(SYMPHONY) Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC

NCT04862780 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: BLU-945-1101
• Study Type: interventional
• Target: 177
• Locations: 10 countries
• Sites: 26

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.

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

Outcome Measures

Primary Outcomes (4)

• [Phase 1] Determine the maximum tolerated dose (MTD) of BLU-945 as monotherapy and BLU-945 in combination with osimertinib

  MTD determination: dose limiting toxicity (DLT) rate

  Up to 12 months

• [Phase 1] Rate and severity of adverse events of BLU-945 as monotherapy and BLU-945 in combination with osimertinib

  Up to 12 months

• [Phase 1] Determine recommended Phase 2 dose (RP2D) of BLU-945 as monotherapy and BLU-945 in combination with osimertinib

  RP2D determination: DLT, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary safety and anticancer activity data

  Up to 12 months

• [Phase 2] Overall response rate (ORR) of BLU-945 as monotherapy and BLU-945 in combination with osimertinib

  ORR, defined as the proportion of patients who experience a best response of confirmed CR or PR according to RECIST 1.1

  Up to 30 months

Secondary Outcomes (21)

• [Phase 1 and Phase 2] Cmax

  Up to 42 months

• [Phase 1 and Phase 2] Tmax

  Up to 42 months

• [Phase 1 and Phase 2] Tlast

  Up to 42 months

• [Phase 1 and Phase 2] AUC (0-24)

  Up to 42 months

• [Phase 1 and Phase 2] Ctrough

  Up to 42 months

Study Arms (6)

Part 1A: BLU-945 as monotherapy

EXPERIMENTAL

Phase 1 dose escalation of BLU-945 as monotherapy at various dose levels

Drug: BLU-945

Part 1B: BLU-945 with osimertinib

EXPERIMENTAL

Phase 1 dose escalation of BLU-945 in combination with osimertinib 80 mg tablets for oral administration

Drug: BLU-945; Drug: osimertinib

Phase 2, Group 1: BLU-945 as monotherapy

EXPERIMENTAL

Phase 2 expansion group for BLU-945 as monotherapy at a dose determined during Part 1A in patients with EGFR T790M and C797S mutations

Drug: BLU-945

Phase 2, Group 2: BLU-945 as monotherapy

EXPERIMENTAL

Phase 2 expansion group for BLU-945 as monotherapy at a dose determined during Part 1A in patients with EGFR T790M mutations

Drug: BLU-945

Phase 2, Group 3: BLU-945 as monotherapy

EXPERIMENTAL

Phase 2 expansion group for BLU-945 as monotherapy at a dose determined during Part 1A in patients with EGFR C797S mutations

Drug: BLU-945

Phase 2, Group 4: BLU-945 with osimertinib

EXPERIMENTAL

Phase 2 expansion group for BLU-945 with osimertinib at a dose determined during Part 1B in patients

Drug: BLU-945; Drug: osimertinib

Interventions

BLU-945 DRUG

Oral administration

Part 1A: BLU-945 as monotherapy; Part 1B: BLU-945 with osimertinib; Phase 2, Group 1: BLU-945 as monotherapy; Phase 2, Group 2: BLU-945 as monotherapy; Phase 2, Group 3: BLU-945 as monotherapy; Phase 2, Group 4: BLU-945 with osimertinib

osimertinib DRUG

Osimertinib tablets for oral administration

Also known as: Tagrisso

Part 1B: BLU-945 with osimertinib; Phase 2, Group 4: BLU-945 with osimertinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥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, and were able to tolerate prior osimertinib 80 mg QD dose.
• 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.
• Dose Escalation (Phase 1 Part 1A and Part 1B): At each dose level, slots may be reserved for patients with the mutations of interest.
• 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).
• 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 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.
• 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

You may not qualify if:

• 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:
• EGFR-targeted TKI within 7 days prior to the first dose of study drug.
• 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).
• 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.
• 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):
• Absolute neutrophil count (ANC) \<1.0×109/L.
• Platelet count \<75×109/L.
• 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).
• 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.
• Total bilirubin \>1.5× ULN; \>3× ULN in presence of Gilbert's disease.
• Estimated (Cockroft-Gault formula) or measured creatinine clearance \<40 mL/min.

Sponsors & Collaborators

• Blueprint Medicines Corporation: lead

Study Sites (26)

UC San Diego Moores Cancer Center

La Jolla, California, 92093, United States

Location

Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute

Los Angeles, California, 90048, United States

Location

UC Irvine Health, Chao Family Comprehensive Cancer Center

Orange, California, 92868, United States

Location

University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)

Aurora, Colorado, 80045, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

NYU Langone Health, Laura and Isaac Perlmutter Cancer Center

New York, New York, 10016, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

Institut Claudius Regaud (IUCT-O) - Cancer Comprehensive Center

Toulouse, 31059, France

Location

Institut Gustave Roussy - DITEP

Villejuif, 94805, France

Location

National Cancer Center Hospital East

Kashiwa, Chiba, 277-8577, Japan

Location

Kanagawa Cancer Center

Yokohama, Kanagawa, 241-8515, Japan

Location

National Cancer Center Hospital

Chuo Ku, Tokyo, 104-0045, Japan

Location

The Netherlands Cancer Institute - Antoni van Leeuwenhoek

Amsterdam, 1066 CX, Netherlands

Location

National Cancer Centre Singapore

Singapore, 169610, Singapore

Location

Seoul National University, Department of Internal Medicine

Seoul, 03080, South Korea

Location

Yonsei Cancer Center, Severance Hospital, Yonsei University

Seoul, 03722, South Korea

Location

Asan Medical Center, Department of Oncology

Seoul, 05505, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

The Catholic University of Korea, Seoul St. Mary's Hospital

Seoul, 06591, South Korea

Location

Vall d'Hebron University Hospital, Oncology Department

Barcelona, 08035, Spain

Location

National Taiwan University Hospital

Taipei, 10002, Taiwan

Location

The Royal Marsden NHS Foundation Trust

Sutton, Surrey, SM2 5PT, United Kingdom

Location

MeSH Terms

Conditions

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Thoracic Neoplasms

Interventions

osimertinib

Condition Hierarchy (Ancestors)

Bronchial Diseases; Neoplasms, Glandular and Epithelial

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 21, 2021
• First Posted: April 28, 2021
• Study Start: June 29, 2021
• Primary Completion: October 7, 2024
• Study Completion: October 7, 2024
• Last Updated: February 10, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (10); ES (1); JP (3); KR (5); TW (1); NL (1); GB (1); CA (1); SG (1); FR (2)