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

A Phase 1/2 Study to Assess BDTX-1535, an Oral EGFR Inhibitor, in Patients With Glioblastoma or Non-Small Cell Lung Cancer

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Non-Small Cell Lung Cancer; NSCLC; Metastatic Lung Cancer; Metastatic Lung Non-Small Cell Carcinoma; EGF-R Positive Non-Small Cell Lung Cancer; Advanced Lung Carcinoma; EGFR-TKI Resistant Mutation; Advanced Non-Small Cell Squamous Lung Cancer; Epidermal Growth Factor Receptor C797S; Epidermal Growth Factor Receptor G719X
• Intervention / Treatment: Drug: silevertinib (BDTX-1535) monotherapy

Detailed Description

BDTX-1535 is an orally available, highly potent, selective, irreversible inhibitor of allosteric epidermal growth factor receptor (EGFR) alterations, including amplification, mutations, and splice variants which have been identified in glioblastoma (GBM) and mutations in non-small cell lung cancer (NSCLC) associated with intrinsic or acquired resistance. The open label, multicenter will assess the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of BDTX-1535 in patients with GBM harboring EGFR alterations and NSCLC with EGFR mutations of intrinsic or acquired resistance who have failed standard treatment. Dose escalation cohorts will be used to determine the maximum tolerated dose and recommended phase 2 dose of BDTX-1535 oral administration

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center
  • California
    • Huntington Beach, California, United States, 92648
      • City of Hope Huntington Beach
    • Irvine, California, United States, 92618
      • City of Hope Orange County Lennar Foundation Cancer Center
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20016
      • Sibley Memorial Hospital Johns Hopkins Medicine
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic- Jacksonville
    • Miami, Florida, United States, 33176
      • Miami Cancer Institute - Baptist Health South Florida
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • UHP- University of Hawaii Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
  • Kansas
    • Fairway, Kansas, United States, 66205
      • University of Kansas Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins Bayview Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic- Rochester
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Siteman Cancer Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering Cancer Center
    • The Bronx, New York, United States, 10461
      • Montefiore Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • UNC Hospitals - Lineberger Comprehensive Cancer Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center - Hillman Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Inova Schar Cancer Institute
    • Fairfax, Virginia, United States, 22031
      • Next Ocology
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Center/University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Phase 2 Eligibility:

Key Inclusion Criteria Required for locally advanced or metastatic NSCLC:

• 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).
  • Cohort 3 (First-line non-classical driver cohort): Treatment-naïve 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.

• 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.

Key Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 Dose Escalation - Monotherapy (Recruitment Closed); 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; 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.
Experimental: Phase 2 Cohort 1: NSCLC EGFR Non-Classical Driver Mutations; 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; 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.
Experimental: Phase 2 Cohort 2: NSCLC EGFR Acquired Resistance (C797S) Mutation; 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; 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.
Experimental: Phase 2 Cohort 3: Treatment Naive NSCLC EGFR Non-Classical Driver Mutations; 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.	Drug: silevertinib (BDTX-1535) monotherapy; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Time Frame
Phase 1 and Phase 2: Incidence and severity of treatment-emergent adverse events (TEAEs)	Through study completion, approximately 1 year
Phase 2: To assess duration of tumor response by RECIST version 1.1	Day 1 every 2 cycles starting at Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 21 days)
Phase 2: To assess progression free survival by RECIST version 1.1	Day 1 every 2 cycles starting at Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 21 days)
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)
Phase 2: To determine the optimal dosage of silevertinib (BDTX-1535) (100 mg or 200 mg daily dose)	At least the first treatment 21-day cycle (Cycle 1) for select patients enrolled into the Phase 2

Collaborators and Investigators

• Sponsor: Black Diamond Therapeutics, Inc.
• Investigators: Study Director: Black Diamond Therapeutics, Black Diamond Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2022
• Primary Completion (Actual): November 3, 2025
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: February 15, 2022
• First Submitted That Met QC Criteria: February 24, 2022
• First Posted (Actual): February 25, 2022

Study Record Updates

• Last Update Posted (Estimated): December 9, 2025
• Last Update Submitted That Met QC Criteria: December 7, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: EGFR inhibitor; brain metastases; EGFR L858R; CNS metastases; intracranial disease; EGFR alterations; central nervous system metastases; EGFR Exon 19 del; intrinsic resistance NSCLC EGFR; acquired resistance NSCLC EGFR; uncommon NSCLC EGFR mutations; C797S acquired resistance EGFR mutation; non-classical NSCLC EGFR mutations; classical NSCLC EGFR mutations; Second-site EGFR mutation; 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
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Nervous System Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Central Nervous System Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Brain Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: BDTX-1535-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No