Abstract CT019: Phase I/II study of the PARP inhibitor olaparib and ATR inhibitor ceralasertib in children with advanced malignancies: Arm N of the AcSé-ESMART trial
Authors: Gatz Susanne A. , Simón Alba Rubio San , Archambaud Baptiste , Abbou Samuel , Cleirec Morgane , Leruste Amaury , Defachelles Anne-Sophie , André Nicolas , Rubino Jonathan , Nebchi Souad , Rondof Windy , Smith Simon A. , Mortimer Peter G. , Loembé Bienvenu , Teuff Gwenael Le , Vassal Gilles , Geoerger Birgit 
Published: May 2023

Abstract
Background: AcSé-ESMART is a European proof-of-concept, phase I/II, platform precision cancer medicine trial designed to explore targeted agents in a molecularly enriched population. Arm N explores the PARP inhibitor (PARPi) olaparib (ola) in combination with the Ataxia telangiectasia mutated rad3 related (ATR) inhibitor (ATRi) ceralasertib (cer). In pediatric cancer, the rationale for this combination is twofold: i) Many cancers show evidence of a constitutively active ATR pathway due to endogenous replication/transcription stress (RS) which can be targeted by ATRi. PARPi in this setting serves as additional replication stressor/ATRi sensitizer. ii) Classical BRCA alterations are rare and alterations conferring homologous recombination deficiency (HRD) likely require a combination approach including PARPi. This is a first-in-child study and we here report the results of the Phase I dose escalation part.
Methods: Children and adolescents with relapsed or refractory cancer and advanced molecular profiling at relapse were eligible. All patients had to have molecular alterations consistent with HRD or RS in their tumor. Ola was administered orally twice daily (BID) continuously and cer orally BID on days 1-14 of a 28-day cycle. Dose level (DL) 1 was ola 150/100/50 mg BID and cer 80/40/30 mg BID in age group 12-18/6-&lt;12/3-&lt;6 years, respectively. Dose-escalation followed a Boin design, 12 patients treated at the recommended Phase II dose (RP2D) were required to conclude the Phase I part. Plasma for pharmacokinetics (PK) of both drugs was collected during Cycle 1.
Results: Eighteen patients (8 sarcomas, 5 central nervous system tumors, 4 neuroblastomas, 1 carcinoma) with a median age of 16 years (range, 4;24) were enrolled over 3 dose levels between Feb 2021 and Sep 2022 and received a median of 3.5 cycles (range 1-12+; data cut-off Jan 2023). The combination was well tolerated overall, toxicity was mainly hematologic (thrombocytopenia, neutropenia, anemia) and gastrointestinal (nausea/vomiting). Five patients encountered dose-limiting toxicities (thrombocytopenia grade 3/4 requiring platelet transfusions &gt; 7 days in all, and grade 4 neutropenia for &gt; 7 days or with documented infection in 1 patient each; 0/3 DL-1, 2/12 in DL1 and 3/3 in DL2), suggesting DL1 as RP2D. One confirmed partial response (PR) was observed in a patient with pinealoblastoma (FANCA VUS), a prolonged stable disease converted to a PR after cycle 9 in a neuroblastoma (11q loss, ATRX VUS, in cycle 10). Four patients are ongoing in cycle 5/6/10/12, respectively. PK and retrospective biomarker analysis are ongoing to identify factors associated with clinical benefit and data will be presented.
Conclusions: Ola and cer in combination are well tolerated. Recruitment in two expansion cohorts (HRD and RS) is ongoing at the RP2D, including confirmation of RP2D in younger children.
Citation Format: Susanne A. Gatz, Alba Rubio San Simón, Baptiste Archambaud, Samuel Abbou, Morgane Cleirec, Amaury Leruste, Anne-Sophie Defachelles, Nicolas André, Jonathan Rubino, Souad Nebchi, Windy Rondof, Simon A. Smith, Peter G. Mortimer, Bienvenu Loembé, Gwenael Le Teuff, Gilles Vassal, Birgit Geoerger. Phase I/II study of the PARP inhibitor olaparib and ATR inhibitor ceralasertib in children with advanced malignancies: Arm N of the AcSé-ESMART trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT019.