Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Symptoms and General Pathology

Nervous System Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Adenocarcinoma

Neoplasm Metastasis

Lung Diseases

Respiratory Tract Diseases

Thoracic Neoplasms

Respiratory Tract Neoplasms

Bronchial Neoplasms

Carcinoma, Bronchogenic

Neoplasms by Histologic Type

Brain Neoplasms

Neoplasms, Glandular and Epithelial

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Bronchial Diseases

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Hematinics

Amino Acids

Vitamins

Carboplatin

Pemetrexed

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Mobocertinib

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Tyrosine

Folinic Acid

Folate

Vitamin B9

BLU-451 monotherapy with dose escalation in participants with metastatic cancer with EGFR Ex20ins or other selected EGFR mutations that have progressed after prior systemic therapies.

BLU-451 with dose escalation in combination with carboplatin and pemetrexed in participants with metastatic NSCLC with common EGFR mutations. This arm will enroll participants only in the United States.

EGFR Ex20ins participants who have previously received platinum-based chemotherapy and either amivantamab or mobocertinib will receive BLU-451.

EGFR Ex20ins participants who have previously received platinum-based chemotherapy but have not received a prior EGFR Ex20ins-targeted agent will receive BLU-451.

EGFR Ex20ins participants with at least one measurable lesion in brain per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 who have previously received platinum-based chemotherapy will receive BLU-451. Previous treatment with EGFR Ex20Ins-targeted therapies is allowed but not required.

Participants with EGFR Ex20ins who have previously received platinum-based chemotherapy and both amivantamab AND mobocertinib, OR received any investigational Ex20Ins targeted agent(s) will receive BLU-451. Participants with Ex20ins or atypical mutations enrolled in other cohorts and who have other oncogenic drivers by central testing at baseline will be moved to this arm.

Participants with EGFR Ex20ins who have not received prior systemic therapy in metastatic setting will receive BLU-451.

Participants with EGFR atypical mutations (e.g., G719X, L861Q) who have previously received at least one EGFR tyrosine kinase inhibitor (TKI) will receive BLU-451. Participants with with other atypical EGFR mutations, such as S768I, may be enrolled if approved by Sponsor Medical Monitor.

Participants with EGFR atypical mutations (e.g., G719X, L861Q) who have not received prior systemic therapy in metastatic setting will receive BLU-451. Participants with with other atypical EGFR mutations, such as S768I, may be enrolled if approved by Sponsor Medical Monitor.

BLU-451 will be administered orally by tablet QD or BID on a 21-day treatment cycle

BLU-451

Carboplatin will be administered intravenously (IV) on Day 1 of each cycle (every 3 weeks) for 4 to 6 cycles

Pemetrexed will be administered prior to carboplatin as an IV infusion on Day 1 of each cycle (every 3 weeks)

This is a Phase 1/2, open-label first-in-human study of the safety, pharmacokinetics (PK), pharmacodynamics, and anti-tumor activity of BLU-451 monotherapy and BLU-451 in combination with platinum-based chemotherapy (carboplatin and pemetrexed). All participants will receive BLU-451 on a 21-day treatment cycle.

The study is a Phase 1/2 Study of BLU-451 in Advanced Cancers with Epidermal growth factor receptor (EGFR) Exon 20 Insertion Mutations (Ex20ins). The study has two phases:

An initial Phase 1 portion will enroll participants with metastatic cancer with EGFR Ex20ins or other selected EGFR mutations that have progressed after prior systemic therapies and will determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of BLU-451.

Part 1B dose-escalation will enroll participants with metastatic Non-small Cell Lung Cancer (NSCLC) in the USA only to determine the MTD and/or RP2D of BLU-451 in combination with carboplatin and pemetrexed.

A Phase 2 portion will further evaluate the efficacy and safety of BLU-451 as monotherapy at RP2D in participants with NSCLC.

The primary objectives of this study are in Phase 1 to identify the MTD and/or RP2D of BLU-451, and in Phase 2, to evaluate the anti-tumor activity of BLU-451.

