Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC

Phase 1

• Conditions: EGFR Mutant Non-Small Cell Lung Cancer; MedDRA version: 21.1Level: PTClassification code 10059515Term: Non-small cell lung cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2020-005822-27-NL
• Lead Sponsor: Blueprint Medicines Corporation

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2021-07-12
• Last Update Posted: 18 March 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 190

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

- 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 < Grade 2 prior to starting BLU 945).
c.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 945 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.
d.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. Participant received 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.
- CNS metastases or spinal cord compression that is associated with progressive neurological symptoms or requires increasing doses of corticosteroids to control the CNS disease. If a patient requires corticosteroids for management of CNS disease, the dose must have been stable for the 2 weeks preceding treatment. Asymptomatic CNS and leptomeningeal disease is allowed and, when measurable, should be captured as target lesions.
- Any of the following abnormalities on the most recent laboratory test prior to the first dose of study drug (ie, Cycle 1 Day 1[C1D1] or screening):
a.Absolute neutrophil count (ANC) <1.0×10^9/L.
b.Platelet count <75×109/L.
c.Hemoglobin =8.0 g/dL (red blood cell transfusion and erythropoietin may be used to reach at least 8.0 g/dL, but must have been administered at least 2 weeks prior to the first dose of study drug).
d.Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >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 <40 mL/min.
g.International normalized ratio (INR) >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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified