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.
Phase 1 enrollment is now complete. Phase 2 is currently ongoing.
Brief Title
Phase 1/2 Study of Silevertinib (BDTX-1535) in Patients With Glioblastoma or Non-Small Cell Lung Cancer With EGFR Mutations
Categories
Completion Date
Completion Date Type
Estimated
Conditions
Non-Small Cell Lung Cancer
Advanced Non-Small Cell Squamous Lung Cancer
Metastatic Lung Non-Small Cell Carcinoma
Metastatic Lung Cancer
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
Eligibility 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.
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.
Inclusion Criteria
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.
* 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.
Gender
All
Gender Based
false
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
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT05256290
Org Class
Industry
Org Full Name
Black Diamond Therapeutics, Inc.
Org Study Id
BDTX-1535-101
Overall Status
Active, not recruiting
Phases
Phase 1
Phase 2
Primary Completion Date
Primary Completion Date Type
Estimated
Official Title
A Phase 1/2 Study to Assess BDTX-1535, an Oral EGFR Inhibitor, in Patients With Glioblastoma or Non-Small Cell Lung Cancer
Primary Outcomes
Outcome Description
Dose-limiting toxicities (DLTs) in Cycle 1
Outcome Measure
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)
Outcome Time Frame
The first treatment 21-day cycle (Cycle 1)
Outcome Description
Objective response rate (ORR) as assessed by Investigator using RECIST version 1.1
Outcome Measure
Phase 2: To assess antitumor efficacy of silevertinib (BDTX-1535)
Outcome Time Frame
Day 1 every 2 cycles starting on Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 21 days)
Secondary Outcomes
Outcome Time Frame
Through study completion, approximately 1 year
Outcome Measure
Phase 1 and Phase 2: Incidence and severity of treatment-emergent adverse events (TEAEs)
Outcome Time Frame
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)
Outcome Measure
Phase 1 and Phase 2: To characterize the plasma concentration of silevertinib (BDTX-1535) following single and multiple dosing
Outcome Time Frame
Day 1 every 2 cycles starting on Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 21 days)
Outcome Measure
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)
Outcome Time Frame
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)
Outcome Measure
Phase 1: To assess the effect of tablet formulation on the plasma concentration of silevertinib (BDTX-1535)
Outcome Time Frame
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)
Outcome Measure
Phase 1: To assess the effect of food on the plasma concentration of silevertinib (BDTX-1535)
Outcome Time Frame
Day 1 every 2 cycles starting at Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 21 days)
Outcome Measure
Phase 2: To assess duration of tumor response by RECIST version 1.1
Outcome Time Frame
Day 1 every 2 cycles starting at Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 21 days)
Outcome Measure
Phase 2: To assess progression free survival by RECIST version 1.1
Outcome Time Frame
At least the first treatment 21-day cycle (Cycle 1) for select patients enrolled into the Phase 2
Outcome Measure
Phase 2: To determine the optimal dosage of silevertinib (BDTX-1535) (100 mg or 200 mg daily dose)
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Balazs Halmos
Investigator Email
bahalmos@montefiore.org