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Ref Type Journal Article
PMID (27601554)
Authors Leijen S, van Geel RM, Pavlick AC, Tibes R, Rosen L, Razak AR, Lam R, Demuth T, Rose S, Lee MA, Freshwater T, Shumway S, Liang LW, Oza AM, Schellens JH, Shapiro GI
Title Phase I Study Evaluating WEE1 Inhibitor AZD1775 As Monotherapy and in Combination With Gemcitabine, Cisplatin, or Carboplatin in Patients With Advanced Solid Tumors.
Journal Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Vol 34
Issue 36
Date 2016 12 20
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Advanced Solid Tumor not applicable Adavosertib + Gemcitabine Phase I Actionable In a Phase I trial, the combination of Adavosertib (MK-1775) and Gemzar (gemcitabine) resulted in a partial response in 5% (4/81) of patients and stable disease in 53% (43/81) of patients, all with advanced solid tumors (PMID: 27601554). 27601554
Unknown unknown Advanced Solid Tumor not applicable Adavosertib Phase I Actionable In a Phase I trial, Adavosertib (MK-1775) combined with a chemotherapy resulted in a partial response of 10% (17/176) and stable disease in 53% (94/176) of patients with advanced solid tumors (PMID: 27601554). 27601554
Unknown unknown Advanced Solid Tumor not applicable Adavosertib + Cisplatin Phase I Actionable In a Phase I trial, the combination of Adavosertib (MK-1775) and Platinol (cisplatin) resulted in a partial response in 15.5% (9/58) of patients and stable disease in 40% (23/58) of patients, all with advanced solid tumors (PMID: 27601554). 27601554
Unknown unknown Advanced Solid Tumor not applicable Adavosertib + Carboplatin Phase I Actionable In a Phase I trial, the combination of Adavosertib (MK-1775) and Paraplatin (carboplatin) resulted in a partial response in 6.5% (4/62) of patients and stable disease in 45% (28/62) of patients, all with advanced solid tumors (PMID: 27601554). 27601554