(Concerto) Study of BLU-451 in Advanced Cancers With EGFR Exon 20 Insertion Mutations

Study Overview
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Brief Summary
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This is a Phase 1/2, open-label first-in-human study of the safety, pharmacokinetics (PK), pharmacodynamics, and anti-tumor activity of BLU-451 monotherapy and BLU-451 in combination with platinum-based chemotherapy (carboplatin and pemetrexed). All participants will receive BLU-451 on a 21-day treatment cycle.

Detailed Description
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The study is a Phase 1/2 Study of BLU-451 in Advanced Cancers with Epidermal growth factor receptor (EGFR) Exon 20 Insertion Mutations (Ex20ins). The study has two phases: An initial Phase 1 portion will enroll participants with metastatic cancer with EGFR Ex20ins or other selected EGFR mutations that have progressed after prior systemic therapies and will determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of BLU-451. Part 1B dose-escalation will enroll participants with metastatic Non-small Cell Lung Cancer (NSCLC) in the USA only to determine the MTD and/or RP2D of BLU-451 in combination with carboplatin and pemetrexed. A Phase 2 portion will further evaluate the efficacy and safety of BLU-451 as monotherapy at RP2D in participants with NSCLC.

Official Title
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Phase I/II Study of BLU-451 in Advanced Cancers With EGFR Exon 20 Insertion Mutations

Conditions
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Lung Neoplasm Malignant, Carcinoma, Non-Small-Cell Lung, Respiratory Tract Neoplasms, Neoplasms, Neoplasms by Site, Lung Diseases, Respiratory Tract Disease, Carcinoma, Bronchogenic, Bronchial Neoplasms, Adenocarcinoma, Carcinoma, Neoplasms by Histologic Type, EGFR Exon 20 Mutation, EGFR Exon 20 Insertion Mutation, EGFR Activating Mutation, Antineoplastic Agents, Metastatic Lung Cancer, Brain Metastases, EGFR-mutated NSCLC, EGFR Atypical Mutations, Including G719X and L861Q

Intervention / Treatment
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* Drug: BLU-451
* Drug: Carboplatin
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: All participants: Documented EGFR mutation, based on Next-generation sequencing (NGS) testing of tumor or liquid biopsy analyzed in a local Clinical Laboratory Improvement Amendments (CLIA) (or International Organization for Standardization (ISO) 15189)-certified or equivalent laboratory are required. Redacted copies of laboratory results must be available for Sponsor review. Able to provide a new or archived pretreatment formalin-fixed, paraffin-embedded (FFPE) tumor sample. For participants who received EGFR-targeted therapy subsequent to the most recent archived biopsy, all efforts should be made to obtain a new biopsy unless it is not safe or feasible to obtain one. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Participants must be without seizures for at least 14 days prior to enrollment, and patients who receive treatment with anti-epileptic drugs must be on stable doses for at least 14 days prior to enrollment. Adequate hematological, renal, and hepatic function: Participants in Phase 1 Histologically or cytologically confirmed metastatic NSCLC (stage IVA and IVB per American Joint Committee on Cancer (AJCC) 8th edition) or other metastatic cancers except for primary CNS tumors (Part 1A or Part 2 only). Must have evaluable or measurable disease per RECIST v1.1. Progression on or after or intolerance to most recent systemic therapy. Participants in Phase 2 Histologically or cytologically confirmed metastatic NSCLC (stage IVA and IVB per AJCC 8th edition). Must have measurable disease by RECIST 1.1. EXCLUSION CRITERIA: Have disease that is suitable for local therapy administered with curative intent. Have tumor that harbors known driver alterations (including, but not limited to ROS, BRAF V600E, ALK, RET, HER2, MET, KRAS, NTRK1/2/3, EGFR C797X, or EGFR T790M mutation). These criteria are not applicable to Phase 1 Part 1B. Have NSCLC with mixed cell histology or a tumor with known histologic transformation (NSCLC to SCLC, SCLC to NSCLC, or epithelial to mesenchymal transition). Other protocol-defined inclusion and exclusion criteria apply

