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

NCT05241873 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: BLU-451-1101
• Study Type: interventional
• Target: 103
• Locations: 5 countries
• Sites: 23

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.

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

Keywords

protein kinase inhibitors; thoracic neoplasms

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (17)

• Phase I - The Overall Response Rate (ORR) rate of BLU-451

  Up to 30 months

• Phase I & II - The Duration of Response (DOR) rate of BLU-451

  12-15 Months

• Phase I & II - The Disease Control Rate (DCR) rate of BLU-451

  12-15 Months

• Phase I & II - The Clinical Benefit Rate (CBR) of BLU-451

  12-15 Months

• Phase I & II - The Progression Free Survival (PFS) rate of BLU-451

  12-15 Months

Study Arms (10)

Phase I - Part 1A Dose Escalation

EXPERIMENTAL

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

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

EXPERIMENTAL

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; Drug: Carboplatin; Drug: Pemetrexed

Phase I - Part 2 BLU-451 Monotherapy Enrichment

EXPERIMENTAL

BLU-451 enrichment at select doses.

Drug: BLU-451

Phase II - Cohort 2A

EXPERIMENTAL

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

Drug: BLU-451

Phase II - Cohort 2B

EXPERIMENTAL

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

Phase II - Cohort 2C

EXPERIMENTAL

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

Phase II - Cohort 2D

EXPERIMENTAL

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

Phase II - Cohort 2E

EXPERIMENTAL

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

Drug: BLU-451

Phase II - Cohort 2F

EXPERIMENTAL

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

Phase II - Cohort 2G

EXPERIMENTAL

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

Interventions

BLU-451 DRUG

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

Phase I - Part 1A Dose Escalation; Phase I - Part 1B Dose Escalation (US only); Phase I - Part 2 BLU-451 Monotherapy Enrichment; Phase II - Cohort 2A; Phase II - Cohort 2B; Phase II - Cohort 2C; Phase II - Cohort 2D; Phase II - Cohort 2E; Phase II - Cohort 2F; Phase II - Cohort 2G

Carboplatin DRUG

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

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

Pemetrexed DRUG

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

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Blueprint Medicines Corporation: lead

Study Sites (23)

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

Duarte, California, 91010, United States

Location

Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute

Los Angeles, California, 90048, United States

Location

University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)

Aurora, Colorado, 80045, United States

Location

Georgetown University Medical Center

Washington D.C., District of Columbia, 20007, United States

Location

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Laura & Isaac Perlmutter Cancer Center at NYU Langone Health

New York, New York, 10016, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

The University of Texas M.D. Anderson Cancer Center

Houston, Texas, 77030-4009, United States

Location

New Experimental Therapeutics of Virginia (NEXT Oncology)

Fairfax, Virginia, 22031, United States

Location

Fred Hutchinson Cancer Center

Seattle, Washington, 98109, United States

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

National Cancer Center Hospital East

Kashiwa, Chiba, 277-8577, Japan

Location

Kanagawa Cancer Center

Yokohama, Kanagawa, 241-8515, Japan

Location

National Cancer Center Hospital

Chuo-ku, Tokyo, 104-0045, Japan

Location

Severance Hospital, Yonsei University Health System

Seoul, 03722, South Korea

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Taichung Veterans General Hospital

Taichung, 1650, Taiwan

Location

National Taiwan University Hospital

Taipei, 100, Taiwan

Location

Taipei Veterans General Hospital

Taipei, 112, Taiwan

Location

Linkou Chang Gung Memorial Hospital (CGMHLK)

Taoyuan District, 333, Taiwan

Location

MeSH Terms

Conditions

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms by Histologic Type; Brain Neoplasms; Thoracic Neoplasms

Interventions

Carboplatin; Pemetrexed

Condition Hierarchy (Ancestors)

Bronchial Diseases; Neoplasms, Glandular and Epithelial; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: January 31, 2022
• First Posted: February 16, 2022
• Study Start: March 4, 2022
• Primary Completion: July 31, 2024
• Study Completion: July 31, 2024
• Last Updated: February 10, 2025

Record last verified: 2025-02

Locations

US (13); CA (1); KR (2); JP (3); TW (4)