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Background: AcSé-ESMART is a proof-of-concept, phase I/II platform trial designed to explore targeted agents in a molecularly enriched pediatric population. WEE1 plays a role in DNA repair and cell cycle control and is overexpressed in pediatric cancers. Adavosertib combinations resulted in enhanced antitumor activity compared to single agent in neuroblastoma, rhabdomyosarcoma, medulloblastoma and high-grade glioma in vivo models. The efficacy and safety of the adavosertib-carboplatin combination has been established in adults with focus on TP53 mutated ovarian cancer. Arm C of AcSé-ESMART applied this regimen to children with advanced malignancies enriched for alterations in TP53, DNA repair/replication stress and cell cycle control. Methods: Adavosertib was administered orally, twice daily on Days 1 to 3 and carboplatin intravenously on Day 1 of a 21-day cycle. Dose finding used the continuous reassessment method starting at adavosertib 100 mg/m2/dose and carboplatin AUC 5. Pharmacokinetic (PK) and retrospective molecular bioinformatic analysis was performed. Results: Twenty patients (median age: 14.0 years, range 3.4-23.5) were included, 18 received a total of 69 cycles. Seven dose-limiting toxicities (DLTs) were observed leading to two de-escalations to adavosertib 75 mg/m2/dose and carboplatin AUC 4. All patients with DLT had thrombocytopenia grade 3/4 requiring transfusions for >7 days and/or neutropenia grade 4 for >7 days. Main overall treatment-related toxicities were hematologic and gastrointestinal. Based on the identified DLT risk, no recommended Phase 2 dose was defined. PK analysis demonstrated equivalent adavosertib exposure in children to that in adults and both doses (75 and 100 mg/m2) achieved the cell kill target. Two patients with neuroblastoma achieved partial response (PR), one with medulloblastoma unconfirmed PR, and five had stable disease (SD) >4 cycles. Patients with PR/SD >4 cycles were considered as clinical benefit (CB) for retrospective molecular analysis. There was no correlation between TP53 genomic alteration alone and response. However, 7 of 8 patients with CB but none of the 10 patients without CB had 1 to 3 genomic alterations in the DNA repair (BRCA2 mutation, 11q loss containing ATM, MRE11A, CHEK1), cell cycle control/replication stress (CCNE1 amplification, RB1 mutation/loss, SETD2 mutation/loss) and RAS pathway (KRAS mutation and amplification, NF1 loss, PTPN11 mutation) in their tumor. Conclusions: Adavosertib combined with carboplatin exhibited significant hematologic toxicity. Activity signals and identified potential molecular biomarkers suggest further combination studies with less hematotoxic DNA damaging therapy in molecularly enriched pediatric cancers. Citation Format: Susanne A. Gatz, Anne C. Harttrampf, Caroline Brard, Francisco J. Bautista, Nicolas André, Samuel Abbou, Jonathan Rubino, Windy Rondof, Marc Deloger, Marc Rübsam, Daniel Hübschmann, Lynley V. Marshall, Souad Nebchi, Isabelle Aerts, Estelle Thebaud, Emilie De Carli, Anne-Sophie Defachelles, Xavier Paoletti, Robert Godin, Kowser Miah, Peter G. Mortimer, Gilles Vassal, Birgit Geoerger. Phase I/II study of the WEE1 inhibitor adavosertib in combination with carboplatin in children with advanced malignancies: arm C 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 CT087.

Background: AcSé-ESMART is a proof-of-concept, phase I/II, platform trial, designed to explore targeted agents in a molecularly enriched relapsed/refractory pediatric population. Arm D was evaluating the PARP inhibitor (PARPi) olaparib (ola) in combination with irinotecan (iri). In contrast to other PARPi/chemotherapy combination studies, we opted for a prolonged course of PARPi and low dose irinotecan as sensitizer. The Phase I part previously established the recommended Phase II dose (RP2D) (Gatz ASCO 2019). This is the report of the Phase II part of the trial assessing the activity in two separate expansion cohorts: cohort 1: homologous recombination repair defect (HRD) and cohort 2: Ewing sarcoma (ES). Methods: Ola was administered orally twice daily at 90 mg/m2 on Days 1 to 10 and iri intravenously at 20 mg/m2 on Days 4 to 8 of a 21-day cycle. Activity assessment followed a Minimax Simon 2-stage design. Each cohort was to progress to the second stage (additional 9 patients) if 2 or more confirmed responses were observed in the first 16 patients. Patients treated in the Phase I part at the RP2D were counting towards the respective expansion cohorts. Results: Seventy patients (median age: 14 years, range 5-23) were included in the whole study, 67 received treatment; 27 patients were treated in the dose escalation part, including 10 at the RP2D (8 in cohort 1 and 2 in cohort 2). Both cohorts passed the 1st stage and a total of 24 and 26 patients were recruited to cohort 1 and 2, respectively. Main diagnoses in cohort 1 were sarcoma (n=10), brain tumor (n=9), neuroblastoma (n=4). In cohort 1, 15 of 24 patients were considered enriched based on molecular alteration at relapse (ATM n=6; BRCA1 n=2; DNA signature 3 n=3; FANCD2, CHEK2, FANCA, ATRX all n=1); all patients in cohort 2 had presence of a ES fusion (ESWR1::FLI1 n=22; EWSR1::ERG n=4). Median number of treatment cycles were 2, range 1;51 in cohort 1 and 1;32+ in cohort 2. In cohort 1, 3 patients had a partial response (PR) (pinealoblastoma, neuroblastoma, choroid plexus carcinoma; treated with 12, 51, 25 cycles), 1 patient an unconfirmed PR (rhabdomyosarcoma, 6 cycles) and 7 patients stable disease (SD) (2 prolonged with 6 and 8 cycles). In cohort 2, 1 patient had a complete response (10 cycles) and 1 a PR (32+ cycles), 7 patients had SD (3 prolonged with 6, 10, 16 cycles). Molecular enrichment did not predict response. Retrospective correlative analysis of the molecular profiling data and tumor tissue expression analysis are ongoing to identify predictive biomarkers for PARPi combination trials and data will be presented. Conclusions: Encouraging clinical benefit was observed with the protracted ola-iri schedule in a subset of patients. Current molecular hypothesis is insufficient for patient selection and better biomarkers are needed. Citation Format: Susanne A. Gatz, Pablo Berlanga, Baptiste Archambaud, Yassine Bouchoucha, Nicolas André, Nadege Corradini, Windy Rondof, Jonathan Rubino, Souad Nebchi, Antonin Marchais, Estelle Thebaud, Alba Rubio San Simón, Natasha K. van Eijkelenburg, Lynley V. Marshall, Anne-Sophie Defachelles, Adela Canyete, Stephane Ducassou, Guy Makin, Michela Casanova, Emilie De Carli, Arnaud Petit, Gwenael Le Teuff, Xavier Paoletti, Peter G. Mortimer, Gilles Vassal, Birgit Geoerger. Phase I/II study of the PARP inhibitor olaparib in combination with irinotecan in children with advanced malignancies: arm D 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 CT088.