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.
abstract: 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.
authors.affiliation: Suzanne Leijen, Robin M.J.M. van Geel, Gabe S. Sonke, Daphne de Jong, Efraim H. Rosenberg, Serena Marchetti, Dick Pluim, Erik van Werkhoven, Jos H. Beijnen, and Jan H.M. Schellens, The Netherlands Cancer Institute, Amsterdam; Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands; and Shelonitda Rose, Mark A. Lee, and Tomoko Freshwater, Merck, Kenilworth, NJ.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Leijen
authors.affiliation: Suzanne Leijen, Robin M.J.M. van Geel, Gabe S. Sonke, Daphne de Jong, Efraim H. Rosenberg, Serena Marchetti, Dick Pluim, Erik van Werkhoven, Jos H. Beijnen, and Jan H.M. Schellens, The Netherlands Cancer Institute, Amsterdam; Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands; and Shelonitda Rose, Mark A. Lee, and Tomoko Freshwater, Merck, Kenilworth, NJ.
authors.forename: Robin M J M
authors.initials: RM
authors.lastname: van Geel
authors.affiliation: Suzanne Leijen, Robin M.J.M. van Geel, Gabe S. Sonke, Daphne de Jong, Efraim H. Rosenberg, Serena Marchetti, Dick Pluim, Erik van Werkhoven, Jos H. Beijnen, and Jan H.M. Schellens, The Netherlands Cancer Institute, Amsterdam; Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands; and Shelonitda Rose, Mark A. Lee, and Tomoko Freshwater, Merck, Kenilworth, NJ.
authors.forename: Gabe S
authors.initials: GS
authors.lastname: Sonke
authors.affiliation: Suzanne Leijen, Robin M.J.M. van Geel, Gabe S. Sonke, Daphne de Jong, Efraim H. Rosenberg, Serena Marchetti, Dick Pluim, Erik van Werkhoven, Jos H. Beijnen, and Jan H.M. Schellens, The Netherlands Cancer Institute, Amsterdam; Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands; and Shelonitda Rose, Mark A. Lee, and Tomoko Freshwater, Merck, Kenilworth, NJ.
authors.forename: Daphne
authors.initials: D
authors.lastname: de Jong
authors.affiliation: Suzanne Leijen, Robin M.J.M. van Geel, Gabe S. Sonke, Daphne de Jong, Efraim H. Rosenberg, Serena Marchetti, Dick Pluim, Erik van Werkhoven, Jos H. Beijnen, and Jan H.M. Schellens, The Netherlands Cancer Institute, Amsterdam; Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands; and Shelonitda Rose, Mark A. Lee, and Tomoko Freshwater, Merck, Kenilworth, NJ.
authors.forename: Efraim H
authors.initials: EH
authors.lastname: Rosenberg
authors.affiliation: Suzanne Leijen, Robin M.J.M. van Geel, Gabe S. Sonke, Daphne de Jong, Efraim H. Rosenberg, Serena Marchetti, Dick Pluim, Erik van Werkhoven, Jos H. Beijnen, and Jan H.M. Schellens, The Netherlands Cancer Institute, Amsterdam; Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands; and Shelonitda Rose, Mark A. Lee, and Tomoko Freshwater, Merck, Kenilworth, NJ.
authors.forename: Serena
authors.initials: S
authors.lastname: Marchetti
authors.affiliation: Suzanne Leijen, Robin M.J.M. van Geel, Gabe S. Sonke, Daphne de Jong, Efraim H. Rosenberg, Serena Marchetti, Dick Pluim, Erik van Werkhoven, Jos H. Beijnen, and Jan H.M. Schellens, The Netherlands Cancer Institute, Amsterdam; Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands; and Shelonitda Rose, Mark A. Lee, and Tomoko Freshwater, Merck, Kenilworth, NJ.
authors.forename: Dick
authors.initials: D
authors.lastname: Pluim
authors.affiliation: Suzanne Leijen, Robin M.J.M. van Geel, Gabe S. Sonke, Daphne de Jong, Efraim H. Rosenberg, Serena Marchetti, Dick Pluim, Erik van Werkhoven, Jos H. Beijnen, and Jan H.M. Schellens, The Netherlands Cancer Institute, Amsterdam; Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands; and Shelonitda Rose, Mark A. Lee, and Tomoko Freshwater, Merck, Kenilworth, NJ.
authors.forename: Erik
authors.initials: E
authors.lastname: van Werkhoven
authors.affiliation: Suzanne Leijen, Robin M.J.M. van Geel, Gabe S. Sonke, Daphne de Jong, Efraim H. Rosenberg, Serena Marchetti, Dick Pluim, Erik van Werkhoven, Jos H. Beijnen, and Jan H.M. Schellens, The Netherlands Cancer Institute, Amsterdam; Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands; and Shelonitda Rose, Mark A. Lee, and Tomoko Freshwater, Merck, Kenilworth, NJ.
authors.forename: Shelonitda
authors.initials: S
authors.lastname: Rose
authors.affiliation: Suzanne Leijen, Robin M.J.M. van Geel, Gabe S. Sonke, Daphne de Jong, Efraim H. Rosenberg, Serena Marchetti, Dick Pluim, Erik van Werkhoven, Jos H. Beijnen, and Jan H.M. Schellens, The Netherlands Cancer Institute, Amsterdam; Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands; and Shelonitda Rose, Mark A. Lee, and Tomoko Freshwater, Merck, Kenilworth, NJ.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lee
authors.affiliation: Suzanne Leijen, Robin M.J.M. van Geel, Gabe S. Sonke, Daphne de Jong, Efraim H. Rosenberg, Serena Marchetti, Dick Pluim, Erik van Werkhoven, Jos H. Beijnen, and Jan H.M. Schellens, The Netherlands Cancer Institute, Amsterdam; Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands; and Shelonitda Rose, Mark A. Lee, and Tomoko Freshwater, Merck, Kenilworth, NJ.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Freshwater
authors.affiliation: Suzanne Leijen, Robin M.J.M. van Geel, Gabe S. Sonke, Daphne de Jong, Efraim H. Rosenberg, Serena Marchetti, Dick Pluim, Erik van Werkhoven, Jos H. Beijnen, and Jan H.M. Schellens, The Netherlands Cancer Institute, Amsterdam; Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands; and Shelonitda Rose, Mark A. Lee, and Tomoko Freshwater, Merck, Kenilworth, NJ.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Suzanne Leijen, Robin M.J.M. van Geel, Gabe S. Sonke, Daphne de Jong, Efraim H. Rosenberg, Serena Marchetti, Dick Pluim, Erik van Werkhoven, Jos H. Beijnen, and Jan H.M. Schellens, The Netherlands Cancer Institute, Amsterdam; Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands; and Shelonitda Rose, Mark A. Lee, and Tomoko Freshwater, Merck, Kenilworth, NJ.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D009426:Netherlands; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D011744:Pyrimidinones; D012074:Remission Induction; D015996:Survival Rate; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016190:Carboplatin; C549567:adavosertib