(Concerto) Study of BLU-451 in Advanced Cancers With EGFR Exon 20 Insertion Mutations

Phase I/II Study of BLU-451 in Advanced Cancers With EGFR Exon 20 Insertion Mutations

MTD determination: Dose-limiting toxicities (DLTs) rate

RP2D determination: DLT, PK, PD, and preliminary safety data

ORR is defined as the proportion of subjects with objective response of CR or PR as determined by the Investigator using RECIST v1.1.

DOR is defined as the time from the first objective response (CR or PR) to documented PD per RECIST v1.1 or death within 30 days of last dose of BLU-451 from any cause.

DCR is defined as best response of CR, PR, non-CR/non-PD (for subjects who have only non-target lesions), or SD per RECIST v1.1.

CBR is defined as confirmed response of CR or PR, or stable disease with a duration of at least 16 weeks from the first dose date.

PFS is defined as the time from the first BLU-451 dose until the date of death or the date of progression of disease or death, respectively.

OS is defined as the time from the first BLU-451 dose until the date of death or the date of progression of disease or death, respectively.

CNS ORR: Defined as the proportion of patients achieving confirmed intra-cranial CR or PR as determined by the RECIST v1.1.

CNS DOR: Defined as the the time from the first objective intra-cranial response (CR or PR) to documented PD in patients with measurable baseline brain metastases

CNS PFS: Defined as the time from the first BLU-451 dose until the date of death or the date of intra-cranial progression of disease or death, respectively in patients with measurable baseline brain metastases

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

Blueprint Medicines Corporation

Anticoagulants

Edetic Acid

Pentetic Acid

Patients presenting advanced NSCLC with EGFR ins20 already treated with amivantamab as monotherapy in France under Temporary Use Authorisation or Early Access Program who will accept to provide blood samples at disease progression.

Blood samples (2\*10 mL on ethylenediaminetetraacetic acid (EDTA)) will be taken at time of disease progression and will be sent for central liquid biopsy ctDNA analysis.

Blood sampling

Laurent GRELLIER

Soizic Ferlandin

Camille MAZZA

Renaud DESCOURT, PhD

Jean-Bernard AULIAC

Isabelle MONNET

Loick GALLAND

Anne Claire TOFFART

Olivier MOLINIER

Pascale Tomasini

Josiane OTTO

Elisa Gobbini

Marie WISLEZ

Antony CANELLAS

Also RENAULT

Michel ANDRE

Florian GUISIER

Diane MOREAU

Sophie BAYLE-BLEUEZ

Gonzague DE CHABOT

Jean-Marc DOT

Maude Dupé-Pelletier

The goal of this prospective, interventional study is to evaluate the mechanisms of acquired resistance to amivantamab monotherapy in patients with advanced NSCLC with EGFR ins20. The main question it aims to answer is:

What are the mechanisms of acquired resistance to amivantamab monotherapy in this population of patients ? How anticipate the efficacy of subsequent systemic therapies ?

After this information session, the participant will be asked to sign the study informed consent. A blood samples (2\*10 mL on ethylenediaminetetraacetic acid (EDTA)) will be taken at time of disease progression and will be sent for central liquid biopsy ctDNA analysis. If available, tumor tissue will also be sent for DNA NGS analysis.

RESAMEX is a prospective study evaluating the mechanisms of acquired resistance to amivantamab monotherapy in patients with advanced NSCLC with EGFR ins20. Biological analysis will be performed on circulating tumor deoxyribonucleic acid (ctDNA) at the time of disease progression and on tumor tissue at the time of disease progression when available.

* ctDNA : The extraction of the ctDNA will be performed in an automated way with the Promega RSC LV cfDNA kit on Maxwell platform. Sequencing will be performed on NextSeq500 platform with a panel of 208 genes (including 190 genes with full coverage of coding regions, and 11 genes with coverage of introns involved in translocations) covering 800 kpb and at a target depth of 8000 X.
* Tissue : Deoxyribonucleic acid (DNA) next generation sequencing (NGS) will be performed on tumor biopsy (10 slides of 5 microns) .

