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

Neoplasms Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05241873
• Other study ID #: BLU-451-1101
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: March 4, 2022
• Est. completion date: July 25, 2026

Study information

• Verified date: January 2024
• Source: Blueprint Medicines Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 332
• Est. completion date: July 25, 2026
• Est. primary completion date: August 23, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Adenocarcinoma
• Antineoplastic Agents
• Brain Metastases
• Brain Neoplasms
• Bronchial Neoplasms
• Carcinoma
• Carcinoma, Bronchogenic
• Carcinoma, Non-Small-Cell Lung
• EGFR Activating Mutation
• EGFR Exon 20 Insertion Mutation
• EGFR Exon 20 Mutation
• Lung Diseases
• Lung Neoplasm Malignant
• Lung Neoplasms
• Metastatic Lung Cancer
• Neoplasms
• Neoplasms by Histologic Type
• Neoplasms by Site
• Respiratory Tract Disease
• Respiratory Tract Diseases
• Respiratory Tract Neoplasms

Intervention

Drug:
• BLU-451
BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle
• Carboplatin
Carboplatin will be administered intravenously (IV) on Day 1 of each cycle (every 3 weeks) for 4 to 6 cycles
• Pemetrexed
Pemetrexed will be administered prior to carboplatin as an IV infusion on Day 1 of each cycle (every 3 weeks)

Locations

Country	Name	City	State
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Japan	National Cancer Center Hospital	Chuo-ku	Tokyo
Japan	National Cancer Center Hospital East	Kashiwa	Chiba
Japan	Kanagawa Cancer Center	Yokohama-shi	Kanagawa
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	National Taiwan University Hospital	Taipei City
Taiwan	Linkou Chang Gung Memorial Hospital (CGMHLK)	Taoyuan
United States	University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)	Aurora	Colorado
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	City of Hope (City of Hope National Medical Center, City of Hope Medical Center)	Duarte	California
United States	New Experimental Therapeutics of Virginia (NEXT Oncology)	Fairfax	Virginia
United States	The University of Texas M.D. Anderson Cancer Center	Houston	Texas
United States	Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute	Los Angeles	California
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	Fred Hutchinson Cancer Center	Seattle	Washington
United States	Georgetown University Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Blueprint Medicines Corporation

Countries where clinical trial is conducted

United States,  Canada,  Japan,  Korea, Republic of,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase I - Determine the maximum tolerated dose (MTD) of BLU-451	MTD determination: Dose-limiting toxicities (DLTs) rate	12-15 Months
Primary	Phase I - Determine the Recommended Phase 2 Dose (RP2D) of BLU-451	RP2D determination: DLT, PK, PD, and preliminary safety data	12-15 Months
Primary	Phase I - Rate and severity of Adverse Events (AEs) of BLU-451		12-15 Months
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Phase I & II - To evaluate the maximum observed blood drug concentration (Cmax) of BLU-451		Up to 30 months
Secondary	Phase I & II - To evaluate the time of maximum blood concentration (tmax) of BLU-451		Up to 30 months
Secondary	Phase I & II - To evaluate the elimination half life (t1/2) of BLU-451		Up to 30 months
Secondary	Phase I & II - To evaluate the area under the blood concentration-time curve (AUC0-t, AUC0-inf) of BLU-451		Up to 30 months
Secondary	Phase I & II - To evaluate the clearance (CL/F) of BLU-451		Up to 30 months
Secondary	Phase I & II - To evaluate the volume of distribution (Vss/F) of BLU-451		Up to 30 months
Secondary	Phase II - Rate and severity of Adverse Events (AEs) of BLU-451		Up to 30 months