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
Interventional Model Description: The primary objectives of this study are in Phase 1 to identify the MTD and/or RP2D of BLU-451, and in Phase 2, to evaluate the anti-tumor activity of BLU-451.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I - Part 1A Dose Escalation<br>BLU-451 monotherapy with dose escalation in participants with metastatic cancer with EGFR Ex20ins or other selected EGFR mutations that have progressed after prior systemic therapies. | Drug: BLU-451<br>* BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle<br>|
| Experimental: Phase I - Part 1B Dose Escalation (US only)<br>BLU-451 with dose escalation in combination with carboplatin and pemetrexed in participants with metastatic NSCLC with common EGFR mutations. This arm will enroll participants only in the United States. | Drug: BLU-451<br>* BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle<br>Drug: Carboplatin<br>* Carboplatin will be administered intravenously (IV) on Day 1 of each cycle (every 3 weeks) for 4 to 6 cycles<br>Drug: Pemetrexed<br>* Pemetrexed will be administered prior to carboplatin as an IV infusion on Day 1 of each cycle (every 3 weeks)<br>|
| Experimental: Phase I - Part 2 BLU-451 Monotherapy Enrichment<br>BLU-451 enrichment at select doses. | Drug: BLU-451<br>* BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle<br>|
| Experimental: Phase II - Cohort 2A<br>EGFR Ex20ins participants who have previously received platinum-based chemotherapy and either amivantamab or mobocertinib will receive BLU-451. | Drug: BLU-451<br>* BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle<br>|
| Experimental: Phase II - Cohort 2B<br>EGFR Ex20ins participants who have previously received platinum-based chemotherapy but have not received a prior EGFR Ex20ins-targeted agent will receive BLU-451. | Drug: BLU-451<br>* BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle<br>|
| Experimental: Phase II - Cohort 2C<br>EGFR Ex20ins participants with at least one measurable lesion in brain per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 who have previously received platinum-based chemotherapy will receive BLU-451. Previous treatment with EGFR Ex20Ins-targeted therapies is allowed but not required. | Drug: BLU-451<br>* BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle<br>|
| Experimental: Phase II - Cohort 2D<br>Participants with EGFR Ex20ins who have previously received platinum-based chemotherapy and both amivantamab AND mobocertinib, OR received any investigational Ex20Ins targeted agent(s) will receive BLU-451. Participants with Ex20ins or atypical mutations enrolled in other cohorts and who have other oncogenic drivers by central testing at baseline will be moved to this arm. | Drug: BLU-451<br>* BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle<br>|
| Experimental: Phase II - Cohort 2E<br>Participants with EGFR Ex20ins who have not received prior systemic therapy in metastatic setting will receive BLU-451. | Drug: BLU-451<br>* BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle<br>|
| Experimental: Phase II - Cohort 2F<br>Participants with EGFR atypical mutations (e.g., G719X, L861Q) who have previously received at least one EGFR tyrosine kinase inhibitor (TKI) will receive BLU-451. Participants with with other atypical EGFR mutations, such as S768I, may be enrolled if approved by Sponsor Medical Monitor. | Drug: BLU-451<br>* BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle<br>|
| Experimental: Phase II - Cohort 2G<br>Participants with EGFR atypical mutations (e.g., G719X, L861Q) who have not received prior systemic therapy in metastatic setting will receive BLU-451. Participants with with other atypical EGFR mutations, such as S768I, may be enrolled if approved by Sponsor Medical Monitor. | Drug: BLU-451<br>* BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I - Determine the maximum tolerated dose (MTD) of BLU-451 | MTD determination: Dose-limiting toxicities (DLTs) rate | 12-15 Months | 
