Trial Title:
(SYMPHONY) Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC
NCT ID:
NCT04862780
Condition:
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
Conditions: Official terms:
Carcinoma
Lung Neoplasms
Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasms by Site
Neoplasms by Histologic Type
Thoracic Neoplasms
Respiratory Tract Neoplasms
Bronchial Neoplasms
Carcinoma, Bronchogenic
Neoplasms, Nerve Tissue
Lung Diseases
Respiratory Tract Diseases
Osimertinib
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Active, not recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
BLU-945
Description:
Oral administration
Arm group label:
Part 1A: BLU-945 as monotherapy
Arm group label:
Part 1B: BLU-945 with osimertinib
Arm group label:
Phase 2, Group 1: BLU-945 as monotherapy
Arm group label:
Phase 2, Group 2: BLU-945 as monotherapy
Arm group label:
Phase 2, Group 3: BLU-945 as monotherapy
Arm group label:
Phase 2, Group 4: BLU-945 with osimertinib
Intervention type:
Drug
Intervention name:
osimertinib
Description:
Osimertinib tablets for oral administration
Arm group label:
Part 1B: BLU-945 with osimertinib
Arm group label:
Phase 2, Group 4: BLU-945 with osimertinib
Other name:
Tagrisso
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.
Criteria for 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).
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
UC San Diego Moores Cancer Center
Address:
City:
La Jolla
Zip:
92093
Country:
United States
Facility:
Name:
Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute
Address:
City:
Los Angeles
Zip:
90048
Country:
United States
Facility:
Name:
UC Irvine Health, Chao Family Comprehensive Cancer Center
Address:
City:
Orange
Zip:
92868
Country:
United States
Facility:
Name:
University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)
Address:
City:
Aurora
Zip:
80045
Country:
United States
Facility:
Name:
Massachusetts General Hospital
Address:
City:
Boston
Zip:
02114
Country:
United States
Facility:
Name:
Dana-Farber Cancer Institute
Address:
City:
Boston
Zip:
02215
Country:
United States
Facility:
Name:
NYU Langone Health, Laura and Isaac Perlmutter Cancer Center
Address:
City:
New York
Zip:
10016
Country:
United States
Facility:
Name:
Icahn School of Medicine at Mount Sinai
Address:
City:
New York
Zip:
10029
Country:
United States
Facility:
Name:
Sarah Cannon Research Institute
Address:
City:
Nashville
Zip:
37203
Country:
United States
Facility:
Name:
The University of Texas MD Anderson Cancer Center
Address:
City:
Houston
Zip:
77030
Country:
United States
Facility:
Name:
Princess Margaret Cancer Centre
Address:
City:
Toronto
Zip:
M5G 2M9
Country:
Canada
Facility:
Name:
Institut Claudius Regaud (IUCT-O) - Cancer Comprehensive Center
Address:
City:
Toulouse
Zip:
31059
Country:
France
Facility:
Name:
Institut Gustave Roussy - DITEP
Address:
City:
Villejuif
Zip:
94805
Country:
France
Facility:
Name:
National Cancer Center Hospital East
Address:
City:
Kashiwa
Zip:
277-8577
Country:
Japan
Facility:
Name:
Kanagawa Cancer Center
Address:
City:
Yokohama-shi
Zip:
241-8515
Country:
Japan
Facility:
Name:
National Cancer Center Hospital
Address:
City:
Chuo Ku
Zip:
104-0045
Country:
Japan
Facility:
Name:
Seoul National University, Department of Internal Medicine
Address:
City:
Seoul
Zip:
03080
Country:
Korea, Republic of
Facility:
Name:
Yonsei Cancer Center, Severance Hospital, Yonsei University
Address:
City:
Seoul
Zip:
03722
Country:
Korea, Republic of
Facility:
Name:
Asan Medical Center, Department of Oncology
Address:
City:
Seoul
Zip:
05505
Country:
Korea, Republic of
Facility:
Name:
Samsung Medical Center
Address:
City:
Seoul
Zip:
06351
Country:
Korea, Republic of
Facility:
Name:
The Catholic University of Korea, Seoul St. Mary's Hospital
Address:
City:
Seoul
Zip:
06591
Country:
Korea, Republic of
Facility:
Name:
The Netherlands Cancer Institute - Antoni van Leeuwenhoek
Address:
City:
Amsterdam
Zip:
1066 CX
Country:
Netherlands
Facility:
Name:
National Cancer Centre Singapore
Address:
City:
Singapore
Zip:
169610
Country:
Singapore
Facility:
Name:
Vall d'Hebron University Hospital, Oncology Department
Address:
City:
Barcelona
Zip:
08035
Country:
Spain
Facility:
Name:
National Taiwan University Hospital
Address:
City:
Taipei
Zip:
10002
Country:
Taiwan
Facility:
Name:
The Royal Marsden NHS Foundation Trust
Address:
City:
Sutton
Zip:
SM2 5PT
Country:
United Kingdom
Start date:
June 29, 2021
Completion date:
January 31, 2025
Lead sponsor:
Agency:
Blueprint Medicines Corporation
Agency class:
Industry
Source:
Blueprint Medicines Corporation
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT04862780
