EGFR Mutant Non-Small Cell Lung Cancer MedDRA version: 21.1 Level: PT Classification code 10059515 Term: Non-small cell lung cancer metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: BLU-945
Pharmaceutical Form: Capsule
INN or Proposed INN: BLU-945
Other descriptive name: BLU-945
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Sponsors
Blueprint Medicines Corporation
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - =18 years of age at the time of signing the informed consent. - Pathologically confirmed, definitively diagnosed, metastatic NSCLC harboring an activating EGFR mutation. - 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. -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 I, 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, pretreatment tumor sample must be obtained during or after disease progression on the last EGFR-targeted TKI received. a. Dose Escalation (Phase 1 Parts 1A and 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. - Pretreatment tumor sample (either an archival sample or a sample obtained by pretreatment biopsy) submitted for central analysis. For Phase I, 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, pretreatment 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. - Phase 2 Expansion Groups: Patient has at least 1 measurable target lesion evaluable by RECIST 1.1 as assessed by the investigator. - Eastern Cooperative Oncology Group (ECOG) performance status is 0-1. - Agrees to use contraception consistent with the protocol and local regulations. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 120 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 70
Exclusion criteria
Exclusion criteria: - 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. - NSCLC with mixed cell histology or a tumor with histologic transformation (NSCLC to SCLC, SCLC to NSCLC, or epithelial to mesenchymal transition). - 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. - Known intracranial hemorrhage and/or bleeding diatheses. - 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 clinically resolved COVID 19 infection may be enrolled upon discussion with, and approval by, the Medical Monitor. - Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adv
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1: - To determine the MTD and RP2D of BLU 945 as monotherapy and in combination with osimertinib. - To determine the safety and tolerability of BLU 945 as monotherapy and in combination with osimertinib. Phase 2: - To assess anticancer activity of BLU 945 at the RP2D as monotherapy and in combination with osimertinib in patients with NSCLC harboring EGFR mutations.;Secondary Objective: Phase 1: - To assess anticancer activity of BLU 945 as monotherapy and in combination with osimertinib - To characterize the PK profile of BLU 945 and correlate drug exposure with safety assessments . - Assess treatment-induced modulation of EGFR pathway biomarkers. Phase 2: - To assess additional measures of anticancer activity of BLU 945 at the RP2D as monotherapy and in combination with osimertinib in patients with NSCLC harboring EGFR mutations. - To determine the safety and tolerability of BLU 945 as monotherapy and in combination with osimertinib. - To assess the effect of BLU 945 on cardiovascular intervals, including QT, and rhythm - To characterize the PK profile of BLU 945 and correlate drug exposure with safety assessments, including changes in ECG intervals and antitumor activity.;Primary end point(s): Phase 1: - MTD determination: DLT rate - RP2D determination: DLT, PK, PD, 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: - ORR, defined as the proportion of patients who experience a best response of confirmed CR or PR according to RECIST 1.1;Timepoint(s) of evaluation of this end point: Phase 1: - MTD determination: Up to 12 months - RP2D determination: Up to 12 months -Overall safety profile of BLU-945: Throughout Phase 1 Phase 2: - ORR: Up to 30 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1: - ORR, defined as the proportion of patients who experience a best response of confirmed CR or PR according to RECIST 1.1 Phase 2: - 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 - Overall safety profile of BLU 945, as assessed by the type, frequency, severity, timing, and relationship to study drug of TEAEs, and changes in vital signs, electrocardiograms, and safety laboratory tests. - ECG parameters extracted from continuous 12 lead Holter recordings for 25 patients in the expansion phase: The primary QTc parameter will be QTcF. Secondary parameters (other correction methods for QT, heart rate, PR, QRS, and T wave morphology) will also be evaluated. - CNS-ORR, defined as the proportion of patients with measurable (target) intracranial metastases at baseline who experience a confirmed intracranial CR or PR according to RECIST 1.1 principles - CNS-DOR, defined as the time from first documented intracranial CR or PR to the date of first documented intracranial PD - CNS progression rate, defined as the proportion of patients with CNS progression as a component of first disease progression on study. - Correlations between PK parameters and safety findings of interest, including ECG intervals, will be performed Phase 1 and 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 - PK parameters of BLU-945 | — |
Countries
Canada, France, Germany, Japan, Korea, Republic of, Netherlands, Singapore, Spain, Taiwan, United Kingdom, United States
Contacts
Public ContactMedical Information
Blueprint Medicines Corporation
Outcome results
None listed