414TiP - Agnostos precision medicine project in patients (PTS) with cancer of unknown primary (CUP)

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Clinical research
Basic Scientific Principles
Presenter Elena Geuna
Citation Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368
Authors E. Geuna1, S. Benvenuti2, F. Verginelli2, D. Galizia1, S. Siena3, G.M. Stella4, A. Gentile2, M. Milan2, A.R. Virzi'2, A. D'ambrosio2, P. Cassoni5, R. Senetta6, A. Balsamo7, M. Spione7, A. Nuzzo8, A. Sapino6, S. Marsoni7, C. Boccaccio2, P.M. Comoglio9, F. Montemurro1
  • 1Investigative Clinical Oncology, IRCCS Istituto di Candiolo, 10060 - Candiolo/IT
  • 2Molecular Therapeutics And Exploratory Research, Istituto di Candiolo-IRCCS-Fondazione Piemontese per la Ricerca sul Cancro-Onlus, 10060 - Candiolo/IT
  • 3Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda and Università degli Studi di Milano, 20162 - Milano/IT
  • 4Pneumologia, Ospedale San Matteo, 27100 - Pavia/IT
  • 5Anatomia Patologica, Città della Saluta e della Scienza - Torino, 10126 - Torino/IT
  • 6Anatomia Patologica, IRCCS Istituto di Candiolo, 10060 - Candiolo/IT
  • 7Clinical Trials Unit - Clinical Research Office, Istituto di Candiolo-IRCCS-Fondazione Piemontese per la Ricerca sul Cancro-Onlus, 10060 - Candiolo/IT
  • 8Clinical Trials Unit - Clinical Research Office, IRCCS Istituto di Candiolo, 10060 - Candiolo/IT
  • 9Sci. Director, Istituto di Candiolo-IRCCS-Fondazione Piemontese per la Ricerca sul Cancro-Onlus, 10060 - Candiolo/IT

Abstract

Background

CUP identifies a heterogeneous clinical and pathological syndrome characterized by absence of an identifiable site-specific tumor of origin, early metastatic dissemination and undifferentiated phenotype. Representing 3-5% of all cancers, CUPs are still an unsolved clinical problem, with elusive biology and paucity of effective therapies. No validated actionable targets and no preferred regimen have emerged so far. With 25-30% response rate (RR) and overall survival (OS) from 6 to 16 months, the current approach is largely suboptimal. The AGNOSTOS project represents a unique clinical and translational initiative aiming to improve the outlook of CUP pts through evaluation of novel chemotherapeutic regimens (AGNOSTOS TRIAL_1) and a better understanding of the complex CUP biology (AGNOSTOS TRASLATIONAL COMPANION STUDY_2).

Trial design

AGNOSTOS_1 is a randomized phase II trial with a ‘Pick the Winner’ design that will assess efficacy of NabPaclitaxel (NabP) in combination with either Carboplatin (C) or Gemcitabine (G) in treatment-naive CUP pts (EudraCT 2014-005018-47). We plan to enroll 132 pts based on a Simon's two-stage design. Inclusion criteria include measurable disease and adequate archived biopsy tissue for immunohistochemical and molecular profiles. Patients will receive NabP 125 mg/m2 plus G 1000 mg/m2 or C AUC 2 on day 1 and 8 by, every 21 days. Tumor response will be assessed every 9 weeks. Primary endpoint is RR while secondary endpoints are time to progression and OS. Furthermore, AGNOSTOS_2 will perform an in-depth molecular characterization of the enrolled CUPs. Vital tissues and liquid biopsies will be collected to derive patient-derived xenografts (PDX) and circulating cancer stem cells, respectively. The comprehensive genetic analysis (by next generation sequencing) aims to pinpoint common denominators of the hypermetastatic phenotype and its molecular link with cancer stemness. Currently we have enrolled 6 pts in AGNOSTOS_1 and 31 in AGNOSTOS_2 (with 8 PDX attempted).

Clinical trial identification

Clinical trial information: NCT02607202

Legal entity responsible for the study

IRCCS Candiolo (ITALY)

Funding

AIRC 5 x 1000; Celgene

Disclosure

S. Siena: Advisory role for Amgen, Roche, Bayer, Ely Lilly, Sanofi, Merck. S. Marsoni: Research funding: Celgene. F. Montemurro: Speaker's bureau member Astra Zeneca, Roche and Novartis. All other authors have declared no conflicts of interest.