Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

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Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

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Lung Diseases

Respiratory Tract Diseases

Thoracic Neoplasms

Respiratory Tract Neoplasms

Bronchial Neoplasms

Carcinoma, Bronchogenic

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Bronchial Diseases

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Osimertinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

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

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

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

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

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

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

BLU-945

Osimertinib tablets for oral administration

osimertinib

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.

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.

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

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

MTD determination: dose limiting toxicity (DLT) rate

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

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

DOR, defined as the time from first documented response of complete response (CR) or partial response (PR) to the date of first documented progressive disease or death due to any cause, whichever occurs first

Profile pharmacodynamic changes in the EGFR pathway biomarker expression levels of dual specificity phosphatase (DUSP6) and sprouty RTK signaling antagonist 4 (SPRY4).

DCR, defined as the proportion of patients who experience a best response of CR, PR, or stable disease (SD) according to RECIST 1.1

CBR, defined as the proportion of patients who experience a confirmed CR or PR, or stable disease (SD) with a duration of at least 16 weeks according to RECIST 1.1

PFS, defined as the time from the first dose of BLU-945 until the date of first documented progressive disease or death due to any cause, whichever occurs first

OS, defined as the time from the first dose of BLU-945 until the date of death due to any cause

CNS-ORR - proportion of patients with measurable (target) intracranial metastases at baseline who experience a confirmed intracranial CR or PR according to RECIST 1.1 principles

CNS-DOR - time from first documented intracranial CR or PR to the date of first documented intracranial PD

CNS progression rate - proportion of patients with CNS progression as a component of first disease progression on study

Effects of BLU-945 on ECG parameters extracted from continuous 12 lead Holter recordings

Blueprint Medicines Corporation

Micronutrients

Hematinics

Vitamins

Carboplatin

Pemetrexed

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Folinic Acid

Folate

Vitamin B9

Phase 1 dose escalation of BLU-701 as monotherapy at various dose levels

BLU-701 in combination with osimertinib 40 mg or 80 mg tablets for oral administration

BLU-701 in combination with platinum-based chemotherapy (carboplatin and pemetrexed):

Carboplatin - IV infusion dosed to target AUC of 5-6 mg/mL min q3w

Pemetrexed - IV infusion dosed to 500 mg/m2 q3w

Phase 2 expansion group for BLU-701 as monotherapy at a dose determined during Part 1A in patients harboring the EGFR C797X resistance mutation

BLU-701

carboplatin

pemetrexed

This is a Phase 1/2, open-label, first-in-human (FIH) study is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of BLU-701 as monotherapy or in combination with either osimertinib or platinum-based chemotherapy in patients with EGFRm NSCLC.

The study was planned to include an initial Phase 1 portion to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of BLU-701 as monotherapy (Part 1A; initially in a once daily (QD) regimen with the option to evaluate twice daily (BID) dosing if supported by emerging PK and safety data), as well as additional dose-escalation portions to determine the RP2D of BLU-701 in combination with osimertinib (Part 1B) or in combination with carboplatin and pemetrexed (Part 1C). A Phase 2 part was planned to further evaluate the efficacy and safety of BLU-701 as monotherapy at RP2D (Part 2A). Phase 1 Part 1 A was initiated; however, the study was terminated prior to establishing BLU-701 MTD and/or RP2D.

(HARMONY) Study of BLU-701 in EGFR-mutant NSCLC

A Phase 1/2 Study of the Highly Selective EGFR Inhibitor, BLU-701, in Patients With EGFR-Mutant Non-Small Cell Lung Cancer

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

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

ORR - the proportion of patients who experience a best response of confirmed complete response (CR) or partial response (PR) according to RECIST 1.1

DOR - time from first documented response of CR or PR to the date of first documented progressive disease or death due to any cause, whichever occurs first

maximum plasma drug concentration (Cmax) time to maximum plasma drug concentration (Tmax) time of last quantifiable plasma drug concentration (Tlast) area under the plasma concentration versus time curve from time 0 to the end of the dosing interval (AUC0-24 for QD and AUC0-12 for BID) trough concentration (Ctrough) apparent volume of distribution (Vz/F) terminal elimination half-life (t½) apparent oral clearance(CL/F) accumulation ratio (R)

dual specificity phosphatase (DUSP6)

sprouty RTK signaling antagonist 4 (SPRY4)

DCR - proportion of patients who experience a best response of CR, PR, or SD according to RECIST 1.1

CBR - proportion of patients who experience a confirmed CR or PR, or SD with a duration of at least 16 weeks according to RECIST 1.1

PFS - time from the first dose of BLU-701 until the date of first documented PD or death due to any cause

OS - time from the first dose of BLU-701 until the date of death due to any cause

ECG parameters extracted from continuous 12-lead Holter recordings

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
(SYMPHONY) Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC	NCT04862780	Lung Neoplasms Carcinoma, Non-... Respiratory Tra... Neoplasms Neoplasms by Si... Lung Diseases Respiratory Tra... Carcinoma, Bron... Bronchial Neopl... Adenocarcinoma Carcinoma Neoplasms by Hi... Neoplasms, Nerv... EGFR T790M EGFR C797S EGFR L858R EGFR Gene Mutat... EGF-R Positive ... EGFR Exon 19 De... EGFR Mutation R... EGFR Activating... Protein Kinase ... Antineoplastic ... Thoracic Neopla...	BLU-945 osimertinib	18 Years -	Blueprint Medicines Corporation
(HARMONY) Study of BLU-701 in EGFR-mutant NSCLC	NCT05153408	Lung Neoplasm Carcinoma, Non-... Respiratory Tra... Neoplasms Neoplasms by Si... Lung Diseases Respiratory Tra... Carcinoma, Bron... Bronchial Neopl... Adenocarcinoma Carcinoma Neoplasms by Hi... Neoplasms, Nerv... EGFR C797S EGFR C797A EGFR L858R EGFR Exon 19 De... EGFR Gene Mutat... EGF-R Positive ... EGFR Mutation R... EGFR Activating... Thoracic Neopla... Antineoplastic ... Protein Kinase ... EGFR C797G EGFR C797X Non Small Cell ...	BLU-701 osimertinib carboplatin pemetrexed	18 Years -	Blueprint Medicines Corporation
(SYMPHONY) Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC	NCT04862780	Lung Neoplasms Carcinoma, Non-... Respiratory Tra... Neoplasms Neoplasms by Si... Lung Diseases Respiratory Tra... Carcinoma, Bron... Bronchial Neopl... Adenocarcinoma Carcinoma Neoplasms by Hi... Neoplasms, Nerv... EGFR T790M EGFR C797S EGFR L858R EGFR Gene Mutat... EGF-R Positive ... EGFR Exon 19 De... EGFR Mutation R... EGFR Activating... Protein Kinase ... Antineoplastic ... Thoracic Neopla...	BLU-945 osimertinib	18 Years -	Blueprint Medicines Corporation

Spots Global Cancer Trial Database for egfr mutation resulting in tyrosine kinase inhibitor resistance