LBA 31 - CRAIN: A Phase Ib Tite-CRM Dose Escalation Study of Tolinapant with Chemoradiotherapy for Locally Advanced Cervical Cancer Including Clinical and Translational Endpoints
Presenter(s)
P. Hoskin1, M. Lee2, D. Dunkley2, G. Saunders2, J. Northey2, E. Tilt2, K. Haslett3, T. Mathew4, V. McFarlane5, D. Smith6, K. Reeves7, A. Choudhury8,9, L. V. Biolatti7, A. Siddique7, M. Radhi7, A. Clipson10, F. Mouliere10, D. Rothwell10, A. Datta11, and G. Griffiths2; 1The Christie NHS Foundation Trust, Manchester, United Kingdom, 2Southampton Clinical Trials Unit, Southampton, United Kingdom, 3Division of Cancer Sciences, University of Mancheter, Manchester, United Kingdom, 4Sheffield teaching hospitals NHS foundation trust, Sheffield, United Kingdom, 5University hospital Southampton, Southampton, United Kingdom, 6University of Birmingham, Birmingham, United Kingdom, 7University of Manchester, Manchester, United Kingdom, 8Division of Cancer Sciences, University of Manchester, Manchester, England, United Kingdom, 9Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom, 10Cancer Research UK National Biomarker Centre, Manchester, United Kingdom, 11Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
Purpose/Objective(s):
Tolinapant is a dual antagonist of the inhibitors of apoptosis proteins XIAP and cIAP1, thereby promoting apoptosis. Reduced in vivo clonogenic survival following Tolinapant, cisplatin and radiation versus radiation alone is seen with no impact on acute gastro-intestinal (GI) toxicity in the crypt assay. CRAIN is a Phase Ib clinical trial to explore combining tolinapant with cisplatin chemoradiation in patients with locally advanced cervical cancer using a TITE-CRM statistical design for dose escalation.Materials/Methods:
The primary endpoint was maximum tolerated safe dose of tolinapant in combination with cisplatin &radiotherapy (CRT). Patients with advanced cervical cancer were allocated to pre-specified tolinapant dose levels starting at 90mg using a TITE-CRM model to define dose escalation. Dose Limiting Toxicities (DLTs) were defined by any grade 3 or 4 adverse event (CTCAEv5) considered definitely or probably related to tolinapant. Secondary endpoints included toxicity , response and CRT treatment disruption. Plasma pharmacokinetics were measured and translational endpoints at diagnosis and after EBRT were markers of hypoxia, proliferation and apoptosis. Blood samples and paired urine samples for cell-free DNA (cfDNA) were also collected.Results:
11 patients (median age 47, range 35-71) were enrolled, with one withdrawing before any treatment; 7 were treated with 90mg with no DLTs but one intercurrent unrelated death (CVA); 3 were treated with 120mg and two DLTs observed: one seizure and one sinus thrombosis. There were no other grade =3 adverse events considered related to tolinapant. Pharmacokinetic parameters were similar to those seen in other studies with tolinapant alone. Mean data (%CV) for 90mg dose: Cmax 164 (48%), Tmax 1hr (range 1-2) and AUC 983 (51%)ng/hr/mL. There was an overall reduction in biomarker expression in most cases for BCL2, GLUT1, Ki67, and SOX2. No statistically significant differences seen between a control group having no tolinapant and CRAIN cohorts for any of the biomarkers. From 18 participants at baseline (tolinapant = 11, control = 7), T7-MBD-seq was performed on cfDNA from plasma (n = 17) and urine (n = 12) to assess tumour fraction, tissue-of-origin classification and HPV 16/18 detection. 10/12 (83%) urine-derived DNA samples were classified as the Cervical Cancer/Gynae classes by CUPiD analysis. This multimodal approach allowed identification of at least one positive feature in 15/18 (83%) subjects.Conclusion:
Tolinapant remains a potential candidate in combination with CRT for cervical cancer and based on CRAIN the recommended dose for phase 2 studies is 90mg daily. Translational sample analysis is feasible, but with small numbers, conclusions are limited. Urine was a better source of cfDNA than plasma and may have a role in screening and follow up.