Clinical trial NCT04862780: (SYMPHONY) Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC
Official title: A Phase 1/2 Study Targeting Acquired Resistance Mechanisms in Patients With EGFR Mutant Non-Small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Disease
Carcinoma, Bronchogenic
Bronchial Neoplasms
Adenocarcinoma
Carcinoma
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
EGFR T790M
EGFR C797S
EGFR L858R
EGFR Gene Mutation
EGF-R Positive Non-Small Cell Lung Cancer
EGFR Exon 19 Deletion
EGFR Mutation Resulting in Tyrosine Kinase Inhibitor Resistance
EGFR Activating Mutation
Protein Kinase Inhibitors
Antineoplastic Agents
Thoracic Neoplasms
Lead sponsor: Blueprint Medicines Corporation
Sponsor class: INDUSTRY
First posted: 2021-04-28
Enrollment: 177
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a Phase 1/2, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anticancer activity of BLU-945, a selective EGFR inhibitor, as monotherapy or in combination with osimertinib.

Detailed description: The study will include an initial Phase 1 portion to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of BLU-945 as monotherapy (initially in a QD regimen with the option to evaluate BID dosing, if supported by emerging PK and safety data), as well as an additional dose-escalation portion to determine the RP2D of BLU-945 in combination with osimertinib. The BLU-945 monotherapy Phase 2 expansion groups will consist of patients with tumors harboring specific mutation profiles (EGFR T790M and C797S mutation \[Group 1\]; EGFR T790M but not C797S \[Group 2\]; or EGFR C797S but not T790M \[Group 3\]). The BLU-945 with osimertinib Phase 2 expansion (Group 4) will include approximately 24 evaluable patients, with at least 12 slots reserved for patients with EGFR T790M and C797S mutation.

Eligibility criteria: 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, and were able to tolerate prior osimertinib 80 mg QD dose.
4. Tumor mutation profile determined locally via a Sponsor-approved testing methodology, 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.

   1. Dose Escalation (Phase 1 Part 1A and Part 1B): At each dose level, slots may be reserved for patients with the mutations of interest.
   2. BLU-945 Monotherapy Expansion Groups (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).
   3. 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 progression 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. 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 is 0-1.
8. Agrees to use contraception consistent with the protocol and local regulations

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:

   1. EGFR-targeted TKI within 7 days prior to the first dose of study drug.
   2. 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).
   3. 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.
   4. 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):

   1. Absolute neutrophil count (ANC) \<1.0×109/L.
   2. Platelet count \<75×109/L.
   3. 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).
   4. 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.
   5. Total bilirubin \>1.5× ULN; \>3× ULN in presence of Gilbert's disease.
   6. Estimated (Cockroft-Gault formula) or measured creatinine clearance \<40 mL/min.
   7. 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 clinically resolved COVID 19 infection may be enrolled upon discussion with, and approval by, the Medical Monitor.
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:

    1. 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
    2. 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 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).

Primary outcomes:
measure: [Phase 1] Determine the maximum tolerated dose (MTD) of BLU-945 as monotherapy and BLU-945 in combination with osimertinib
timeFrame: Up to 12 months
measure: [Phase 1] Rate and severity of adverse events of BLU-945 as monotherapy and BLU-945 in combination with osimertinib
timeFrame: Up to 12 months
measure: [Phase 1] Determine recommended Phase 2 dose (RP2D) of BLU-945 as monotherapy and BLU-945 in combination with osimertinib
timeFrame: Up to 12 months
measure: [Phase 2] Overall response rate (ORR) of BLU-945 as monotherapy and BLU-945 in combination with osimertinib
timeFrame: Up to 30 months
Secondary outcomes:
measure: [Phase 1 and Phase 2] Cmax
timeFrame: Up to 42 months
measure: [Phase 1 and Phase 2] Tmax
timeFrame: Up to 42 months
measure: [Phase 1 and Phase 2] Tlast
timeFrame: Up to 42 months
measure: [Phase 1 and Phase 2] AUC (0-24)
timeFrame: Up to 42 months
measure: [Phase 1 and Phase 2] Ctrough
timeFrame: Up to 42 months
measure: [Phase 1 and Phase 2] Vz/F
timeFrame: Up to 42 months
measure: [Phase 1 and Phase 2] T 1/2
timeFrame: Up to 42 months
measure: [Phase 1 and Phase 2] CL/F
timeFrame: Up to 42 months
measure: [Phase 1] Overall response rate (ORR) of BLU-945 as monotherapy and BLU-945 in combination with osimertinib
timeFrame: Up to 12 months
measure: [Phase 1 and Phase 2] Duration of response (DOR) of BLU-945 as monotherapy and BLU-945 in combination with osimertinib
timeFrame: Up to 42 months
measure: [Phase 1 and Phase 2] Accumulation ratio
timeFrame: Up to 42 months
measure: [Phase 1 and Phase 2] Assess treatment-induced modulation of EGFR pathway biomarkers.
timeFrame: Up to 42 months
measure: [Phase 2] Disease control rate (DCR) of BLU-945 as monotherapy and BLU-945 in combination with osimertinib
timeFrame: Up to 30 months
measure: [Phase 2] Clinical benefit rate (CBR) of BLU-945 as monotherapy and BLU-945 in combination with osimertinib
timeFrame: Up to 30 months
measure: [Phase 2] Progression free survival (PFS) of BLU-945 as monotherapy and BLU-945 in combination with osimertinib
timeFrame: Up to 42 months
measure: [Phase 2] Overall survival (OS) of BLU-945 as monotherapy and BLU-945 in combination with osimertinib
timeFrame: Up to 42 months
measure: [Phase 2] Central Nervous System Overall Response Rate (CNS-ORR) of BLU-945 as monotherapy and BLU-945 in combination with osimertinib
timeFrame: Up to 42 months
measure: [Phase 2] Central Nervous System Duration of Response (CNS-DOR) of BLU-945 as monotherapy and BLU-945 in combination with osimertinib
timeFrame: Up to 42 months
measure: [Phase 2] Central Nervous System Progression Rate of BLU-945 as monotherapy and BLU-945 in combination with osimertinib
timeFrame: Up to 42 months
measure: [Phase 2] Rate and severity of adverse events of BLU-945 as monotherapy and BLU-945 in combination with osimertinib
timeFrame: Up to 42 months
measure: [Phase 2] QTc Assessment
timeFrame: Up to 25 months
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute
state: California
city: Orange
country: United States
facility: UC Irvine Health, Chao Family Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)
state: Colorado
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: NYU Langone Health, Laura and Isaac Perlmutter Cancer Center
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Toulouse
country: France
facility: Institut Claudius Regaud (IUCT-O) - Cancer Comprehensive Center
city: Villejuif
country: France
facility: Institut Gustave Roussy - DITEP
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Yokohama-shi
country: Japan
facility: Kanagawa Cancer Center
state: Kanagawa
city: Chuo Ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Seoul National University, Department of Internal Medicine
city: Seoul
country: Korea, Republic of
facility: Yonsei Cancer Center, Severance Hospital, Yonsei University
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center, Department of Oncology
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute - Antoni van Leeuwenhoek
city: Singapore
country: Singapore
facility: National Cancer Centre Singapore
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital, Oncology Department
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
state: Surrey
Study officials:
References: