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

NCT ID: NCT05241873

Last Updated: 2025-02-10

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 103 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-03-04
• Study Completion Date: 2024-07-31

Brief Summary

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

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.

Conditions

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase II - Cohort 2B

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

Group Type: EXPERIMENTAL

BLU-451

Intervention Type: DRUG

BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle

Phase II - Cohort 2C

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.

Group Type: EXPERIMENTAL

BLU-451

Intervention Type: DRUG

BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle

Phase II - Cohort 2D

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.

Group Type: EXPERIMENTAL

BLU-451

Intervention Type: DRUG

BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle

Phase II - Cohort 2E

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

Group Type: EXPERIMENTAL

BLU-451

Intervention Type: DRUG

BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle

Phase II - Cohort 2F

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.

Group Type: EXPERIMENTAL

BLU-451

Intervention Type: DRUG

BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle

Phase II - Cohort 2G

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.

Group Type: EXPERIMENTAL

BLU-451

Intervention Type: DRUG

BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle

Phase I - Part 1A Dose Escalation

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.

Group Type: EXPERIMENTAL

BLU-451

Intervention Type: DRUG

BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle

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

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.

Group Type: EXPERIMENTAL

BLU-451

Intervention Type: DRUG

BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle

Carboplatin

Intervention Type: DRUG

Carboplatin will be administered intravenously (IV) on Day 1 of each cycle (every 3 weeks) for 4 to 6 cycles

Pemetrexed

Intervention Type: DRUG

Pemetrexed will be administered prior to carboplatin as an IV infusion on Day 1 of each cycle (every 3 weeks)

Phase I - Part 2 BLU-451 Monotherapy Enrichment

BLU-451 enrichment at select doses.

Group Type: EXPERIMENTAL

BLU-451

Intervention Type: DRUG

BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle

Phase II - Cohort 2A

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

Group Type: EXPERIMENTAL

BLU-451

Intervention Type: DRUG

BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle

Interventions

BLU-451

BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle

Intervention Type: DRUG

Carboplatin

Carboplatin will be administered intravenously (IV) on Day 1 of each cycle (every 3 weeks) for 4 to 6 cycles

Intervention Type: DRUG

Pemetrexed

Pemetrexed will be administered prior to carboplatin as an IV infusion on Day 1 of each cycle (every 3 weeks)

Intervention Type: DRUG

Eligibility Criteria

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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Blueprint Medicines Corporation

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

City of Hope (City of Hope National Medical Center, City of Hope Medical Center)

Duarte, California, United States

Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute

Los Angeles, California, United States

University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)

Aurora, Colorado, United States

Georgetown University Medical Center

Washington D.C., District of Columbia, United States

Northwestern Memorial Hospital

Chicago, Illinois, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Laura & Isaac Perlmutter Cancer Center at NYU Langone Health

New York, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

The University of Texas M.D. Anderson Cancer Center

Houston, Texas, United States

New Experimental Therapeutics of Virginia (NEXT Oncology)

Fairfax, Virginia, United States

Fred Hutchinson Cancer Center

Seattle, Washington, United States

Princess Margaret Cancer Centre

Toronto, Ontario, Canada

National Cancer Center Hospital East

Kashiwa, Chiba, Japan

Kanagawa Cancer Center

Yokohama, Kanagawa, Japan

National Cancer Center Hospital

Chuo-ku, Tokyo, Japan

Severance Hospital, Yonsei University Health System

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Taichung Veterans General Hospital

Taichung, , Taiwan

National Taiwan University Hospital

Taipei, , Taiwan

Taipei Veterans General Hospital

Taipei, , Taiwan

Linkou Chang Gung Memorial Hospital (CGMHLK)

Taoyuan District, , Taiwan

Countries

United States; Canada; Japan; South Korea; Taiwan

Other Identifiers

BLU-451-1101

Identifier Type: -

Identifier Source: org_study_id