IGNITE-Cerala: A phase II signal-seeking trial of ceralasertib targeting recurrent high-grade serous ovarian cancer with cyclin E1 overexpression with and without gene amplification.

Abstract

5587 Background: Cyclin E1 ( CCNE1 ) gene amplification and protein over-expression is a marker of platinum resistance in high grade serous ovarian, fallopian tube or primary peritoneal cancer (HGSC). Preclinical studies in breast and HGSC models have identified cyclin E1 amplification or over-expression as a potential predictive biomarker for improved sensitivity to ATR inhibition. We aimed to assess the efficacy of ceralasertib, an ATR inhibitor, in HGSC with cyclin E1 over-expression. Methods: IGNITE is a multicentre, Phase 2 trial enrolling women with recurrent platinum resistant HGSC. Tumors were assessed for Cyclin E1 protein expression by IHC and CCNE1 copy number by FISH. Patients with evaluable disease by RECIST v1.1 or GCIG CA-125 criteria were included. Ceralasertib 160mg PO was given twice daily on days 1-14 of a 28-day cycle. The primary endpoint was investigator assessed overall response rate (ORR), defined as partial response (PR) or complete response (CR) at 16 weeks by RECIST v1.1 among patients with measurable disease, or by GCIG CA-125 criteria for patients with non-measurable disease. Here we present the 16-week response data for all patients treated with ceralasertib with a data cut-off of July 2025. Results: Between Feb-2024 and Apr-2025, 32 patients were accrued to IGNITE-Cerala. One patient was deemed ineligible after registration and was excluded. Median age was 64 years (range 40-76) and 74% had received ≥2 prior lines of chemotherapy. Median cyclin E1 IHC H-score was 190 (range 60 – 260). Twenty-seven patients (87%) had measurable disease by RECIST. Median number of cycles commenced was 3 (range 1-18). The ORR at 16 weeks was 10% (0 CR and 3 PR). The 6 month progression free survival estimate was 26% (range 12-42%). Treatment related adverse events (TRAE) were mostly grade 1-2 with the most common being gastrointestinal or hematologic. Six patients (19%) had Grade 3 TRAE, and one patient had Grade 4 TRAE. Six patients (19%) required a dose reduction, and no patients discontinued study drug due to toxicity. Conclusions: Ceralasertib was a well tolerated treatment, however responses did not appear to be enriched in a biomarker selected population and therefore future studies should consider rationale combinations with ceralasertib. Cyclin E1 over-expression and amplification remains an important biomarker in HGSC, with other strategies such as CDK2 or PK-MYT1 inhibitors under active investigation. Clinical trial information: ACTRN12619001185156. Response at 16 weeks Response evaluable patients (n=31) RECIST measurable patients (n=27) CR 0 (0%) 0 (0%) PR 3 (10%) 3 (11%) SD 7 (23%) 7 (26%) No CA-125 response and no PD 1 (3%) - PD 20 (65%) 17 (63%) ORR (CR/PR) 3 (10% [2, 26]) 3 (11% [2, 9])