Samples will be sent for centralized analysis to Centre de Recherche en Cancérologie de Marseille (CRCM), 27 Bd Lei Roure, 13009 Marseille (Prof. Tomasini and Gwenaël Lumet), and will be stored at Centre de Ressources Biologiques de l'Assistance Publique Hôpitaux de Marseille (CRB AP-HM), 264 Rue Saint-Pierre, 13005 Marseille.

Mechanisms of Resistance to Amivantamab in Patients With NSCLC With EGFR Exon 20 Insertion

Percentage of molecular alterations found at the time of disease progression on amivantamab monotherapy in patients with advanced NSCLC with EGFR ins20.

Progression free survival with the first subsequent therapy after amivatamab, defined as the time from first dose to first documentation of objective disease progression according to Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 or to death from any cause.

Groupe Francais De Pneumo-Cancerologie

Mitogens

Aflutinib

This arm plans to enroll 20 subjects, treating with furmonertinib 160mg/d, until disease recurrence, death or intolerability. The maximum duration of treatment is three years.

Furmonertinib

Juan Li, MD

This is a phase II, prospective, multi-centre study. To assess the efficacy and safety of furmonertinib in patients with epidermal growth factor receptor 20ins mutation positive stage IB-IIIA Non-small Cell Lung Carcinoma, following complete tumour resection with or without adjuvant chemotherapy.

The study plans to enroll 20 subjects, treating with furmonertinib 160mg/d, until disease recurrence, death or intolerability. The maximum duration of treatment is three years.

The primary endpoint is DFS. The secondary endpoint include DFS rate , OS and the change of HRQoL.

In addition, the peripheral blood ctDNA will be collected and analyzed in this study

To Assess the Efficacy and Safety of Furmonertinib in Patients With Epidermal Growth Factor Receptor 20ins Mutation Positive Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy

A Phase II, Prospective, Multi-centre, Study to Assess the Efficacy and Safety of Furmonertinib in Patients With Epidermal Growth Factor Receptor 20ins Mutation Positive Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy

Disease free survival (DFS) rate at 2, 3 and 5 years

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
(Concerto) Study of BLU-451 in Advanced Cancers With EGFR Exon 20 Insertion Mutations	NCT05241873	Lung Neoplasm M... Carcinoma, Non-... Respiratory Tra... Neoplasms Neoplasms by Si... Lung Diseases Respiratory Tra... Carcinoma, Bron... Bronchial Neopl... Adenocarcinoma Carcinoma Neoplasms by Hi... EGFR Exon 20 Mu... EGFR Exon 20 In... EGFR Activating... Antineoplastic ... Metastatic Lung... Brain Metastase... EGFR-mutated NS... EGFR Atypical M...	BLU-451 Carboplatin Pemetrexed	18 Years -	Blueprint Medicines Corporation
Mechanisms of Resistance to Amivantamab in Patients With NSCLC With EGFR Exon 20 Insertion	NCT06247826	Non-small Cell ... EGFR Exon 20 In...	Blood sampling	18 Years -	Groupe Francais De Pneumo-Cancerologie
To Assess the Efficacy and Safety of Furmonertinib in Patients With Epidermal Growth Factor Receptor 20ins Mutation Positive Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy	NCT06192849	Non Small Cell ... EGFR Exon 20 In...	Furmonertinib	18 Years -	Sichuan Cancer Hospital and Research Institute
To Assess the Efficacy and Safety of Furmonertinib in Patients With Epidermal Growth Factor Receptor 20ins Mutation Positive Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy	NCT06192849	Non Small Cell ... EGFR Exon 20 In...	Furmonertinib	18 Years -	Sichuan Cancer Hospital and Research Institute

Spots Global Cancer Trial Database for egfr exon 20 insertion mutation