Abstract CT214: AlfaOmega- a master protocol empowering precision research in colorectal cancer
Authors: Lazzari Luca , Luraghi Paolo , Amirouchene-Angelozzi Nabil , Bertotti Andrea , Medico Enzo , Nicolantonio Federica Di , Fagagna Fabrizio d'Adda di , Abrignani Sergio , Regge Daniele , Sapino Anna , Bonoldi Emanuela , Vanzulli Angelo , Zagonel Vittorina , Braud Filippo de , Trusolino Livio , Bardelli Alberto , Siena Salvatore , Marsoni Silvia 
Published: August 2019

Abstract
Background
The overall survival of mCRC patients has been increased by the availability of new cytotoxic and targeted agents and today potentially by the advent of immunotherapies. However, the impact of these advances has been incremental rather than transformative, and a number of unmet medical needs still await rational solutions. In order to navigate the co-evolutionary pathways of CRC tumors during their natural history and under the Darwinian pressure of therapies, we need to feed the experimental laboratories with “the right sample, at the right time, for the right experiment”. This can be accomplished through the design of master protocols that represent a new subset of observational trials aimed to empower the bi-directional collaboration between pre-clinical and clinical research, an essential prerequisite to feed and implement precision oncology.
Methods
AlfaΩmega (protocol number IFOM-CPO003/2018/PO002) has been designed to streamline the study of the co-evolutionary landscape between tumor and host cells in a stage-mixed cohort of at least 500 CRC patients, with the aim of understanding how their outcomes can be significantly improved. This resource for integrative clinical data and sample collection will allow the molecular story-telling of CRC metastatic spread along time and space and the selection of appropriate patients for experimentally-driven trials.
To achieve the required level of ‘experimental precision’, patients can enter AlfaΩmega at two different ‘therapeutic checkpoints’: i) prior to a surgical event or ii) prior to a systemic treatment. Moreover, to optimize the enrollment of patients, the longitudinal collection of data/samples and their logistic management, AlfaΩmega has been designed as a flexible infrastructure organized in TIERs, each of which represents a building block for the stepwise comprehension of the biological processes that drive tumor evolution and that will have an independent informed consensus process:
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TIER1, Monitoring: the ability to follow CRC evolution under standard of care treatments and to define new evolution-linked biomarkers: access to clinical & imaging data, FFPE, plasma and PBMCs. TIER1 informed consent is mandatory for the enrolment.
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TIER2, Modelling: the ability to develop pertinent experimental models to study evolutionary mechanisms and define evolution-targeting therapeutic strategies: access to fresh tissue, blood, stools, buccal swabs and other fluids. Sample collection in TIER2 is discretionary, i.e. may not be applied to all patients entering TIER1.
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TIER3, Linking: the ability to access data and samples of patients enrolled in proof-of-concept trials to prove the efficacy and study/understand resistance mechanisms of evolution-targeting therapies: linking with AlfaΩmega logistic backbone and IT architecture.
Citation Format: Luca Lazzari, Paolo Luraghi, Nabil Amirouchene-Angelozzi, Andrea Bertotti, Enzo Medico, Federica Di Nicolantonio, Fabrizio d'Adda di Fagagna, Sergio Abrignani, Daniele Regge, Anna Sapino, Emanuela Bonoldi, Angelo Vanzulli, Vittorina Zagonel, Filippo de Braud, Livio Trusolino, Alberto Bardelli, Salvatore Siena, Silvia Marsoni. AlfaOmega- a master protocol empowering precision research in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT214.