Clinical trial NCT05241873: (Concerto) Study of BLU-451 in Advanced Cancers With EGFR Exon 20 Insertion Mutations
Official title: Phase I/II Study of BLU-451 in Advanced Cancers With EGFR Exon 20 Insertion Mutations
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
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
Lead sponsor: Blueprint Medicines Corporation
Sponsor class: INDUSTRY
First posted: 2022-02-16
Enrollment: 103
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Phase I - Determine the maximum tolerated dose (MTD) of BLU-451
timeFrame: 12-15 Months
measure: Phase I - Determine the Recommended Phase 2 Dose (RP2D) of BLU-451
timeFrame: 12-15 Months
measure: Phase I - Rate and severity of Adverse Events (AEs) of BLU-451
timeFrame: 12-15 Months
measure: Phase II - The Overall Response Rate (ORR) rate of BLU-451
timeFrame: Up to 30 months
Secondary outcomes:
measure: Phase I - The Overall Response Rate (ORR) rate of BLU-451
timeFrame: Up to 30 months
measure: Phase I & II - The Duration of Response (DOR) rate of BLU-451
timeFrame: 12-15 Months
measure: Phase I & II - The Disease Control Rate (DCR) rate of BLU-451
timeFrame: 12-15 Months
measure: Phase I & II - The Clinical Benefit Rate (CBR) of BLU-451
timeFrame: 12-15 Months
measure: Phase I & II - The Progression Free Survival (PFS) rate of BLU-451
timeFrame: 12-15 Months
measure: Phase I & II - The Overall Survival (OS) rate of BLU-451
timeFrame: 12-15 Months
measure: Phase I & II - To evaluate the Central Nervous System (CNS) Overall Response Rate (ORR) of BLU-451 in subjects with measurable baseline brain metastases
timeFrame: Up to 30 months
measure: Phase I & II - To evaluate the Central Nervous System (CNS) Duration of Response (DOR) of BLU-451 in subjects with measurable baseline brain metastases
timeFrame: Up to 30 months
measure: Phase I & II - To evaluate the Central Nervous System (CNS) Progression Free Survival (PFS) of BLU-451 in subjects with measurable baseline brain metastases
timeFrame: Up to 30 months
measure: Phase I - Assess treatment-induced modulation of EGFR pathway biomarkers
timeFrame: 12-15 Months
measure: Phase I & II - To evaluate the maximum observed blood drug concentration (Cmax) of BLU-451
timeFrame: Up to 30 months
measure: Phase I & II - To evaluate the time of maximum blood concentration (tmax) of BLU-451
timeFrame: Up to 30 months
measure: Phase I & II - To evaluate the elimination half life (t1/2) of BLU-451
timeFrame: Up to 30 months
measure: Phase I & II - To evaluate the area under the blood concentration-time curve (AUC0-t, AUC0-inf) of BLU-451
timeFrame: Up to 30 months
measure: Phase I & II - To evaluate the clearance (CL/F) of BLU-451
timeFrame: Up to 30 months
measure: Phase I & II - To evaluate the volume of distribution (Vss/F) of BLU-451
timeFrame: Up to 30 months
measure: Phase II - Rate and severity of Adverse Events (AEs) of BLU-451
timeFrame: Up to 30 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope (City of Hope National Medical Center, City of Hope Medical Center)
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)
state: Colorado
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Laura & Isaac Perlmutter Cancer Center at NYU Langone Health
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Houston
country: United States
facility: The University of Texas M.D. Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: New Experimental Therapeutics of Virginia (NEXT Oncology)
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Yokohama-shi
country: Japan
facility: Kanagawa Cancer Center
state: Kanagawa
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei City
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taoyuan
country: Taiwan
facility: Linkou Chang Gung Memorial Hospital (CGMHLK)
Study officials:
References: