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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Neoplasms; Neoplasms by Histologic Type; Lung Diseases; Neoplasms by Site; Adenocarcinoma; Carcinoma; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Metastatic Lung Cancer; Antineoplastic Agents; Brain Metastases; Lung Neoplasm Malignant; EGFR Activating Mutation; Respiratory Tract Disease; EGFR Exon 20 Mutation; EGFR Exon 20 Insertion Mutation; EGFR-mutated NSCLC; EGFR Atypical Mutations, Including G719X and L861Q
• Intervention / Treatment: Drug: BLU-451; Drug: Carboplatin; Drug: Pemetrexed

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.

• Study Type: Interventional
• Enrollment (Estimated): 332
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Blueprint Medicines; Phone Number: 617-714-6707; Email: medinfo@blueprintmedicines.com

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
• Japan
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • National Cancer Center Hospital East
  • Kanagawa
    • Yokohama-shi, Kanagawa, Japan, 241-8515
      • Kanagawa Cancer Center
  • Tokyo
    • Chuo-ku, Tokyo, Japan, 104-0045
      • National Cancer Center Hospital
• Korea, Republic of
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital, Yonsei University Health System
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
• Taiwan
  • Taichung, Taiwan, 1650
    • Taichung Veterans General Hospital
  • Taipei, Taiwan, 112
    • Taipei Veterans General Hospital
  • Taipei City, Taiwan, 100
    • National Taiwan University Hospital
  • Taoyuan, Taiwan, 333
    • Linkou Chang Gung Memorial Hospital (CGMHLK)
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope (City of Hope National Medical Center, City of Hope Medical Center)
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10016
      • Laura & Isaac Perlmutter Cancer Center at NYU Langone Health
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
  • Texas
    • Houston, Texas, United States, 77030-4009
      • The University of Texas M.D. Anderson Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • New Experimental Therapeutics of Virginia (NEXT Oncology)
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: BLU-451; BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle
Experimental: 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.	Drug: BLU-451; BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle; Drug: Carboplatin; Carboplatin will be administered intravenously (IV) on Day 1 of each cycle (every 3 weeks) for 4 to 6 cycles; Drug: Pemetrexed; Pemetrexed will be administered prior to carboplatin as an IV infusion on Day 1 of each cycle (every 3 weeks)
Experimental: Phase I - Part 2 BLU-451 Monotherapy Enrichment; BLU-451 enrichment at select doses.	Drug: BLU-451; BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle
Experimental: Phase II - Cohort 2A; EGFR Ex20ins participants who have previously received platinum-based chemotherapy and either amivantamab or mobocertinib will receive BLU-451.	Drug: BLU-451; BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle
Experimental: 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.	Drug: BLU-451; BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle
Experimental: 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.	Drug: BLU-451; BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle
Experimental: 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.	Drug: BLU-451; BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle
Experimental: Phase II - Cohort 2E; Participants with EGFR Ex20ins who have not received prior systemic therapy in metastatic setting will receive BLU-451.	Drug: BLU-451; BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle
Experimental: 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.	Drug: BLU-451; BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle
Experimental: 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.	Drug: BLU-451; BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Blueprint Medicines Corporation

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2022
• Primary Completion (Estimated): August 23, 2024
• Study Completion (Estimated): July 25, 2026

Study Registration Dates

• First Submitted: January 31, 2022
• First Submitted That Met QC Criteria: February 14, 2022
• First Posted (Actual): February 16, 2022

Study Record Updates

• Last Update Posted (Actual): January 16, 2024
• Last Update Submitted That Met QC Criteria: January 12, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: thoracic neoplasms; protein kinase inhibitors
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms, Glandular and Epithelial; Bronchial Diseases; Thoracic Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms; Lung Diseases; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma; Brain Neoplasms; Respiratory Tract Diseases; Neoplasms by Site; Neoplasms by Histologic Type; Bronchial Neoplasms; Carcinoma, Bronchogenic; Respiratory Tract Neoplasms; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Folic Acid Antagonists; Carboplatin; Pemetrexed
• Other Study ID Numbers: BLU-451-1101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No