Phase I Study Evaluating WEE1 Inhibitor AZD1775 As Monotherapy and in Combination With Gemcitabine, Cisplatin, or Carboplatin in Patients With Advanced Solid Tumors

Abstract

Purpose AZD1775 is a WEE1 kinase inhibitor targeting G2 checkpoint control, preferentially sensitizing TP53-deficient tumor cells to DNA damage. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of oral AZD1775 as monotherapy or in combination with chemotherapy in patients with refractory solid tumors. Patients and Methods In part 1, patients received a single dose of AZD1775 followed by 14 days of observation. In part 2, patients received AZD1775 as a single dose (part 2A) or as five twice per day doses or two once per day doses (part 2B) in combination with one of the following chemotherapy agents: gemcitabine (1,000 mg/m²), cisplatin (75 mg/m²), or carboplatin (area under the curve, 5 mg/mL⋅min). Skin biopsies were collected for pharmacodynamic assessments. TP53 status was determined retrospectively in archival tumor tissue. Results Two hundred two patients were enrolled onto the study, including nine patients in part 1, 43 in part 2A (including eight rollover patients from part 1), and 158 in part 2B. AZD1775 monotherapy given as single dose was well tolerated, and the maximum-tolerated dose was not reached. In the combination regimens, the most common adverse events consisted of fatigue, nausea and vomiting, diarrhea, and hematologic toxicity. The maximum-tolerated doses and biologically effective doses were established for each combination. Target engagement, as a predefined 50% pCDK1 reduction in surrogate tissue, was observed in combination with cisplatin and carboplatin. Of 176 patients evaluable for efficacy, 94 (53%) had stable disease as best response, and 17 (10%) achieved a partial response. The response rate in TP53-mutated patients (n = 19) was 21% compared with 12% in TP53 wild-type patients (n = 33). Conclusion AZD1775 was safe and tolerable as a single agent and in combination with chemotherapy at doses associated with target engagement.

Trial registration: ClinicalTrials.gov NCT00648648.

Fig 1.

Study setup. The first part of the study consisted of monotherapy with AZD1775 given as one single dose. Parts 2A and 2B consist of three different treatment arms, with gemcitabine, carboplatin, or cisplatin, in the following two different schedules: one single dose of AZD1775 administered the day after the chemotherapy (part 2A) or five doses of AZD1775 given twice a day, with the first dose always starting concomitantly with chemotherapy. (*) AZD1775 administered on days 1 to 3, 8 to 10, and 15 to 17. (†) AZD1775 50 mg twice a day on days 1, 8, and 15; AZD1775 25 mg twice a day on days 2, 9, and 16; and 25 mg once a day on days 3, 10, and 16. AUC, area under the curve; MTD, maximum-tolerated dose.

Fig 2.

Mean concentration-time profiles for single-dose (SD) AZD1775 and multiple doses of AZD1775 alone and in combination with gemcitabine, carboplatin, or cisplatin (semi-log plot).

Fig A1.

Gene signature: fold-change means and 90% CIs for AZD1775 monotherapy doses (back-transformed from statistics on log2 scale).

Fig A2.

Gene signature: quantitative polymerase chain reaction four-gene signature score means and 90% CIs for monotherapy doses.