Study of BDTX-1535 in Patients With Glioblastoma or Non-Small Cell Lung Cancer With EGFR Mutations

Study Overview
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Brief Summary
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BDTX-1535-101 is a first-in-human, open-label, Phase 1 dose escalation and multiple expansion cohort study designed to evaluate the safety, tolerability, pharmacokinetics (PK), central nervous system (CNS) activity, and preliminary antitumor activity of BDTX-1535. The study population comprises adults with either advanced/metastatic non-small cell lung cancer (NSCLC) harboring sensitive epidermal growth factor receptor (EGFR) mutations with or without CNS disease, or glioblastoma multiforme (GBM) expressing EGFR alterations. All patients will self administer BDTX-1535 monotherapy in 21-day cycles. One expansion cohort will include patients with newly diagnosed GBM who will self administer BDTX-1535 in combination with temozolomide in 28-day cycles.

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

Conditions
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NSCLC, Non-Small Cell Lung Cancer, Glioblastoma, EGFR Gene Mutation, Recurrent Glioblastoma, GBM, Advanced Solid Tumor, Advanced Non-Small Cell Squamous Lung Cancer, Metastatic Cancer, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Lung Cancer, Advanced Lung Carcinoma, New Diagnosis Tumor

Intervention / Treatment
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* Drug: BDTX-1535 monotherapy
* Drug: BDTX-1535 in combination with temozolomide