| Phase I - Determine the Recommended Phase 2 Dose (RP2D) of BLU-451 | RP2D determination: DLT, PK, PD, and preliminary safety data | 12-15 Months | 
| Phase I - Rate and severity of Adverse Events (AEs) of BLU-451 |  | 12-15 Months | 
| Phase II - The Overall Response Rate (ORR) rate of BLU-451 | ORR is defined as the proportion of subjects with objective response of CR or PR as determined by the Investigator using RECIST v1.1. | Up to 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I - The Overall Response Rate (ORR) rate of BLU-451 | ORR is defined as the proportion of subjects with objective response of CR or PR as determined by the Investigator using RECIST v1.1. | Up to 30 months | 
| Phase I & II - The Duration of Response (DOR) rate of BLU-451 | DOR is defined as the time from the first objective response (CR or PR) to documented PD per RECIST v1.1 or death within 30 days of last dose of BLU-451 from any cause. | 12-15 Months | 
| Phase I & II - The Disease Control Rate (DCR) rate of BLU-451 | DCR is defined as best response of CR, PR, non-CR/non-PD (for subjects who have only non-target lesions), or SD per RECIST v1.1. | 12-15 Months | 
| Phase I & II - The Clinical Benefit Rate (CBR) of BLU-451 | CBR is defined as confirmed response of CR or PR, or stable disease with a duration of at least 16 weeks from the first dose date. | 12-15 Months | 
| Phase I & II - The Progression Free Survival (PFS) rate of BLU-451 | PFS is defined as the time from the first BLU-451 dose until the date of death or the date of progression of disease or death, respectively. | 12-15 Months | 
| Phase I & II - The Overall Survival (OS) rate of BLU-451 | OS is defined as the time from the first BLU-451 dose until the date of death or the date of progression of disease or death, respectively. | 12-15 Months | 
| Phase I & II - To evaluate the Central Nervous System (CNS) Overall Response Rate (ORR) of BLU-451 in subjects with measurable baseline brain metastases | CNS ORR: Defined as the proportion of patients achieving confirmed intra-cranial CR or PR as determined by the RECIST v1.1. | Up to 30 months | 
| Phase I & II - To evaluate the Central Nervous System (CNS) Duration of Response (DOR) of BLU-451 in subjects with measurable baseline brain metastases | CNS DOR: Defined as the the time from the first objective intra-cranial response (CR or PR) to documented PD in patients with measurable baseline brain metastases | Up to 30 months | 
| Phase I & II - To evaluate the Central Nervous System (CNS) Progression Free Survival (PFS) of BLU-451 in subjects with measurable baseline brain metastases | CNS PFS: Defined as the time from the first BLU-451 dose until the date of death or the date of intra-cranial progression of disease or death, respectively in patients with measurable baseline brain metastases | Up to 30 months | 
| Phase I - Assess treatment-induced modulation of EGFR pathway biomarkers | Profile pharmacodynamic changes in gene expression levels of the EGFR pathway biomarkers dual specificity phosphatase (DUSP6) and sprouty RTK signaling antagonist 4 (SPRY4) | 12-15 Months | 
| Phase I & II - To evaluate the maximum observed blood drug concentration (Cmax) of BLU-451 |  | Up to 30 months | 
| Phase I & II - To evaluate the time of maximum blood concentration (tmax) of BLU-451 |  | Up to 30 months | 
| Phase I & II - To evaluate the elimination half life (t1/2) of BLU-451 |  | Up to 30 months | 
| Phase I & II - To evaluate the area under the blood concentration-time curve (AUC0-t, AUC0-inf) of BLU-451 |  | Up to 30 months | 
| Phase I & II - To evaluate the clearance (CL/F) of BLU-451 |  | Up to 30 months | 
| Phase I & II - To evaluate the volume of distribution (Vss/F) of BLU-451 |  | Up to 30 months | 
| Phase II - Rate and severity of Adverse Events (AEs) of BLU-451 |  | Up to 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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protein kinase inhibitors, thoracic neoplasms