A Phase 1/2 Study of the Highly Selective EGFR Inhibitor, BLU-701, in Patients With EGFR-Mutant Non-Small Cell Lung Cancer
Overview
- Phase
- Phase 1
- Intervention
- BLU-701
- Conditions
- Lung Neoplasm
- Sponsor
- Blueprint Medicines Corporation
- Enrollment
- 20
- Locations
- 7
- Primary Endpoint
- [Phase 1] Determine the maximum tolerated dose (MTD) of BLU-701 monotherapy, BLU-701 in combination with osimertinib, and BLU-701 in combination with platinum-based chemotherapy
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a Phase 1/2, open-label, first-in-human (FIH) study is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of BLU-701 as monotherapy or in combination with either osimertinib or platinum-based chemotherapy in patients with EGFRm NSCLC.
Detailed Description
The study was planned to include an initial Phase 1 portion to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of BLU-701 as monotherapy (Part 1A; initially in a once daily (QD) regimen with the option to evaluate twice daily (BID) dosing if supported by emerging PK and safety data), as well as additional dose-escalation portions to determine the RP2D of BLU-701 in combination with osimertinib (Part 1B) or in combination with carboplatin and pemetrexed (Part 1C). A Phase 2 part was planned to further evaluate the efficacy and safety of BLU-701 as monotherapy at RP2D (Part 2A). Phase 1 Part 1 A was initiated; however, the study was terminated prior to establishing BLU-701 MTD and/or RP2D.
Investigators
Eligibility Criteria
Inclusion Criteria
- •≥18 years of age at the time of signing the informed consent.
- •Pathologically confirmed metastatic NSCLC.
- •Tumor mutation profile determined locally via next generation sequencing (NGS), using tumor tissue (preferably 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, samples used for analysis must be obtained during or after disease progression on the last EGFR-targeted TKI received.
- •All Parts: activating EGFR mutation (Ex19Del or L858R)
- •Part 2A: Tumor must additionally harbor an EGFR C797X resistance mutation.
- •Previously received:
- •Part 1A and 2A: At least 1 prior third-generation EGFR-targeted TKI, such as osimertinib
- •Part 1B: 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.
- •Part 1C: At least 1 prior EGFR-targeted TKI
Exclusion Criteria
- •Have disease that is suitable for local therapy administered with curative intent.
- •Have tumor that harbors EGFR T790M mutation or any additional known driver alterations (including but not limited to, EGFR exon 20 insertions, or pathologic abnormalities of KRAS, BRAF V600E, NTRK1/2/3, HER2, ALK, ROS1, MET, or RET).
- •Have NSCLC with mixed cell histology or a tumor with known histologic transformation (NSCLC to SCLC, SCLC to NSCLC, or epithelial to mesenchymal transition).
- •Have received the following anticancer therapy:
- •Any third-generation EGFR TKI (such as osimertinib) within 7 days prior to the planned first dose of study drug. Note: patients in Part 1B do not require a wash-out period for osimertinib.
- •Part 2A: Previous therapy with first- or second-generation EGFR TKI, such as erlotinib, gefitinib, afatinib or dacomitinib.
- •Part 1C: Prior platinum-based chemotherapy for advanced or metastatic disease.
- •Any immunotherapy or other antibody therapy (including EGFR-targeted antibodies or bi-specific antibodies) within 21 days prior to the first dose of study drug.
- •Any other systemic anticancer therapy within 14 days or 5 half-lives prior to the first dose of study drug, whichever is the shortest, but with a minimum of 7 days in all circumstances. BLU-701 may be started within these washout periods if considered by the Investigator to be safe and within the best interest of the patient, with prior Sponsor approval.
- •Radiotherapy to a large field or including a vital organ (including whole brain radiotherapy or stereotactic radiosurgery to brain) within 14 days before the first dose of study drug. Radiotherapy to a focal site of disease that did not include a vital organ (such as a limb) within 7 days before the first dose of study drug.
