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

Sep 23, 2026

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Cyclin-dependent kinase dysregulation is common in pediatric cancers, motivating evaluation of the dual CDK2/9 inhibitor fadraciclib. 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.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Abstract

Background

Objective

Patients and Methods

Results

Conclusions

Introduction

Precision cancer medicine and unmet need

AcSé-ESMART trial platform

Rationale for targeting CDKs

Targeted Oncology (2026) 21:199–211 [https://doi.org/10.1007/s1](https://doi.org/10.1007/s1) 1523-026-01208-1 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 Alba Rubio‑San‑Simón1 · Lynley V. 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 Received: 24 November 2025 / Accepted: 2 March 2026 / Published online: 16 March 2026 © The Author(s) 2026 Abstract Background 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. Patients 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. Results 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. Conclusions 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. Trial registry [ClinicalTrials.gov](ClinicalTrials.gov) NCT2813135 . Registered on: 24 June 2016. 1 Introduction There 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 Alba Rubio-San-Simón and Lynley V. Marshall have contributed equally to this work. Extended author information available on the last page of the article unique actionable key driver events [2 , 3] . However, most patients have complex cancers that mandate adapted combination strategies [4–7] . The 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] . Among 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

FAQs

What was the primary aim of Arm K in the AcSé-ESMART trial?

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.

How were fadraciclib and temozolomide administered in the study?

Fadraciclib was administered intravenously once on Day 1 ± Day 15, while temozolomide was given orally on Days 1–5.

What efficacy and safety outcomes were reported for the treated patients?

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).

Sep 23, 2026

Uploaded by Jake