A Phase 1/2 Study Targeting Acquired Resistance Mechanisms in Patients with EGFR Mutant Non-Small Cell Lung Cancer

Phase 2

Completed

Conditions: NSCLC
Non-Small Cell Lung Cancer
10038666

Registration Number: NL-OMON52248

Lead Sponsor: Blueprint Medicines Corporation

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 6

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

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 < 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.
4. 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.
5. 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) <1.0×109/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.
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