Dose‐finding study of the checkpoint kinase 1 inhibitor, prexasertib, in Japanese patients with advanced solid tumors

Abstract

Prexasertib is a novel inhibitor of checkpoint kinase 1. The primary objective of this study was to evaluate prexasertib tolerability in Japanese patients with advanced solid tumors. This nonrandomized single‐arm open‐label phase 1 study of prexasertib consisted of 2 dose levels, 80 mg/m2 and the global‐recommended dose based on a US study of 105 mg/m2, administered intravenously once every 14 days (n = 6 for each dose). Transition to the higher dose proceeded if the frequency of dose‐limiting toxicity observed in cycle 1 was <33% at the lower dose. Safety measures, pharmacokinetics and antitumor activity were assessed. A total of 12 patients were treated. Two patients, one in each dose group, experienced dose‐limiting toxicities of febrile neutropenia, one grade 4 and the other grade 3; both patients recovered and continued the study treatment. The grade 4 treatment‐emergent adverse events related to study treatment were neutropenia (6 patients [50.0%]), leukopenia (4 patients [33.3%]), and 1 instance each (8.3%) of anemia, febrile neutropenia and thrombocytopenia. Neutropenia was generally transient and reversible; 11 patients (91.7%) required granulocyte colony‐stimulating factor treatment during the study. There were no discontinuations due to adverse events or deaths. The prexasertib pharmacokinetics displayed dose‐independent and time‐independent behavior across both dose levels, similar to the profile observed in the US‐based phase 1 study. Eight patients had a best overall response of stable disease. These data are consistent with the known safety profile for prexasertib and confirm its tolerability in Japanese patients with advanced solid tumors.

A phase 1 study of prexasertib (LY2606368), a CHK1/2 inhibitor, in pediatric patients with recurrent or refractory solid tumors, including CNS tumors: A report from the Children's Oncology Group Pediatric Early Phase Clinical Trials Network (ADVL1515)

“…The single-agent RP2D of prexasertib administered in adult patients on an every 14-day schedule was determined to be 105 mg/m 2 . 11,19,20 In a phase 1b expansion that treated over 100 patients with squamous cell carcinoma at this dose and schedule, 89% of patients had treatment-emergent grade 3/4 neutropenia, which is similar to the 100% seen on our study. 19 Rates of grade 3/4 anemia (14%) and approximately 24 hours and the drug exposure measured as the AUC 0-24hr was greater than the median AUC 0-72hr value (1896 ng•hr/mL) predicted for efficacy based on the Calu-6 preclinical PK/PD model.…”

“…11 There are limited published adult PK data for prexasertib administered as a single agent in phase I clinical trials, and no adult data at the pediatric RP2D. 11,20 Although an MTD was not reached in our study, the dose of 150 mg/m 2 was well tolerated and provided twice the exposure than the RP2D from either adult study. In the absence of strong PK or PD data to suggest otherwise, the typical approach taken in pediatric phase 1 trials is to use the estimated highest tolerable dose as the RP2D.…”

“…Thus, prexasertib plasma concentrations were maintained above the IC 50 (14.1 ng/mL) for pCHK1 inhibition for approximately 24 hours and the drug exposure measured as the AUC 0‐24hr was greater than the median AUC 0‐72hr value (1896 ng•hr/mL) predicted for efficacy based on the Calu‐6 preclinical PK/PD model 11 . There are limited published adult PK data for prexasertib administered as a single agent in phase I clinical trials, and no adult data at the pediatric RP2D 11,20 . Thus, we compared the pediatric PK data measured at 100 mg/m 2 /dose with the adult PK data measured at 105 mg/m 2 /dose.…”

Integrative transcriptomics analysis for uterine leiomyosarcoma identifies aberrant activation of cell cycle-dependent kinases and their potential therapeutic significance

“…In patients who administered BI 2536 or volasertib, neutropenia was the most frequently observed adverse event, and about 30%-40% of the patients experienced grade 3 or 4 neutropenia (23)(24)(25)27,28). Similarly, hematological adverse events were frequently observed in the patients that were treated with prexasertib, and almost all the patients experienced grade 3 or 4 neutropenia (44)(45)(46)(47). Therefore, the hematological toxicity of these drugs should be kept in mind; however, it is important to also note that all clinical trials have concluded the safety profile.…”

Exploiting replicative stress in gynecological cancers as a therapeutic strategy

“… 48 Although dose-limiting cardiac toxicities were reported in 4.7% of patients enrolled on a phase I dose-escalation study of the CHK1/2 inhibitor AZD7762 (AstraZeneca) in combination with gemcitabine, 49 praxasertib has not been associated with this feared side effect, even at the maximal tolerated dose. 50 As we have learned from difficulties combining high-potency PARPi with chemotherapy due to toxic myelosuppression, the sequential administration of chemotherapy followed by maintenance PARPi has led to clinical approvals, and this may be the required approach for novel ATRi–WEE1i–CHK1i.…”