821TiP - Phase I study of ceralasertib (cerala) in combination with AZD5305 in patients (pts) with advanced/metastatic ovarian cancer (OC) previously treated with PARP inhibitors (PARPis)

Background

Combined inhibition of ATR and PARP has been shown to overcome resistance to PARPis in PARPi-resistant cell lines and pt-derived xenograft (PDX) models. Cerala, a selective and potent ATR inhibitor, in combination with olaparib, has demonstrated activity in pts with homologous recombination deficiency-positive, PARPi-resistant OC (CAPRI; NCT03462342). However, in combination with olaparib, the dose and duration of cerala treatment is limited by haematological toxicity. Compared to approved PARPis which target both PARP1 and PARP2, AZD5305 is a highly selective and potent PARP1i which may improve upon the current safety profile of the olaparib and cerala combination. AZD5305 monotherapy was well tolerated in an ongoing phase 1 study of pts with BRCA1/2-, PALB2- or RAD51C/D-mutant advanced breast, prostate, pancreatic or OC (PETRA; NCT04644068); AZD5305 in combination with cerala demonstrated durable tumour regression in BRCA1/2-mutant, PARPi-resistant, breast and OC PDX models. Thus, combining cerala and AZD5305 may provide a better therapeutic index compared with olaparib and cerala.

Trial design

D5330C00004 (NCT02264678) is a modular, phase 1, open-label trial assessing cerala in combination with anti-cancer agents in pts with advanced solid malignancies. Module 5 investigates cerala in combination with AZD5305 in pts with recurrent platinum-sensitive, high-grade, epithelial ovarian, fallopian tube or primary peritoneal cancer (including serous or endometrioid histology), in dose escalation (Part A) and expansion (Part B) cohorts. Key inclusion criteria are age ≥18 years and prior PARPi treatment. Pts in Part B must have a known or suspected BRCA, RAD51C/D or PALB2 mutation. Primary objectives are safety and tolerability of cerala in combination with AZD5305 including the number of adverse events (AEs) and serious AEs, in order to select a recommended phase 2 dose (Part A). Secondary objectives include assessment of antitumour activity, pharmacokinetics and pharmacodynamic biomarkers. Recruitment started in April 2023 and sites across North America, Europe and Asia Pacific will enrol up to 150 pts in total.

Clinical trial identification

NCT02264678; 15 October 2014.

Editorial acknowledgement

Medical writing support for this abstract, under the direction of the authors, was provided by Harriet Gallegos of Ashfield MedComms, an Inizio company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

