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

Phase 1TerminatedNCT05241873

Blueprint Medicines Corporation103 enrolled

Overview

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.

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

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

103

Conditions

Lung Neoplasm Malignant Carcinoma, Non-Small-Cell Lung

Interventions

BLU-451DRUG

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

CarboplatinDRUG

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

PemetrexedDRUG

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (23)

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

...and 13 more locations

Outcomes

Primary Outcomes

Phase I - Determine the maximum tolerated dose (MTD) of BLU-451

MTD determination: Dose-limiting toxicities (DLTs) rate

Time frame: 12-15 Months

Phase I - Determine the Recommended Phase 2 Dose (RP2D) of BLU-451

RP2D determination: DLT, PK, PD, and preliminary safety data

Time frame: 12-15 Months

Phase I - Rate and severity of Adverse Events (AEs) of BLU-451

Time frame: 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.

Time frame: Up to 30 months

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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)

Time frame: 12-15 Months

Phase I & II - To evaluate the maximum observed blood drug concentration (Cmax) of BLU-451

Time frame: Up to 30 months

Phase I & II - To evaluate the time of maximum blood concentration (tmax) of BLU-451

Time frame: Up to 30 months

Phase I & II - To evaluate the elimination half life (t1/2) of BLU-451

Time frame: Up to 30 months

Phase I & II - To evaluate the area under the blood concentration-time curve (AUC0-t, AUC0-inf) of BLU-451

Time frame: Up to 30 months

Phase I & II - To evaluate the clearance (CL/F) of BLU-451

Time frame: Up to 30 months

Phase I & II - To evaluate the volume of distribution (Vss/F) of BLU-451

Time frame: Up to 30 months

Phase II - Rate and severity of Adverse Events (AEs) of BLU-451

Time frame: Up to 30 months