoma; NSCLC; Advanced Lung Carcinoma; Epidermal Growth Factor Receptor C797S; Epidermal Growth Factor Receptor G719X; EGF-R Positive Non-Small Cell Lung Cancer; EGFR-TKI Resistant Mutation; Non-Small Cell Lung Cancer; Metastatic Lung Cancer; Advanced Non-Small Cell Squamous Lung Cancer

Keywords

EGFR alterations; EGFR L858R; EGFR Exon 19 del; EGFR inhibitor; intrinsic resistance NSCLC EGFR; acquired resistance NSCLC EGFR; intracranial disease; brain metastases; central nervous system metastases; CNS metastases; uncommon NSCLC EGFR mutations; C797S acquired resistance EGFR mutation; non-classical NSCLC EGFR mutations; classical NSCLC EGFR mutations; EGFR PACC NSCLC mutations; EGFR E709A/G/K/Q/V; EGFR E709_T710delinsD/T; EGFR G719A/C/D/R/S; EGFR G724S; EGFR L718Q/V; EGFR L747S/P, L747_A750delinsP, L747_P753delinsS; Second-site EGFR mutation

Outcome Measures

Primary Outcomes (2)

• Phase 1 Dose Escalation: To determine the maximum tolerated dose (MTD), if one exists, and the preliminary recommended Phase 2 dose(s) (RP2D[s]) of silevertinib (BDTX-1535)

  Dose-limiting toxicities (DLTs) in Cycle 1

  The first treatment 21-day cycle (Cycle 1)

• Phase 2: To assess antitumor efficacy of silevertinib (BDTX-1535)

  Objective response rate (ORR) as assessed by Investigator using RECIST version 1.1

  Day 1 every 2 cycles starting on Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 21 days)

Secondary Outcomes (8)

• Phase 1 and Phase 2: Incidence and severity of treatment-emergent adverse events (TEAEs)

  Through study completion, approximately 1 year

• Phase 1 and Phase 2: To characterize the plasma concentration of silevertinib (BDTX-1535) following single and multiple dosing

  Cycle 1 Days 1, 2, 15, and 16, Cycles 2 to 5 Day 1, and Day 1 of every other cycle thereafter to study completion, approximately 1 year (each cycle is 21 days)

• Phase 1: To assess the preliminary antitumor activity of silevertinib (BDTX-1535) by objective response as assessed by RECIST version 1.1 (for patients with NSCLC) or Response Assessment in Neuro-oncology (RANO) (for patients with GBM)

  Day 1 every 2 cycles starting on Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 21 days)

• Phase 1: To assess the effect of tablet formulation on the plasma concentration of silevertinib (BDTX-1535)

  Two timepoints during the first cycle: Cycle 0 (7 days prior to Cycle 1 Day 1) and Cycle 1 Day 1 only (each cycle is 21 days)

• Phase 1: To assess the effect of food on the plasma concentration of silevertinib (BDTX-1535)

  Two timepoints during the first cycle: Cycle 0 (7 days prior to Cycle 1 Day 1) and Cycle 1 Day 1 only (each cycle is 21 days)

Study Arms (4)

Phase 1 Dose Escalation - Monotherapy (Recruitment Closed)

EXPERIMENTAL

* Advanced/metastatic NSCLC with acquired resistance EGFR mutation (eg, C797S), following a 3rd generation EGFR inhibitor in the 1st line setting (in the absence of concurrent T790M). * Advanced/metastatic NSCLC with non-classical EGFR mutation (eg, G719X) following standard-of-care therapy with an EGFR inhibitor * Recurrent GBM with confirmed EGFR alterations (including amplification, mutation, and/or variant)

Drug: silevertinib (BDTX-1535) monotherapy

Phase 2 Cohort 1: NSCLC EGFR Non-Classical Driver Mutations

EXPERIMENTAL

Advanced/metastatic NSCLC with a non-classical driver EGFR mutation following up to 2 lines of therapy with only 1 prior EGFR targeted regimen (third-generation preferred; other approved EGFR inhibitors acceptable)

Drug: silevertinib (BDTX-1535) monotherapy

Phase 2 Cohort 2: NSCLC EGFR Acquired Resistance (C797S) Mutation

EXPERIMENTAL

Advanced/metastatic NSCLC with the acquired resistance C797S EGFR mutation following up to 2 lines of therapy, including only 1 EGFR targeted regimen, which must be a third generation EGFR TKI (eg, osimertinib)

Drug: silevertinib (BDTX-1535) monotherapy

Phase 2 Cohort 3: Treatment Naive NSCLC EGFR Non-Classical Driver Mutations

EXPERIMENTAL

Treatment-naïve (first-line) advanced/metastatic NSCLC with a non-classical driver EGFR mutation (1 cycle of chemotherapy or immune checkpoint inhibitor are permitted). Patients with co-occurring L858R mutations and a non-classical mutation are eligible for inclusion.

