Abstract 815TiP
Background
Clinical outcomes for patients with rare subtypes of advanced/relapsed gynaecological cancers including clear cell, carcinosarcomas and cervical cancer, are exceptionally poor with limited effective treatment options. Loss of function mutations in the tumour suppressor gene ARID1A have been reported in rarer gynaecological cancers including clear cell subtypes, although the clinical significance of ARID1A alterations remains unclear. Preclinical data demonstrate cancers with ARID1A gene defects (ARID1A-loss) display increased sensitivity to ATR inhibitor therapy. Cancers without ARID1A mutations (ARID1A no-loss) are sensitive to treatment with ATR inhibitors in combination with PARP inhibitors.
Trial design
ATARI (ENGOT/GYN1/NCRI) is a multi-centre, international, proof of concept, phase II, parallel cohort trial assessing ceralasertib activity (ATR inhibitor) as single agent and in combination with olaparib (PARP inhibitor) in ARID1A stratified gynaecological cancers. Patients with relapsed ovarian or endometrial clear cell carcinoma with ARID1A loss receive single agent ceralasertib (Cohort 1A). If no observed clinical activity, combination therapy will be tested in this patient group (Cohort 1B). Patients with relapsed ovarian or endometrial clear cell carcinoma with no ARID1A loss (Cohort 2) or patients with cancers of other histological subtypes (endometrioid, carcinosarcoma, cervical) (Cohort 3) receive combination therapy (olaparib/ceralasertib). Each cohort has a Simon 2-stage design (p0=0.1, p1=0.3, alpha=5%, power=80%), recruiting independently ten patients/cohort at Stage 1 and, depending on response rate, a further 19 patients/cohort may enter the corresponding Stage 2. Histological sub-type and ARID1A status are confirmed for all patients at registration, prior to trial entry. Treatment continues until disease progression. Primary endpoint is best overall objective response rate (RECIST v1.1). Exploratory translational biomarker analysis is incorporated. ATARI is open to recruitment in the UK and France. Canadian participation is also intended. 64 patients registered with 36 progressing to trial entry to date (28.04.2021).
Clinical trial identification
NCT04065269.
Editorial acknowledgement
Legal entity responsible for the study
The Institute of Cancer Research: Royal Cancer Hospital.
Funding
AstraZeneca UK Limited.
Disclosure
S. Banerjee: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Invited Speaker: Clovis; Financial Interests, Personal, Advisory Board: Genmab; Financial Interests, Personal, Advisory Board: Immunogen; Financial Interests, Personal, Advisory Board: Mersana; Financial Interests, Personal, Advisory Board: Merck Sereno; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Tesaro; Financial Interests, Personal, Invited Speaker: Tesaro; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Tesaro; Non-Financial Interests, , Principal Investigator, Phase II clinical trial Global lead: Verastem; Non-Financial Interests, Principal Investigator, ATARI phase II international trial (academic sponsored): AstraZeneca; Non-Financial Interests, Advisory Role: Epsilogen; Non-Financial Interests, Other, Member of membership committee: ESGO; Non-Financial Interests, Advisory Role, Medical advisor to UK Ovarian Cancer Charity: Ovacome Charity; Non-Financial Interests, Other, Received research funding from UK based charity I have provided medical advice (non-remunerated): Lady GardenFoundation Charity. A. Leary: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Board, and travel to congress: AstraZeneca; Financial Interests, Institutional, Research Grant: Tesaro; Financial Interests, Personal, Advisory Board, and travel to congress: Tesaro; Financial Interests, Institutional, Research Grant: Clovis; Financial Interests, Personal, Advisory Board, and travel to congress: Clovis; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Biocad; Financial Interests, Institutional, Research Grant: Ability; Financial Interests, Personal, Advisory Board: Ability; Other, Institutional, Advisory Board, with fees to institution: Merck Serono; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Advisory Board: GSK; Financial Interests, Institutional, Other, travel to congress: GSK; Financial Interests, Personal, Advisory Board: Zentalis. C.J. Lord: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Merck KGaA; Financial Interests, Institutional, Research Grant: Artios; Financial Interests, Personal, Other, Consultancy, SAB membership or honoraria : Syncona; Financial Interests, Personal, Other, Consultancy, SAB membership or honoraria: Sun Pharma; Financial Interests, Personal, Other, Consultancy, SAB membership or honoraria: Gerson Lehrman Group; Financial Interests, Personal, Other, Consultancy, SAB membership or honoraria: Merck KGaA; Financial Interests, Personal, Other, Consultancy, SAB membership or honoraria: Vertex; Financial Interests, Personal, Other, Consultancy, SAB membership or honoraria: AstraZeneca; Financial Interests, Personal, Other, Consultancy, SAB membership or honoraria: Tango; Financial Interests, Personal, Other, Consultancy, SAB membership or honoraria : 3rd Rock; Financial Interests, Personal, Other, Consultancy, SAB membership or honoraria: Ono Pharma; Financial Interests, Personal, Other, Consultancy, SAB membership or honoraria: Artios; Financial Interests, Personal, Other, Consultancy, SAB membership or honoraria: Abingworth; Financial Interests, Personal, Stocks/Shares: Tango; Financial Interests, Personal, Stocks/Shares: Ovibio. J. Bliss: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant: Puma Biotechnology; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: Janssen-Cilag; Financial Interests, Institutional, Research Grant: Clovis Oncology. All other authors have declared no conflicts of interest.