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

Blueprint Medicines

Status and phase: Terminated; Phase 1

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

Treatments: Drug: BLU-451; Drug: Pemetrexed; Drug: Carboplatin

Study type: Interventional

Funder types: Industry

Identifiers

NCT05241873

BLU-451-1101

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 103 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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103 participants in 10 patient groups

Phase I - Part 1A Dose Escalation

Experimental group

Description:

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.

Treatment:

Drug: BLU-451

Phase I - Part 1B Dose Escalation (US only)

Experimental group

Description:

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.

Treatment:

Drug: Carboplatin

Drug: Pemetrexed

Drug: BLU-451

Phase I - Part 2 BLU-451 Monotherapy Enrichment

Experimental group

Description:

BLU-451 enrichment at select doses.

Treatment:

Drug: BLU-451

Phase II - Cohort 2A

Experimental group

Description:

EGFR Ex20ins participants who have previously received platinum-based chemotherapy and either amivantamab or mobocertinib will receive BLU-451.

Treatment:

Drug: BLU-451

Phase II - Cohort 2B

Experimental group

Description:

EGFR Ex20ins participants who have previously received platinum-based chemotherapy but have not received a prior EGFR Ex20ins-targeted agent will receive BLU-451.

Treatment:

Drug: BLU-451

Phase II - Cohort 2C

Experimental group

Description:

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.

Treatment:

Drug: BLU-451

Phase II - Cohort 2D

Experimental group

Description:

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.

Treatment:

Drug: BLU-451

Phase II - Cohort 2E

Experimental group

Description:

Participants with EGFR Ex20ins who have not received prior systemic therapy in metastatic setting will receive BLU-451.

Treatment:

Drug: BLU-451

Phase II - Cohort 2F

Experimental group

Description:

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.

Treatment:

Drug: BLU-451

Phase II - Cohort 2G

Experimental group

Description:

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.

Treatment:

Drug: BLU-451