230TiP - Exploring mechanisms of action and resistance in innovate cancer therapies: The UNLOCK program

Background

In recent years, cancer research has improved knowledge of tumor biology and immunology, leading to the development of new therapeutic approaches. However, the mechanisms of action (MoA) and resistance (MoR) to these novel drugs remain poorly understood and it is essential to develop research strategies targeting this area. Phase I/II trials allow to conduct molecular and biological analyses of treatment response alongside primary trial endpoints, aiming to redefine new drug combinations to overcome resistance. UNLOCK is a research academic program designed to better understand MoA and MoR to highly innovative drugs, through the integration of clinical, translational, and fundamental research.

Trial design

This is a prospective, single-center, ongoing study that use high-throughput sequencing on baseline, on-treatment, and resistant biopsies (bx) of metastatic patients (pts), in the context of phase 1 (NCT04932525) or dedicated phase 2 trials. It is planned to enroll 100 pts per year over next 5 years. Eligible pts are ≥ 18 years old, have histologically confirmed malignant tumor and are included in first-in-human (FIH) and first-in-class (FIC) clinical trials, currently ongoing at the Drug Development Department (DITEP) at Gustave Roussy. Innovative therapies including epigenetic modifiers, Bi-specific T-cell engagers (BITE), radioligands, antibody-drug conjugates, next generation tyrosine kinase inhibitors, fall within the program´s scope and will be updated twice a year. Enrolled pts benefit from systematic liquid and tumor bx as shown in the table. Table: 230TiP

Unlock program working sequence over treatment (T)

WES and RNA-seq in pre- and post-treatment samples are performed to detect resistance alterations. MOA are studied using scRNA-seq or spatial transcriptomics on pre- and on treatment tumor bx. Molecular results obtained will be compared with blood assays. Concurrently, preclinical models will be developed from tumor bx to validate clinical findings.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Institut Gustave Roussy.

Funding

Has not received any funding.

Disclosure

B. Alonso de Castro: Financial Interests, Personal, Research Grant: SEOM Fellowship. F. André: Financial Interests, Personal, Advisory Board: Lilly France; Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo, Roche, Lilly, Pfizer, Owkin, Novartis, Guardant Health, N-Power Medicine, Servier, Gilead, Boston Pharmaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi Sankyo, Guardant Health, Owkin. S. Ponce Aix: Financial Interests, Institutional, Advisory Board: Roche, MSD, AstraZeneca, Bristol Myers Squibb, PharmaMar, Boehringer Ingelheim, BMS; Financial Interests, Personal, Speaker’s Bureau: Roche. C.P. Massard: Other, Christophe Massard: Consultant/Advisory fees from Amgen, Astellas, AstraZeneca, Bayer Ipsen, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, Netcancer, PegascyPrincipal/sub-Investigator of Clinical Trials for AbbVie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, BeiGene, Blueprint, BMS, Boehringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, PharmaMar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor: Company. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Coordinating PI: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. Y. Loriot: Financial Interests, Personal, Advisory Board: Merck Kga, Pfizer, Gilead, Seattle Genetics, Tahio; Financial Interests, Personal, Other, lectures, advisory boards: MSD, AstraZeneca, Astellas, Janssen; Financial Interests, Personal, Other, lectures, advisory boards: Roche, BMS; Financial Interests, Institutional, Research Grant: Janssen, Sanofi, MSD, Roche, Celsius; Financial Interests, Institutional, Steering Committee Member: Janssen; Financial Interests, Steering Committee Member: MSD, Astellas, Gilead/Immunomedics, Tahio; Financial Interests, Personal, Steering Committee Member: Basilea; Financial Interests, Institutional, Local PI: Pfizer, MSD, Janssen, Exelixis, AstraZeneca, Pfizer, Merck Kga, BMS, Astellas, Gilead, Incyte; Financial Interests, Institutional, Coordinating PI: Janssen; Non-Financial Interests, Member: ESMO, ASCO, AACR; Non-Financial Interests, Other, scientific committee: ARC. L. Friboulet: Financial Interests, Institutional, Coordinating PI: Debiopharm, Incyte; Non-Financial Interests, Institutional, Coordinating PI: Illumina, Relay Therapeutic, Nuvalent, Sanofi, Guardant Health. All other authors have declared no conflicts of interest.