Advanced Lung Carcinoma, Advanced Non-Small Cell Squamous Lung Cancer, EGF-R Positive Non-Small Cell Lung Cancer, EGFR-TKI Resistant Mutation, Epidermal Growth Factor Receptor C797S, Epidermal Growth Factor Receptor G719X, Metastatic Lung Cancer, Metastatic Lung Non-Small Cell Carcinoma, Non-Small Cell Lung Cancer, NSCLC
Conditions
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
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.
Interventions
DRUGsilevertinib (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.
Sponsors
Black Diamond Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | The first treatment 21-day cycle (Cycle 1) | Dose-limiting toxicities (DLTs) in Cycle 1 |
| Phase 2: To assess antitumor efficacy of silevertinib (BDTX-1535) | Day 1 every 2 cycles starting on Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 21 days) | Objective response rate (ORR) as assessed by Investigator using RECIST version 1.1 |
Secondary
| Measure | Time frame |
|---|---|
| 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) |
| 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 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 |
Countries
United States
Contacts
STUDY_DIRECTORBlack Diamond Therapeutics
Black Diamond Therapeutics
Outcome results
None listed