(Concerto) Study of BLU-451 in Advanced Cancers With EGFR Exon 20 Insertion Mutations
- Conditions
- Lung Neoplasm MalignantCarcinoma, Non-Small-Cell LungRespiratory Tract NeoplasmsNeoplasmsNeoplasms by SiteLung DiseasesRespiratory Tract DiseaseCarcinoma, BronchogenicBronchial NeoplasmsAdenocarcinoma
- Interventions
- Registration Number
- NCT05241873
- Lead Sponsor
- Blueprint Medicines Corporation
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 103
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase I - Part 1A Dose Escalation BLU-451 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. Phase I - Part 1B Dose Escalation (US only) Carboplatin 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. Phase I - Part 1B Dose Escalation (US only) Pemetrexed 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. Phase II - Cohort 2A BLU-451 EGFR Ex20ins participants who have previously received platinum-based chemotherapy and either amivantamab or mobocertinib will receive BLU-451. Phase I - Part 2 BLU-451 Monotherapy Enrichment BLU-451 BLU-451 enrichment at select doses. Phase I - Part 1B Dose Escalation (US only) BLU-451 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. Phase II - Cohort 2D BLU-451 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. Phase II - Cohort 2B BLU-451 EGFR Ex20ins participants who have previously received platinum-based chemotherapy but have not received a prior EGFR Ex20ins-targeted agent will receive BLU-451. Phase II - Cohort 2C BLU-451 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. Phase II - Cohort 2E BLU-451 Participants with EGFR Ex20ins who have not received prior systemic therapy in metastatic setting will receive BLU-451. Phase II - Cohort 2F BLU-451 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. Phase II - Cohort 2G BLU-451 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.
- Primary Outcome Measures
Name Time Method Phase I - Rate and severity of Adverse Events (AEs) of BLU-451 12-15 Months Phase I - Determine the maximum tolerated dose (MTD) of BLU-451 12-15 Months MTD determination: Dose-limiting toxicities (DLTs) rate
Phase I - Determine the Recommended Phase 2 Dose (RP2D) of BLU-451 12-15 Months RP2D determination: DLT, PK, PD, and preliminary safety data
Phase II - The Overall Response Rate (ORR) rate of BLU-451 Up to 30 months ORR is defined as the proportion of subjects with objective response of CR or PR as determined by the Investigator using RECIST v1.1.
- Secondary Outcome Measures
Name Time Method 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 Phase I - The Overall Response Rate (ORR) rate of BLU-451 Up to 30 months ORR is defined as the proportion of subjects with objective response of CR or PR as determined by the Investigator using RECIST v1.1.
Phase I & II - The Duration of Response (DOR) rate of BLU-451 12-15 Months 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.
Phase I & II - The Disease Control Rate (DCR) rate of BLU-451 12-15 Months 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.
Phase I & II - The Clinical Benefit Rate (CBR) of BLU-451 12-15 Months 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.
Phase I & II - The Progression Free Survival (PFS) rate of BLU-451 12-15 Months 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.
Phase I & II - The Overall Survival (OS) rate of BLU-451 12-15 Months 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.
Phase I & II - To evaluate the Central Nervous System (CNS) Overall Response Rate (ORR) of BLU-451 in subjects with measurable baseline brain metastases Up to 30 months CNS ORR: Defined as the proportion of patients achieving confirmed intra-cranial CR or PR as determined by the RECIST v1.1.
Phase I & II - To evaluate the Central Nervous System (CNS) Duration of Response (DOR) of BLU-451 in subjects with measurable baseline brain metastases Up to 30 months 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
Phase I & II - To evaluate the Central Nervous System (CNS) Progression Free Survival (PFS) of BLU-451 in subjects with measurable baseline brain metastases Up to 30 months 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
Phase I - Assess treatment-induced modulation of EGFR pathway biomarkers 12-15 Months Profile pharmacodynamic changes in gene expression levels of the EGFR pathway biomarkers dual specificity phosphatase (DUSP6) and sprouty RTK signaling antagonist 4 (SPRY4)
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
Trial Locations
- Locations (23)
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
City of Hope (City of Hope National Medical Center, City of Hope Medical Center)
🇺🇸Duarte, California, United States
National Cancer Center Hospital East
🇯🇵Kashiwa, Chiba, Japan
Laura & Isaac Perlmutter Cancer Center at NYU Langone Health
🇺🇸New York, New York, United States
Kanagawa Cancer Center
🇯🇵Yokohama-shi, Kanagawa, Japan
National Cancer Center Hospital
🇯🇵Chuo-ku, Tokyo, Japan
Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute
🇺🇸Los Angeles, California, United States
Hospital of the University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Northwestern Memorial Hospital
🇺🇸Chicago, Illinois, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, 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
Georgetown University Medical Center
🇺🇸Washington, District of Columbia, United States
National Taiwan University Hospital
🇨🇳Taipei City, Taiwan
Linkou Chang Gung Memorial Hospital (CGMHLK)
🇨🇳Taoyuan, Taiwan
Taichung Veterans General Hospital
🇨🇳Taichung, Taiwan
Taipei Veterans General Hospital
🇨🇳Taipei, Taiwan
University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)
🇺🇸Aurora, Colorado, United States