Arms & Interventions
Part 1A: BLU-701 as monotherapy
Phase 1 dose escalation of BLU-701 as monotherapy at various dose levels
Intervention: BLU-701
Part 1B: BLU-701 with osimertinib
BLU-701 in combination with osimertinib 40 mg or 80 mg tablets for oral administration
Intervention: BLU-701
Part 1B: BLU-701 with osimertinib
BLU-701 in combination with osimertinib 40 mg or 80 mg tablets for oral administration
Intervention: osimertinib
Part 1C: BLU-701 with platinum-based chemotherapy
BLU-701 in combination with platinum-based chemotherapy (carboplatin and pemetrexed): Carboplatin - IV infusion dosed to target AUC of 5-6 mg/mL min q3w Pemetrexed - IV infusion dosed to 500 mg/m2 q3w
Intervention: BLU-701
Part 1C: BLU-701 with platinum-based chemotherapy
BLU-701 in combination with platinum-based chemotherapy (carboplatin and pemetrexed): Carboplatin - IV infusion dosed to target AUC of 5-6 mg/mL min q3w Pemetrexed - IV infusion dosed to 500 mg/m2 q3w
Intervention: carboplatin
Part 1C: BLU-701 with platinum-based chemotherapy
BLU-701 in combination with platinum-based chemotherapy (carboplatin and pemetrexed): Carboplatin - IV infusion dosed to target AUC of 5-6 mg/mL min q3w Pemetrexed - IV infusion dosed to 500 mg/m2 q3w
Intervention: pemetrexed
Part 2A: BLU-701 as monotherapy
Phase 2 expansion group for BLU-701 as monotherapy at a dose determined during Part 1A in patients harboring the EGFR C797X resistance mutation
Intervention: BLU-701
Outcomes
Primary Outcomes
[Phase 1] Determine the maximum tolerated dose (MTD) of BLU-701 monotherapy, BLU-701 in combination with osimertinib, and BLU-701 in combination with platinum-based chemotherapy
Time Frame: Up to 12 months
MTD determination: dose limiting toxicity (DLT) rate
[Phase 1] Determine the recommended Phase 2 dose (RP2D) of BLU-701 monotherapy, BLU-701 in combination with osimertinib, and BLU-701 in combination with platinum-based chemotherapy
Time Frame: Up to 12 months
RP2D determination: DLT, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary safety and antitumor activity data
[Phase 2] Overall response rate (ORR)
Time Frame: Up to 30 months
ORR - the proportion of patients who experience a best response of confirmed CR or PR according to RECIST 1.1
[Phase 1] Overall safety profile
Time Frame: Up to 12 months
Rate and severity of adverse events
Secondary Outcomes
- [Phase 2] Overall safety profile(Up to 42 months)
- [Phase 2] Clinical Benefit Rate (CBR)(Up to 42 months)
- [Phase 2] Central Nervous System Duration of Response (CNS-DOR)(Up to 42 months)
- [Phase 1] Overall response rate (ORR)(Up to 12 months)
- [Phase 1] To assess treatment-induced modulation of EGFR pathway biomarkers for BLU-701 monotherapy(Up to 42 months)
- [Phase 1 and Phase 2] Duration of response (DOR)(Up to 42 months)
- [Phase 2]Disease Control Rate (DCR)(Up to 42 months)
- [Phase 2] Central Nervous System Progression Rate(Up to 42 months)
- [Phase 1 and Phase 2] To characterize the PK profile of BLU-701(Up to 42 months)
- [Phase 2] Progression Free Survival (PFS)(Up to 42 months)
- [Phase 2] Central Nervous System Overall Response Rate (CNS-ORR)(Up to 42 months)
- [Phase 2] To assess the effect of BLU-701 on cardiovascular intervals, including QT, and rhythm(Up to 42 months)
- [Phase 2] Overall Survival (OS)(Up to 42 months)