Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC

JRCT ID: jRCT2031210431

Registered date:19/11/2021

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: EGFR Mutant Non-Small Cell Lung Cancer
• Date of first enrollment: 16/12/2021
• Target sample size: 19
• Countries of recruitment: US,Japan,UK,Japan,Taiwan,Japan,Spain,Japan,South Korea,Japan,Singapore,Japan,Netherlands,Japan,Germany,Japan,France,Japan,Canada,Japan
• Study type: Interventional
• Intervention(s): Determined dose in each cohort is administered orally as BLU-945 monotheraphy or in combination with Osimertinib in each cohort/phase.

Outcome(s)

Primary Outcome

Phase 1
a, MTD determination of BLU-945 as monotherapy and in combination with osimertinib: DLT rate
b, RP2D determination of BLU-945 as monotherapy and in combination with osimertinib: DLT, PK, PD, and preliminary safety and anticancer activity data
c, Overall safety profile of BLU-945 as monotherapy and in combination with osimertinib, 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 .

Phase 2
a, ORR of BLU-945 as monotherapy and in combination with osimertinib, defined as the proportion of patients who experience a best response of confirmed CR or PR according to RECIST 1.1

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1. Greater than or equal to 20 years of age at the time of signing the informed consent.
2. Pathologically confirmed, definitively diagnosed, metastatic NSCLC harboring an activating EGFR mutation (exon 19 deletion mutation or EGFR L858R mutation).
3. Previously received at least 1 prior approved EGFR-targeted TKI with activity against the T790M mutation, such as osimertinib, and must have received or are not a candidate for additional available standard of care treatments.
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, pretreatment 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. It For Phase 1, it is preferable that pretreatment tumor samples be obtained from a progression 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.
6. Phase 2 Expansion Groups: Patient has at least 1 measurable target lesion evaluable by RECIST 1.1 as assessed by the investigator.
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) is 0-1.
8. Agrees to use contraception consistent with the protocol and local regulations.

Exclude 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 mixe 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 x 10^9/L.
b.Platelet count <75 x 10^9/L.
c.Hemoglobin less than or equal to 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) >3x the upper limit of normal (ULN) if no hepatic metastases are present; >5x ULN if hepatic metastases are present.
e.Total bilirubin >1.5x ULN; >3x ULN in presence of Gilbert's disease.
f.Estimated (Cockroft-Gault formula) 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.The following are excluded:
a. Clinically active ongoing interstitial lung disease (ILD) and radiation pneumonitis within 28 days prior to initiation of study treatment
b. A history of ILD other than radiation pneumonitis.
Patients with radiation pneumonitis more than 28 days before the start of administration of the drug, which is not clinically significant or not problematic (not active) radiation pneumonitis at the time of enrollment, can be enrolled.
8.Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or that have not resolved to baseline at the time of starting the study. Exceptions include alopecia and fatigue, and, upon discussion with and approval by the Medical Monitor, other toxicities that are not thought to present a risk to patient safety.
9.Mean resting QT interval corrected using Fridericia's formula (QTcF) > 450 msec, a history of prolonged QT syndrome or Torsades de pointes, or a familial history of prolonged QT syndrome.
10.Clinically significant, uncontrolled, cardiovascular disease including congestive heart failure Grade III or IV according to the New York Heart Association classification; myocardial infarction or unstable angina within the previous 6 months, uncontrolled hypertension, or clinically significant, uncontrolled arrhythmias, including bradyarrhythmia that may cause QT prolongation (eg, Type II second degree heart block or third degree heart block).
11.History of another primary malignancy (other than completely resected carcinomas in situ) that has been diagnosed or required therapy within 2 years prior to initiation of study treatment. However, upon discussion with the Sponsor, the following categories of patients with prior malignancy are eligible to participate:
a.Patients with a previous malignancy that completed all anticancer treatment at least 2 years before and with no evidence of residual disease from the prior malignancy at registration
b.Patients who have another concurrent malignancy (not lung cancer) that is clinically stable and does not require tumor-directed treatment. (Examples include, but are not limited to, completely resected basal cell carcinoma and squamous cell carcinoma of skin, curatively treated prostate cancer, breast cancer, and early gastric cancer cured by endoscopic mucosal resection or endoscopic submucosal dissection.)
12.Active, uncontrolled infection (viral, bacterial, or fungal) or active tuberculosis, hepatitis B, hepatitis C, AIDS-related illness, or known Coronavirus diseases 2019 (COVID 19) infection. Controlled infections, including HIV and "cured" hepatitis C (no active fever, no evidence of systemic inflammatory response syndrome) that are stable on antiviral treatment may be eligible if benefit/risk is justified and permission is granted from the Sponsor.
13.Dose escalation (Parts 1A and 1B): Received neutrophil or platelet growth factor support within 14 days of the first dose of study drug.
14.Requires treatment with a prohibited medication or herbal remedy that cannot be discontinued at least 2 weeks before the start of study drug administration. BLU 945 may be started within 14 days or 5 half-lives of these therapies if considered by the Investigator to be safe and within the best interest of the patient, with prior Sponsor approval.
15.Major surgical procedure within 14 days of the first dose of study drug (procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures).

Related Information

• Primary Sponsor: Zalutskaya Alena
• Secondary ID(s): NCT04862780