S418
Clinical - Gynaecological
ESTRO 2026
7 Clinical oncology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom. 8 Clinical oncology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom. 9 Clinical oncology, University College London Hospitals NHS Foundation Trust, London, United Kingdom. 10 Applied Health Sciences, University of Birmingham, Birmingham, United Kingdom. 11 Cancer Sciences, University of Manchester, Manchester, United Kingdom. 12 Director, Cancer Research UK Southampton Clinical Trials Unit, Southampton, United Kingdom Purpose/Objective: The standard of care for locally advanced cervical cancer in the UK is concurrent chemoradiotherapy with weekly cisplatin (1). This phase 1b dose escalation trial assessed the safety and tolerability of adding the novel agent tolinapant to this regimen. Tolinapant is a dual antagonist of the inhibitors of apoptosis proteins XIAP and cIAP1 (2), which had previously shown synergistic effects with cisplatin and radiotherapy, without significant overlapping toxicities in vitro. Material/Methods: The Cancer Research UK CRAIN trial (CRCPJT\100019) recruited participants from five UK centres with histologically proven adenocarcinoma or squamous cell carcinoma of the cervix (stages IB2/IB3/IIA1/IIA2/IIB/IIIA/IIIB/IIIC1). Each patient was scheduled to receive standard external radiotherapy: 45Gy in 25 daily fractions over 5 weeks, with weekly cisplatin at 40mg/m2, followed by brachytherapy - either 28Gy in 4 fractions high-dose-rate, 34Gy in 2 fractions pulsed-dose-rate, or an equivalent schedule. Patients were allocated to pre-specified tolinapant dose levels starting at 90mg. Escalation was guided by emerging safety data, recommendations from the TiTE-CRM statistical design and decision by the Safety Review Committee (SRC). Dose Limiting Toxicities (DLTs) were assessed for a period of 12 weeks. Blood,
tissue, and urine translational samples, along with MR imaging, were collected throughout the trial to enable biomarker discovery. Results: Eleven eligible patients (median age 47, range 35-71) were enrolled between February 2023 and November 2024 with one being un- evaluable due to subject withdrawal before any treatment. Seven patients were treated at the 90mg level with no DLTs observed as per protocol but one intercurrent death due to a cerebrovascular accident. Three further patients were treated with the 120mg dose with two DLTs observed; one seizure and one sinus thrombosis. No grade three or above adverse events for neutropenia or thrombocytopenia considered related to Tolinapant were seen. The Tolinapant regimen had a median relative dose intensity of 94%, although full protocol treatment overall was received by only 30% of participants (all on the 90mg dose). The TiTE CRM model suggested the 120mg dose was closest to the pre-determined target toxicity level but when a sensitivity analysis was carried out classifying the death as a DLT, the 90mg dose was determined the recommended phase II dose (RP2D). Pharmacokinetic data is shown in Table 1.
Conclusion: The 90mg dose was best tolerated for patients and selected by the SRC as the recommended phase II dose. A phase II study exploring the efficacy is warranted References: 1) Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized
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