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