Adenocarcinoma, Antineoplastic Agents, Brain Metastases, Bronchial Neoplasms, Carcinoma, Carcinoma, Bronchogenic, Carcinoma, Non-Small-Cell Lung, EGFR Activating Mutation, EGFR Atypical Mutations, Including G719X and L861Q, EGFR Exon 20 Insertion Mutation, EGFR Exon 20 Mutation, EGFR-mutated NSCLC, Lung Diseases, Lung Neoplasm Malignant, Metastatic Lung Cancer, Neoplasms, Neoplasms by Histologic Type, Neoplasms by Site, Respiratory Tract Disease, Respiratory Tract Neoplasms
Conditions
Keywords
protein kinase inhibitors, thoracic neoplasms
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.
Interventions
DRUGBLU-451
BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle
DRUGCarboplatin
Carboplatin will be administered intravenously (IV) on Day 1 of each cycle (every 3 weeks) for 4 to 6 cycles
DRUGPemetrexed
Pemetrexed will be administered prior to carboplatin as an IV infusion on Day 1 of each cycle (every 3 weeks)
Sponsors
Blueprint Medicines Corporation
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 - 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 - 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 | — |
| Phase I & II - To evaluate the maximum observed blood drug concentration (Cmax) of BLU-451 | Up to 30 months | — |
| 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. |
Countries
Canada, Japan, South Korea, Taiwan, United States
Outcome results
None listed