Interventions

silevertinib (BDTX-1535) monotherapy DRUG

Silevertinib (BDTX-1535) is a 4th generation irreversible brain penetrant EGFR MasterKey inhibitor, which targets a family of oncogenic EGFR classical and non-classical driver and resistance mutations in NSCLC.

Phase 1 Dose Escalation - Monotherapy (Recruitment Closed); Phase 2 Cohort 1: NSCLC EGFR Non-Classical Driver Mutations; Phase 2 Cohort 2: NSCLC EGFR Acquired Resistance (C797S) Mutation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Measurable disease by RECIST 1.1 criteria.
• Adequate bone marrow or organ function.
• Life expectancy of ≥ 3 months.
• Sufficient performance status.
• Confirmed NSCLC, without small cell lung cancer transformation with or without brain metastases.
• Disease progression following or intolerance of standard of care (excluding patients in the treatment-naïve non-classical driver cohort):
• Cohort 1 (Non-Classical driver cohort): Advanced/metastatic NSCLC with a non-classical driver EGFR mutation (eg, G719X) following up to 2 lines of therapy with only 1 prior EGFR TKI regimen (third-generation preferred; other approved EGFR TKI acceptable).
• Cohort 2 (Acquired resistance C797S cohort): Advanced/metastatic NSCLC with the acquired resistance C797S EGFR mutation following up to 2 lines of therapy, including only one EGFR TKI, which must be a third generation EGFR TKI (eg, osimertinib).
• Identification of one (or more) of the following EGFR mutations by Next Generation Sequencing (NGS) as determined by a local assay performed in a validated laboratory in the absence of other known resistance mutations (eg, T790M, MET):
• Non-classical driver EGFR mutations (eg, L861R, S768I, G719X).
• EGFR acquired resistance mutation (eg, C797S) to a 3rd generation EGFR TKI.
• For Phase 2, dose expansion, patients in Cohort 1 who received 3rd generation EGFR TKI (eg, osimertinib), the NGS report within 6 months prior to the start of Screening is acceptable. For patients in Cohort 2, the NGS report must be from the last disease progression on the immediate prior therapy. For patients in Cohort 3, the NGS report must be at the time of diagnosis.

You may not qualify if:

• Known resistant mutations in tumor tissue or by liquid biopsy (eg, T790M, MET).
• Received more than 1 EGFR TKI therapy (ie, erlotinib or gefitinib) for the treatment of metastatic or recurrent EGFR NSCLC.
• Any history of interstitial lung disease related to EGFR TKI use.
• Symptomatic or radiographic leptomeningeal disease.
• Symptomatic brain metastases or spinal cord compression requiring urgent clinical intervention.
• Unresolved toxicity from prior therapy.
• Significant cardiovascular disease.
• Major surgery within 4 weeks of study entry or planned during study.
• Ongoing or recent anticancer therapy or radiation therapy.
• Evidence of malignancy (other than study-specific malignancies) requiring active therapy within the next 2 years.
• Active hepatitis B or C infection and/or known human immunodeficiency virus (HIV) carrier.
• Poorly controlled gastrointestinal disorders.

Sponsors & Collaborators

• Black Diamond Therapeutics, Inc.: lead

Study Sites (25)

University of Alabama

Birmingham, Alabama, 35294, United States

Location

Banner MD Anderson Cancer Center

Gilbert, Arizona, 85234, United States

Location

City of Hope Huntington Beach

Huntington Beach, California, 92648, United States

Location

City of Hope Orange County Lennar Foundation Cancer Center

Irvine, California, 92618, United States

Location

Cedars Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Sibley Memorial Hospital Johns Hopkins Medicine

Washington D.C., District of Columbia, 20016, United States

Location

Mayo Clinic- Jacksonville

Jacksonville, Florida, 32224, United States

Location

Miami Cancer Institute - Baptist Health South Florida

Miami, Florida, 33176, United States

Location

UHP- University of Hawaii Cancer Center

Honolulu, Hawaii, 96813, United States

Location

Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Kansas Cancer Center

Fairway, Kansas, 66205, United States

Location

Johns Hopkins Bayview Medical Center

Baltimore, Maryland, 21224, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Mayo Clinic- Rochester

Rochester, Minnesota, 55905, United States

Location

Siteman Cancer Center

St Louis, Missouri, 63110, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10021, United States

Location

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

Montefiore Medical Center

The Bronx, New York, 10461, United States

Location

UNC Hospitals - Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, 27514, United States

Location

University of Pittsburgh Medical Center - Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

Tennessee Oncology

Nashville, Tennessee, 37203, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Inova Schar Cancer Institute

Fairfax, Virginia, 22031, United States

Location

Next Ocology

Fairfax, Virginia, 22031, United States

Location

Fred Hutchinson Cancer Center/University of Washington

Seattle, Washington, 98109, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Brain Neoplasms

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Black Diamond Therapeutics

  Black Diamond Therapeutics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 15, 2022
• First Posted: February 25, 2022
• Study Start: March 31, 2022
• Primary Completion: November 3, 2025
• Study Completion (Estimated): June 1, 2026
• Last Updated: December 9, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (25)