Non-Small Cell Lung Cancer NSCLC
Conditions
Interventions
Oral administration of BLU-945 capsules or tablets as monotherapy or in
combination with osimertinib.
Sponsors
Blueprint Medicines Corporation
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. >=18 years of age at the time of signing the informed consent. 2. Pathologically confirmed, definitively diagnosed, metastatic NSCLC harboring an activating EGFR mutation. 3. Previously received at least 1 prior EGFR-targeted TKI with activity against the T790M mutation, such as osimertinib. a. Phase 1 Part 1B and Phase 2 Group 4: Patients must have experienced progressive disease while on osimertinib, were able to tolerate prior osimertinib 80 mg QD dose, and continuing on osimertinib is deemed to be in the patient*s best interests in the opinion of the Investigator. Patients who have discontinued osimertinib may be eligible if no more than 6 weeks elapse between the discontinuation of prior osimertinib and resumption of osimertinib on study. 4. Tumor mutation profile determined locally via a Sponsor-approved testing methodology (NGS is preferred and will be required for Phase 2), using tumor tissue (ideally from a progressing lesion) and/or ctDNA in plasma. For Phase 1, it is preferable that samples used for analysis be obtained during or after disease progression on the last EGFR-targeted TKI received. For Phase 2, pre-treatment tumor sample must be obtained during or after disease progression on the last EGFR-targeted TKI received. a. Dose Escalation (Phase 1 Part 1A and Part 1B): At each dose level, slots may be reserved for patients with the mutations of interest. b. BLU-945 Monotherapy Expansion (Phase 2 Group 1, Group 2, and Group 3): Patients must have NSCLC harboring EGFR T790M and C797S mutation (Group 1); EGFR T790M but not C797S (Group 2); or EGFR C797S but not T790M (Group 3). c. BLU-945 with Osimertinib Expansion (Phase 2 Group 4): Slots may be reserved for patients with mutations of interest, but at least 12 slots will be allocated to patients with NSCLC harboring EGFR T790M and C797S mutation. 5. Pretreatment tumor sample (either an archival sample or a sample obtained by pretreatment biopsy) submitted for central analysis. For Phase 1, it is preferable that pretreatment tumor samples be obtained from a progressing lesion, during or after disease progression on the last EGFR-targeted TKI received. For Phase 2, pre-treatment tumor sample must be obtained during or after disease progression on the last EGFR-targeted TKI received. Patients without appropriate archival tissue available, where biopsy is not considered safe and/or medically feasible, may be discussed with the study medical monitor and may be approved for enrollment on a case-by-case basis. 6. Patients enrolled in Phase 1 Part 1A at doses expected to result in efficacious exposure levels (anticipated to be >=100 mg QD, but may be modified by the Sponsor based on emerging PK and clinical data) must consent to undergo on-treatment biopsy for central submission of tumor sample. Following approval from the Sponsor, on-treatment biopsy may be omitted for patients for whom the investigator does not feel that biopsy would be safe and/or feasible. Collection of these tumor samples may be discontinued for particular dose-escalation cohorts or expansion groups, if the Sponsor determines that adequate data have been obtained. 7. Phase 2 Expansion Groups: Patient has at least 1 measurable target lesion evaluable by RECIST 1.1 as assessed by the investigator. 8. Able to swallow an oral medicati
Exclusion criteria
Exclusion criteria: 1. Tumor harbors any additional known driver alterations (including but not limited to EGFR exon 20 insertion, or pathologic abnormalities of KRAS, BRAF V600E, NTRK1/2/3, HER2, ALK, ROS1, MET, or RET). 2. NSCLC with mixed cell histology or a tumor with histologic transformation (NSCLC to SCLC, SCLC to NSCLC, or epithelial to mesenchymal transition). 3. Received the following anticancer therapy: a. EGFR-targeted TKI within 7 days prior to the first dose of study drug. Note: patients in Phase 1 Part 1B and Phase 2 Group 4 do not require a wash-out period for osimertinib. b. Any immunotherapy or other antibody therapy (including EGFR-targeted antibodies or bi-specific antibodies) within 28 days prior to the first dose of study drug (immune-related toxicities must have resolved to 3× the upper limit of normal (ULN) if no hepatic metastases are present; >5× ULN if hepatic metastases are present. e. Total bilirubin >1.5× ULN; >3× ULN in presence of Gilbert*s disease. f. Estimated (Cockroft-Gault formula, Appendix 1) or measured creatinine clearance 2.3 or prothrombin time (PT) >6 seconds above control or a patient-specific INR or PT abnormality that the treating investigator considers clinically relevant and/or increases the risk for hemorrhage in that individual patient. 6. Known intracranial hemorrhage and/or bleeding diatheses. 7. Clinically active ongoing interstitial lung disease (ILD) of any etiology, including drug-induced ILD, and radiation pneumonitis within 28 days prior to initiation of study treatment. Patients with prior ILD associated with
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Phase 1 Maximum tolerated dose (MTD) is calculated with dose-limiting toxicity rate Recommended Phase 2 dose (RP2D) of BLU-945 is based on dose-limiting toxicity, pharmacokinetics, pharmacodynamics, and preliminary safety and anticancer activity data. Overall safety profile of BLU-945, as assessed by the type, frequency, severity, timing, and relationship to study drug of treatment-emergent adverse events (TEAEs), and changes in vital signs, electrocardiograms, and safety laboratory tests Phase 2 Overall response rate, defined as the proportion of patients who experience a best response of confirmed complete response or partial response according to RECIST 1.1 | — |
Secondary
| Measure | Time frame |
|---|---|
| Phase 1 • ORR, defined as the proportion of patients who experience a best response of confirmed CR or PR according to RECIST 1.1 • DOR, defined as the time from first documented response of CR or PR to the date of first documented progressive disease or death due to any cause, whichever occurs first • PK parameters of BLU-945: Pharmacokinetic parameters of interest will include, as appropriate, maximum plasma drug concentration (Cmax), time to maximum plasma drug concentration (Tmax), time of last quantifiable plasma drug concentration (Tlast), area under the plasma concentration versus time curve from time 0 to the end of the dosing interval (AUC0-24 for QD and AUC0-12 for BID), trough concentration (Ctrough), apparent volume of distribution (Vz/F), terminal elimination half-life (t*), apparent oral clearance (CL/F), and accumulation ratio®. BLU-945 metabolites may also be measured. • Profile pharmacodynamic changes in expression levels of the EGFR pathway biomarkers dual specificity phosphatase (DUSP6) and sprouty RTK signaling antagonist 4 (SPRY4). Phase 2 • DOR, defined as the time from first documented response of CR or PR to the date of first documented progressive disease or death due to any cause, whichever occurs first • DCR, defined as the proportion of patients who experience a best response of CR, PR, or stable disease (SD) according to RECIST 1.1 • CBR, defined as the proportion of patients who experience a confirmed CR or PR, or SD with a duration of at least 16 weeks according to RECIST 1.1 • PFS, defined as the time from the first dose of BLU-945 until the date of first documented progressive disease or death due to any cause, whichever occurs first • Overall survival (OS), defined as the time from the first dose of BLU-945 until the date of death due to any cause • CNS-ORR, defined as the proportion of patients with measurable (target) intracranial metastases at baseline who experience a confirmed intracranial CR or | — |
Countries
Netherlands
Outcome results
None listed