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Required for ALL Patients: Evaluable or measurable disease in dose escalation and measurable disease only for dose expansion cohorts. Fulfills appropriate disease criteria as defined in Arms and Interventions Adequate bone marrow or organ function. Life expectancy of ≥ 3 months. Sufficient performance status. Inclusion Criteria Required for NSCLC Patients Only: Confirmed NSCLC, without small cell lung cancer transformation. Locally advanced or metastatic disease, with or without central nervous system metastases. Disease progression following or intolerance of standard of care: Dose escalation cohorts only: NSCLC with uncommon EGFR mutation (eg, G719X) following standard-of-care therapy with an EGFR inhibitor. 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). Dose expansion cohorts only: NSCLC with intrinsic resistance EGFR mutation (eg, L858R, G719X) with up to 2 lines of standard-of-care therapy with an EGFR inhibitor. NSCLC with acquired resistance EGFR mutation (eg, C797S) with up to 2 lines of therapy, the first line of which must be a 3rd generation EGFR inhibitor (in the absence of concurrent T790M). Note: therapies targeted for 3rd generation EGFR tyrosine kinase resistance are excluded for this patient population. • Identification of one (or more) EGFR mutations identified in the absence of other known resistance mutations: Intrinsic resistance EGFR mutations [eg, L858R [dose expansion only], G719X). EGFR acquired resistance mutation (eg, C797S) to a 3rd generation EGFR inhibitor. Inclusion Criteria Required for All GBM Patients Only: Confirmed diagnosis of GBM. Tumor evidence of EGFR alterations including variants, or mutations with or without amplifications (eg, A289T/V, G598V, S645C). Inclusion Criteria Required for Recurrent GBM Patients Only: Disease progression after treatment with available therapies or who refuse or are intolerant to treatment. Radiological diagnosis of recurrent disease following available standard-of-care therapy of surgery, radiation, and/or temozolomide. Inclusion Criteria Required for Newly Diagnosed GBM Patients Only: Recovered from maximal debulking surgery (gross total resection or partial resection are also acceptable). Received radiation therapy and temozolomide at least 6 weeks, but no more than 8 weeks, prior to Cycle 1 Day 1. Key Exclusion Criteria for ALL Patients: Known resistant mutations. For GBM patients only: treated with a prior EGFR inhibitor. 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. Ongoing or recent 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Cohorts - Monotherapy<br>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 uncommon 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: BDTX-1535 monotherapy<br>* BDTX-1535 is a mutant-selective, irreversible 4th generation EGFR inhibitor<br>|
| Experimental: Disease-Specific Dose Expansion Cohorts - Monotherapy<br>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 intrinsic resistance EGFR mutation (eg, L858R, G719X) following standard-of-care therapy with an EGFR inhibitor Recurrent GBM with confirmed EGFR alterations with or without amplifications | Drug: BDTX-1535 monotherapy<br>* BDTX-1535 is a mutant-selective, irreversible 4th generation EGFR inhibitor<br>|
| Experimental: Disease-Specific Dose Expansion Cohort - Combination Treatment<br>• Newly diagnosed GBM (postsurgical resection and radiation therapy with temozolomide) harboring EGFR mutations or variants | Drug: BDTX-1535 in combination with temozolomide<br>* BDTX-1535 is a mutant-selective, irreversible 4th generation EGFR inhibitor. Temozolomide is an alkylating agent considered standard-of-care for treatment of GBM.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation: Incidence of dose-limiting toxicities (DLTS) to estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of BDTX-1535 as monotherapy. |  | The first monotherapy treatment 21-day cycle (Cycle 1) | 
| Dose Expansion - Combination Treatment: Incidence of dose-limiting toxicities (DLTS) to estimate the MTD and/or the recommended phase 2 combination dose (RP2cD) of BDTX-1535 in combination with temozolomide for patients with newly diagnosed GBM. |  | The first combination treatment 28-day cycle (Cycle 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation/Dose Expansion - Monotherapy and Combination Treatment: Incidence and severity of treatment-emergent adverse events (TEAEs) |  | Through study completion, approximately 1 year | 
| Dose Escalation/Dose Expansion - Monotherapy: Maximum plasma concentration (Cmax) of 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) | 
| Dose Expansion - Combination Treatment: Cmax of BDTX-1535 and temozolomide when administered in combination |  | Cycle 1 Days 1 and 2, Cycle 2 to 6 Days 1 and 2, Cycle 7 Day 1, and Day 1 of every other cycle thereafter to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Dose Expansion - Monotherapy: Time for maximum plasma concentration (Tmax) of 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) | 
| Dose Expansion - Combination Treatment: Tmax of BDTX-1535 and temozolomide when administered in combination |  | Cycle 1 Days 1 and 2, Cycle 2 to 6 Days 1 and 2, Cycle 7 Day 1, and Day 1 of every other cycle thereafter to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Dose Expansion - Monotherapy: Area under the plasma concentration-time curve (AUC) of 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) | 
| Dose Expansion - Combination Treatment: AUC of BDTX-1535 and temozolomide when administered in combination |  | Cycle 1 Days 1 and 2, Cycle 2 to 6 Days 1 and 2, Cycle 7 Day 1, and Day 1 of every other cycle thereafter to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Dose Expansion - Monotherapy: Elimination half-life (t1/2) of 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) | 
| Dose Expansion - Combination Treatment: t1/2 of BDTX-1535 and temozolomide when administered in combination |  | Cycle 1 Days 1 and 2, Cycle 2 to 6 Days 1 and 2, Cycle 7 Day 1, and Day 1 of every other cycle thereafter to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Expansion - Monotherapy: Objective response (OR) |  | Day 1 every 2 cycles starting on Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 21 days) | 
| Dose Expansion - Combination Treatment: OR |  | Day 1 every 2 cycles starting at Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Expansion - Monotherapy: Duration of response (DOR) |  | Day 1 every 2 cycles starting on Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 21 days) | 
| Dose Expansion - Combination Treatment: DOR |  | Day 1 every 2 cycles starting at Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Expansion - Monotherapy: Disease control rate (DCR) |  | Day 1 every 2 cycles starting on Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 21 days) | 
| Dose Expansion - Combination Treatment: DCR |  | Day 1 every 2 cycles starting at Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Expansion - Monotherapy: Progression-Free Survival (PFS) |  | Day 1 every 2 cycles starting on Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 21 days) | 
| Dose Expansion - Combination Treatment: PFS |  | Day 1 every 2 cycles starting at Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 28 days) | 
| Dose Escalation/Expansion - Monotherapy: Brain metastasis-free survival (patients with NSCLC with no brain metastasis at baseline) |  | Day 1 every 2 cycles starting on Cycle 3 Day 1 to study completion, approximately 1 year (each cycle is 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EGFR alterations, L858R, G719X, EGFR inhibitor, newly diagnosed glioblastoma, newly diagnosed GBM, intrinsic resistance EGFR, acquired resistance EGFR, temozolomide, TMZ, intracranial disease, brain metastases, central nervous system metastases, CNS metastases, dose escalation, dose expansion, recommended phase 2 dose, RP2D, uncommon EGFR mutations, C797S EGFR mutations, recommended phase 2 combination dose, RP2cD