Reference Detail

Ref Type

Journal Article

PMID

(27998224)

Authors

Leijen S, van Geel RM, Sonke GS, de Jong D, Rosenberg EH, Marchetti S, Pluim D, van Werkhoven E, Rose S, Lee MA, Freshwater T, Beijnen JH, Schellens JH

Title

Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology	34	36	2016 Dec 20	4354-4361	J Clin Oncol

URL

Abstract Text

Purpose AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. In a phase I study, the maximum tolerated dose of AZD1775 in combination with carboplatin demonstrated target engagement. We conducted a proof-of-principle phase II study in patients with p53 tumor suppressor gene ( TP53)-mutated ovarian cancer refractory or resistant (< 3 months) to first-line platinum-based therapy to determine overall response rate, progression-free and overall survival, pharmacokinetics, and modulation of phosphorylated cyclin-dependent kinase (CDK1) in skin biopsies. Patients and Methods Patients were treated with carboplatin (area under the curve, 5 mg/mL⋅min) combined with AZD1775 225 mg orally twice daily over 2.5 days every 21-day cycle until disease progression. Results AZD1775 plus carboplatin demonstrated manageable toxicity; fatigue (87%), nausea (78%), thrombocytopenia (70%), diarrhea (70%), and vomiting (48%) were the most common adverse events. The most frequent grade 3 or 4 adverse events were thrombocytopenia (48%) and neutropenia (37%). Of 24 patients enrolled, 21 patients were evaluable for efficacy end points. The overall response rate was 43% (95% CI, 22% to 66%), including one patient (5%) with a prolonged complete response. Median progression-free and overall survival times were 5.3 months (95% CI, 2.3 to 9.0 months) and 12.6 months (95% CI, 4.9 to 19.7), respectively, with two patients with ongoing response for more than 31 and 42 months at data cutoff. Conclusion To our knowledge, this is the first report providing clinical proof that AZD1775 enhances carboplatin efficacy in TP53-mutated tumors. The encouraging antitumor activity observed in patients with TP53-mutated ovarian cancer who were refractory or resistant (< 3 months) to first-line therapy warrants further development.

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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
TP53 Y163*	ovarian cancer	predicted - sensitive	Adavosertib + Carboplatin	Case Reports/Case Series	Actionable	In a Phase II trial, Paraplatin (carboplatin) and Adavosertib (MK-1775) combination treatment resulted in partial response in an ovarian cancer patient harboring TP53 Y163* (PMID: 27998224; NCT01164995).	27998224
TP53 mutant	ovarian cancer	predicted - sensitive	Adavosertib + Carboplatin	Phase II	Actionable	In a Phase II trial, Paraplatin (carboplatin) and Adavosertib (MK-1775) combination treatment resulted in an overall response rate of 43% (9/21), a median progression-free survival of 5.3 months and a median overall survival of 12.6 months in ovarian cancer patients harboring TP53 mutations (PMID: 27998224; NCT01164995).	27998224
TP53 P98fs TP53 R175C TP53 S215G	ovarian cancer	predicted - resistant	Adavosertib + Carboplatin	Case Reports/Case Series	Actionable	In a Phase II trial, Paraplatin (carboplatin) and Adavosertib (MK-1775) combination treatment resulted in disease progression in an ovarian cancer patient harboring TP53 P98fs, R175C, and S215G (PMID: 27998224; NCT01164995).	27998224