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

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.

to DNA damage. 1,2 The proteins ataxia telangiectasia mutated and RAD3-related (ATR) and/or ataxia telangiectasia mutated (ATM) are activated in response to DNA damage, which in turn phosphorylate CHK1 and checkpoint kinase 2 (CHK2), respectively. 3 p53 is another critical mediator of the response to DNA damage. It is activated through phosphorylation by CHK2 and ATM, and participates in a parallel pathway to ATR and CHK1. 3 CHK1 can also regulate DNA replication checkpoints by maintaining or enhancing the inhibitory phosphorylation of cyclin-dependent kinases, which are key drivers of cell cycle progression. 2 In addition, CHK1 can stabilize replication forks and promote DNA repair, control initiation of DNA replication, and coordinate mitosis. 2 Inhibitors of CHK1 have been developed as combination therapy to augment the efficacy of DNA-damaging chemotherapeutics. [4][5][6][7] Given the central role that CHK1 has in DNA replication and regulation of the cell cycle, inhibitors of CHK1 are also being developed as single-agent therapies. 3,8 Prexasertib (LY2606368) is an inhibitor of CHK1 and, to a lesser extent, CHK2 that can disrupt DNA replication, induce DNA damage, and prevent DNA repair, eventually leading to cell death via interruption of DNA replication. 1 Preclinical studies in solid tumor models have shown that prexasertib as a single agent, or in combination with other agents, has both in vitro and in vivo antitumor activity. 1,9,10 Prexasertib, in combination with cetuximab and irradiation, has also been shown to have antitumor effects in head and neck squamous cell carcinoma (SCC) in vitro and in vivo. 11 A phase 1 nonrandomized, open-label, dose-escalation study of prexasertib monotherapy, conducted in the US in 45 patients with advanced solid tumors, resulted in a recommended prexasertib dose of 105 mg/m 2 administered once every 14 days for further evaluation. 8 The most common drug-related grade 3 or 4 treatment-emergent adverse events (TEAE) in the dose-escalation portion of this phase 1 study were reversible neutropenia, leukopenia, anemia, thrombocytopenia and fatigue. 8 Two patients (4%) had a partial response, 1 with SCC of the anus and 1 with SCC of the head and neck, and 15 patients (33%) with various cancer types had a best overall response (BOR) of stable disease. 8 In a phase 2 single-center study of prexasertib in 28 women with BRCA wild-type recurrent high-grade serous ovarian cancer, partial responses were reported for 8 patients (29%) in the intention-to-treat population, with the most common grade 3 or 4 TEAE being neutropenia, leukopenia, thrombocytopenia and anemia. 12 This phase 1 study was conducted to investigate the safety, tolerability, pharmacokinetics (PK) and antitumor activity of prexasertib in Japanese patients with advanced solid tumors. This study is registered with ClinicalTrials.gov, identifier NCT02514603.

| Eligibility
Japanese patients at least 20 years of age with advanced and/or metastatic solid tumors who experienced treatment failure with standard therapies and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and adequate organ and coagulation function, including absolute neutrophil count ≥1.5 × 10 9 /L, platelets ≥120 × 10 9 /L and hemoglobin ≥9 g/dL, were enrolled.
Patients had to have discontinued previous treatments for cancer and to have recovered from the acute effects of therapies before enrollment. Exclusion criteria included serious preexisting medical condition(s), active infection(s), a second primary malignancy, a corrected QT interval of >470 ms on screening electrocardiogram in repeated (at least 2) measurements, or a family history of long-QT syndrome.

| Study design and treatment
All eligible patients in this nonrandomized single-arm open-label phase 1 study received prexasertib at 80 or 105 mg/m 2 , administered intravenously on day 1 of every 14-day cycle, with each dose level consisting of a maximum of 6 patients. The primary objective was to evaluate tolerability, which was confirmed if the dose-limiting toxicity (DLT) frequency observed in cycle 1 was <33%, of prexasertib in Japanese patients with advanced solid tumors. The secondary objectives were the characterization of the prexasertib safety and toxicity profile, PK, and documentation of antitumor activity.
This study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki, and with approval from each institution's ethical review board. Patients provided written informed consent. This study is registered with ClinicalTrials.gov, identifier NCT02514603.

