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/m), cisplatin (75 mg/m), 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.

Synergy of WEE1 and mTOR Inhibition in Mutant KRAS-Driven Lung Cancers

“…It will be of interest to determine whether combinatorial effects are even more profound in LKB1-deficient mouse models. Notably, we did not detect any drug-related toxicity during the course of 3-week treatment on mice, consistent with a recent Phase I study showing AZD1775 tolerability and safety as monotherapy and in combination with standard chemotherapy in 202 patients (49). …”

A Small-Molecule Inhibitor of WEE1, AZD1775, Synergizes with Olaparib by Impairing Homologous Recombination and Enhancing DNA Damage and Apoptosis in Acute Leukemia

“…At doses achievable in the plasma of patients (28), AZD1775 potentiated the reduction in proliferation induced by olaparib in four out of five cell lines (Figure 2a and Supplemental Figure 3). In order to better model a clinical setting in which cancer cells are exposed to varying drug concentrations over time, we examined a wider range of drug combinations in MV4;11 cells.…”

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

“…Responses were observed in patients with ovarian cancer (n ¼ 7), melanoma (n ¼ 3), breast cancer (n ¼ 2), head and neck cancer (n ¼ 3), colorectal cancer (n ¼ 1), and SCC of the skin (n ¼ 1). Patients with TP53 mutations (4/19, 23%) had a partial response compared with 4/33 (12%) of patients with TP53 wild-type tumors (38).…”