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Arm K of the AcSé-ESMART proof-of-concept phase I/II platform trial assessed the recommended phase II dose, pharmacokinetics, antitumor activity, and predictive biomarkers for fadraciclib plus temozolomide in children with recurrent or refractory solid malignancies. Fadraciclib was given intravenously on Day 1 ± Day 15 with temozolomide orally on Days 1–5, using dose escalation and molecularly enriched cohorts. Twelve patients were treated, hematologic toxicities were dose-limiting, no objective responses were observed, and limited stable disease occurred, supporting a manageable safety profile with constrained clinical activity.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/phase-iii-study-of-the-cdk29-inhibitor-fadraciclib-in-combination-with-chemotherapy-in-children-with-advanced-malignancies-arm-k-of-the-acse-esmart-trial/356543/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/phase-iii-study-of-the-cdk29-inhibitor-fadraciclib-in-combination-with-chemotherapy-in-children-with-advanced-malignancies-arm-k-of-the-acse-esmart-trial/356543.png","ImageObject",300,407,{"name":92,"@type":93},"Jake","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-23","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":29},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What was the primary aim of Arm K in the AcSé-ESMART trial?","Question",{"text":112,"@type":113},"Arm K aimed to determine the recommended phase II dose, characterize pharmacokinetics, assess antitumor activity, and identify predictive biomarker(s) for fadraciclib combined with temozolomide in pediatric patients with recurrent or refractory solid malignancies.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were fadraciclib and temozolomide administered in the study?",{"text":117,"@type":113},"Fadraciclib was administered intravenously once on Day 1 ± Day 15, while temozolomide was given orally on Days 1–5.",{"name":119,"@type":110,"acceptedAnswer":120},"What efficacy and safety outcomes were reported for the treated patients?",{"text":121,"@type":113},"No objective responses were observed. 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Marshall2 · Eleni Karamouza3 · Nicolas André4,5 · Samuel Abbou6 · Jonathan Rubino7 · Souad Nebchi5 · Isabelle Aerts8 · Estelle Thebaud9 · Claire Brisset10 · Stephane Ducassou11 · Gwénaël LeTeuff3 · Birgit Geoerger6,12  \nReceived: 24 November 2025 / Accepted: 2 March 2026 / Published online: 16 March 2026 © The Author(s) 2026  \nAbstract  \nBackground Cyclin-dependent kinase (CDK) dysregulation is common in pediatric cancers. The dual CDK2/9 inhibitor fadraciclib has shown preclinical antitumor activity, alone and in combination, supporting clinical evaluation in children. Objective Arm K of the AcSé-ESMART proof-of-concept phase I/II platform trial aimed to define the recommended phase II dose (RP2D), pharmacokinetics, antitumor activity and predictive biomarker(s) of fadraciclib in combination with temozolomide in pediatric patients with recurrent/refractory solid malignancies.  \nPatients and Methods Fadraciclib was administered intravenously once on Day 1 ± Day 15, and temozolomide orally on Days 1–5. Dose escalation of fadraciclib followed the continuous reassessment method starting at 135 mg/m2/day on Day 1, equivalent to 70% of the adult RP2D; temozolomide was given at the pediatric RP2D dose of 150 mg/m2/day. The cohort was enriched for patients with molecular alterations in cell cycle pathways.  \nResults Twelve patients were enrolled and treated (median age: 12.1 years, range 4.0–17.9) . Main diagnoses were sarcoma and central nervous system tumors. Dose-limiting toxicities and main treatment-related adverse events were hematologic. The final tolerated intravenous fadraciclib dose could be estimated at 135 mg/m2 on Day 1 or Day 1 and 15 as the trial was closed prematurely following emerging adult data and the company’s shift from an intravenous to a new oral formulation. No objective response was observed; two patients with ependymoma and extra-cerebral malignant rhabdoid tumor had stable disease for 6 and 9 cycles, respectively.  \nConclusions This pediatric study was the first to explore the CDK2/9 inhibitor fadraciclib. Fadraciclib combined with temozolomide showed a manageable safety profile with limited clinical activity.  \nTrial registry [ClinicalTrials.gov](ClinicalTrials.gov) NCT2813135 . Registered on: 24 June 2016.  \n1 Introduction  \nThere is still a high unmet medical need to provide more effective treatments for the 20% of children with cancer who are not currently cured [1] . Precision cancer medicine programs aim to adapt rescue treatments to the biological features of recurrent or refractory tumors, and to move the most promising agents into earlier lines of therapy, including front-line therapy, where relevant. Successful treatments have already been defined for small populations exhibiting  \nAlba Rubio-San-Simón and Lynley V. Marshall have contributed equally to this work.  \nExtended author information available on the last page of the article  \nunique actionable key driver events [2 , 3] . However, most patients have complex cancers that mandate adapted combination strategies [4–7] .  \nThe pediatric precision cancer medicine platform trial AcSé-ESMART (European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsedor Refractory Tumors; [ClinicalTrials.gov](ClinicalTrials.gov) identifier: NCT02813135) was developed as a proof-of-concept, phase I/II trial, designed to explore targeted agents in a molecularly guided and enriched pediatric cancer patient population [8, 9] .  \nAmong the broad range of molecular targets under investigation in AcSé-ESMART are cyclin-dependent kinases (CDKs) . These enzymes regulate two fundamental processes in cancer cells: cell-cycle progression a","cbCaibVZHF6m7eRZ","https://ap.wps.com/l/cbCaibVZHF6m7eRZ","pdf",718483,13,"English","# Abstract\n## Background\n## Objective\n## Patients and Methods\n## Results\n## Conclusions\n# Introduction\n## Precision cancer medicine and unmet need\n## AcSé-ESMART trial platform\n## Rationale for targeting CDKs","[{\"question\":\"What was the primary aim of Arm K in the AcSé-ESMART trial?\",\"answer\":\"Arm K aimed to determine the recommended phase II dose, characterize pharmacokinetics, assess antitumor activity, and identify predictive biomarker(s) for fadraciclib combined with temozolomide in pediatric patients with recurrent or refractory solid malignancies.\"},{\"question\":\"How were fadraciclib and temozolomide administered in the study?\",\"answer\":\"Fadraciclib was administered intravenously once on Day 1 ± Day 15, while temozolomide was given orally on Days 1–5.\"},{\"question\":\"What efficacy and safety outcomes were reported for the treated patients?\",\"answer\":\"No objective responses were observed. Dose-limiting toxicities and main treatment-related adverse events were hematologic, and the final tolerated fadraciclib dose was estimated at 135 mg/m2 (Day 1, or Day 1 and 15).\"}]","Phase I/II Study of the CDK2/9 Inhibitor Fadraciclib in Combination with Chemotherapy in Children with Advanced Malignancies - Arm K of the AcSé-ESMART Trial | PDF",1790125885,33]