| Safety evaluations
A DLT was defined as an adverse event (AE) during cycle 1 (the first 14 days of treatment) that was possibly related to prexasertib and fulfilled any of the following criteria using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) ver-

| Efficacy evaluations
Patients were assessed for tumor measurement by computed tomography scan or mRI using RECIST version 1.1. The BOR was defined as the best response recorded from the start of the treatment until disease progression. The best response of stable disease was defined as disease that did not meet the criteria for complete response, partial response or progressive disease and had been evaluated approximately 4 weeks (defined as ≥28 days) after the date of the first dose.

| Patients
Between 16 October 2015 and 25 January 2017, 12 eligible patients were enrolled and treated, 6 with prexasertib 80 mg/m 2 and 6 with prexasertib 105 mg/m 2 . Two-thirds of patients (66.7%) were male, the median age was 62 years, and most patients (58.3%) had an ECOG performance status of 1 ( Table 1)

| Pharmacokinetics
The PK profile of prexasertib displayed a multiexponential decline in plasma concentrations with dose-dependent increases in systemic exposure and consistent PK profiles after single-dose and multipledose administration across the dose range investigated. Figure 1 shows the arithmetic mean plasma concentration vs time profiles of prexasertib after a single dose in cycle 1 ( Figure 1A) and multiple doses in cycle 2 ( Figure 1B). There was no intercycle accumulation of prexasertib between cycle 1 and cycle 2 in both treatment groups (Table 3). Mean t 1/2 values were consistent across different dose levels (Table 3). A small-to-moderate degree of interpatient variability (mean percent coefficient of variation range: 7%-25%) in prexasertib CL was observed in both treatment groups. The CL and V ss were consistent after repeat administration at both dose levels (Table 3), indicating dose-independent and time-independent PK behavior.  Prexasertib PK in Japanese patients displayed dose-independent and time-independent PK behavior at both dose levels investigated.
After administration of prexasertib 105 mg/m 2 , the geometric mean AUC (0-72) achieved the median AUC (0-72) of 1896 ng h/mL predicted from the nonclinical Calu-6 xenograft PK/pharmacodynamic model to achieve the maximal tumor response following prexasertib monotherapy. 8 In addition, after administration of prexasert-ib105 mg/m 2 in cycle 1 and cycle 2, 8 of 9 (89%) of the noncompartmental AUC (0-72) values were greater than the median AUC  predicted to correlate with the maximum tumor response after prexasertib monotherapy. 8 The mean average prexasertib plasma concentrations over the first 72 hours (C av,72 ) after administration of 105 mg/m 2 in cycle 1 and cycle 2 were also greater than the IC 50 (14.1 ng/mL) derived from the single-agent Calu-6 xenograft model. 8 Prexasertib PK are, therefore, suitable for achieving the median human exposure predicted from the nonclinical Calu-6 xenograft PK/ pharmacodynamic model. 8 Prexasertib PK for Japanese patients are also consistent with the PK reported in the US-based phase 1 study in non-Japanese patients. 8 Taken together, these data indicate that prexasertib PK in Japanese patients are suitable for minimizing intercycle accumulation and for achieving the median predicted maximum efficacious systemic exposure following intravenous administration of 105 mg/m 2 once every 14 days.
In conclusion, the overall safety findings in this study were consistent with the known safety profile for prexasertib, and tolerability at the recommended dose of 105 mg/m 2 was confirmed in Japanese patients with advanced solid tumors, including those with cancer types not previously investigated with prexasertib treatment.

ACKNOWLEDG MENTS
We thank the patients, their families, the study sites, and the study personnel who participated in this clinical trial. We also thank Hisaki Fujii for contributions to the interpretation of the data in the manuscript. Medical writing support was provided by Andrew Sakko, PhD, CMPP, and editorial support was provided by Noelle Gasco, of Syneos Health and funded by Eli Lilly and Company in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).