G.I. Shapiro: Financial Interests, Personal, Advisory Board: Merck KGaA/EMD-Serono, Bicycle Therapeutics, Cybrexa Therapeutics, Bayer, Boehringer Ingelheim, ImmunoMet, Artios, Concarlo Holdings, Syros, Zentalis, CytomX Therapeutics, Blueprint Medicines, Kymera Therapeutics, Janssen, Xinthera; Financial Interests, Institutional, Research Grant: Merck KGaA/EMD-Serono, Tango, Bristol Myers Squibb, Merck & Co; Financial Interests, Institutional, Principal Investigator: Pfizer, Eli Lilly; Non-Financial Interests, Other, Patents-“Dosage regimen for sapacitabine and seliciclib,” also issued to Cyclacel Pharmaceuticals: Cyclacel Pharmaceutical; Non-Financial Interests, Other, “Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition,” together with Liam Cornell: N/A. B. Basu: Financial Interests, Personal, Invited Speaker: Eisai Europe Limited; Financial Interests, Personal, Speaker’s Bureau: Eisai Europe Limited; Financial Interests, Institutional, Advisory Board: GenMab A/S, Eisai Limited, Roche; Financial Interests, Institutional, Research Grant: Varsity Pharmaceuticals, Celgene; Financial Interests, Personal, Other, Conference registration attendance: Roche. A.B. El-Khoueiry: Financial Interests, Institutional, Research Grant, Grant/contract: Astex, Fulgent, AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory board and consulting: Merck, AstraZeneca, Genentech, Senti Bio, Qurient, Servier, Tallac, Exelixis. S. Postel-Vinay: Financial Interests, Institutional, Advisory Board, Steering Committee: Daiichi Sankyo; Financial Interests, Institutional, Local PI, As part of the Drug Development Department (DITEP) SPV is Principal/sub-Investigator of Clinical Trials for AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd., Bayer Healthcare Ag, Bbb Technologies Bv, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd., Forma Tharapeutics, Gamamabs, Genentech, GSK, H3 Biomedicine, F. Hoffmann-La Roche AG, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus: Various drug companies; Financial Interests, Institutional, Research Grant, Translational research funding: IMCore F. Hoffmann-LaRoche; Financial Interests, Institutional, Research Grant, preclinical research funding: AstraZeneca; Non-Financial Interests, Principal Investigator, Principal investigator of phase I/II clinical trials: AstraZeneca, GSK, PEP therapy, BMS, Novartis; AMGEN, Oxford Biotherapeutics, Clovis, Roche. S. Im: Financial Interests, Personal, Advisory Board, no payment: AstraZeneca, Novartis, Eisai, Roche, Hanmi, Pfizer, Lilly, MSD, GSK, Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: Bertis; Financial Interests, Personal, Advisory Board: Idience; Financial Interests, Institutional, Research Grant: AstraZeneca, Pfizer, Roche, Eisai, Dae Woong; Financial Interests, Institutional, Local PI, Clinical Trial Budget: AstraZeneca, Hanmi, Novartis, Roche, Pfizer, Daiichi Sankyo, MSD, Lilly; Financial Interests, Institutional, Coordinating PI, Clinical Trial Budget: Eisai; Financial Interests, Institutional, Research Grant, Clinical Trial Budget: Boryung Pharm. S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, Amgen, LG biochemical, Astellas; Financial Interests, Personal, Invited Speaker: MSD, lilly, Daiichi Sankyo; Financial Interests, Personal, Steering Committee Member: Amgen; Financial Interests, Institutional, Funding: MSD, Lilly; Financial Interests, Institutional, Research Grant: BMS, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Indivumed, AstraZeneca; Financial Interests, Other, Durg supply for clinical trial: Merck; Financial Interests, Institutional, Coordinating PI, Drug supply for clincal trial: MSD; Financial Interests, Institutional, Local PI, drug supply for clinical trial: zy,meworks; Financial Interests, Institutional, Local PI, drug supply for clincial trial: Beigine; Financial Interests, Coordinating PI, Drug supply for clnical trial: Incyte. C.F. Friedman: Non-Financial Interests, Personal, Advisory Board: Merck, Genentech, Marengo; Financial Interests, Institutional, Principal Investigator: Merck, AstraZeneca, Daiichi Sankyo, Hotspot, Genentech/Roche, Seagen, Mersana; Financial Interests, Personal, Advisory Role: Aadi Biosciences; Financial Interests, Personal, Other, Travel support: Puma. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Coordinating PI: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. M. Lim: Financial Interests, Personal, Principal Investigator, Institutional PI: AstraZeneca, Boryung, CKD Pharm, Genexine, Hospicare, GI Innovation, Takeda; Financial Interests, Institutional, Research Funding: AbbVie, Amgen, Astellas, AstraZeneca, BeiGene, Cellid, CKD Pharm, Clovis, Eisai, Genexine, GSK, Incyte, MSD, OncoQuest, Pfizer, Roche, Merck. R. Roux: Non-Financial Interests, Personal, Invited Speaker, Olaprib in early breast cancer, meeting chair, AstraZeneca sponsored: AstraZeneca. J.F. Liu: Financial Interests, Personal, Invited Speaker: Clovis Oncology; Financial Interests, Personal, Advisory Board: AstraZeneca, Genentech, GSK, Regeneron, Zentalis; Financial Interests, Personal, Other, Consulting: Bristol Myers Squibb. M. Brown, N. Lukashchuk, E.J. Dean, B. Loembé: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. B.W. Webb, J. Nehra: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. M.G. Krebs: Financial Interests, Personal, Advisory Board: Bayer, Roche, Janssen, Guardant Health; Financial Interests, Personal, Invited Speaker: Roche, Janssen; Financial Interests, Institutional, Advisory Board: AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Carrick, Janssen, Pyramid Biosciences; Financial Interests, Institutional, Local PI: Blueprint, Astex, Bayer, BerGenBio, Immutep, Novartis, Nurix, Nuvalent, Roche, Seattle Genetics, Turning Point Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Novartis; Other, Travel expenses for congress: Immutep, Janssen; Other, Travel expenses: Roche. All other authors have declared no conflicts of interest.