Mdb-65. Results From the Sj-eliot Phase 1 Clinical Trial Evaluating Prexasertib (ly2606368) in Combination With Cyclophosphamide or Gemcitabine for Children and Adolescents With Refractory or Recurrent Medulloblastoma
Year: 2024
Type: conference-abstract
Abstract: BACKGROUND SJ-ELIOT (NCT04023669) was a phase 1 trial that explored the combination of the checkpoint kinase inhibitor, prexasertib with the DNA-damaging agents, cyclophosphamide and gemcitabine, in recurrent or refractory medulloblastoma. METHODS Participants ≥ 1 year and < 25 years were stratified to one of two treatment strata: stratum A prexasertib and cyclophosphamide and stratum B prexasertib and gemcitabine. Patients with Group 3/4 medulloblastoma were assigned to either stratum A or B, whereas patients with SHH medulloblastoma were assigned to stratum A. A Rolling-6 design was used. RESULTS Fifteen patients were enrolled on stratum A and six patients on stratum B. The study was closed early due to drug supply issues. In stratum A, three patients were escalated to dose level (DL) 3 and none had dose limiting toxicity (DLT). For stratum B, of the first three patients enrolled on DL1, two had DLTs (grade 3 hypotension) related to drug reactions. Consequently, stratum B was amended to add hydrocortisone prophylaxis. A further three patients were enrolled. One patient had a grade 3 DLT (ALT increase). The remaining two patients electively stopped therapy within the first two courses. One patient on stratum A, with SHH TP53 mutant, MYCN amplified medulloblastoma, achieved a complete sustained response, received 12 cycles, and electively stopped treatment after 408 days. They progressed nine months later. The remaining 14 patients on stratum A progressed. There were no objective responses on stratum B. Median PFS were 1.9 and 2.1 months for stratum A and B respectively. CONCLUSIONS The MTD/RP2D was not established for either arm. In stratum A, DL3 was tolerated, whereas DL1 for Stratum B was not tolerated. Despite robust preclinical data, no efficacy signal was observed. Intriguingly, one patient with a highly aggressive tumor (SHH TP53 mutant, MYCN amplified) appeared to derive a sustained benefit from the combination of prexasertib and cyclophosphamide.
Source: Neuro-Oncology
Institutions: The Kids Research Institute Australia, The University of Western Australia, Princess Margaret Hospital for Children, Perth Children's Hospital, St. Jude Children's Research Hospital, Royal Children's Hospital, The University of Melbourne, Murdoch Children's Research Institute, Children's Health Queensland Hospital and Health Service, UNSW Sydney, Sydney Children's Hospital
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,389
OpenAlex ID: W4399785244