TY - JOUR
T1 - WEE1 inhibitor adavosertib in combination with carboplatin in advanced TP53 mutated ovarian cancer
T2 - A biomarker-enriched phase II study
AU - Embaby, Alaa
AU - Kutzera, Joachim
AU - Geenen, Jill J
AU - Pluim, Dick
AU - Hofland, Ingrid
AU - Sanders, Joyce
AU - Lopez-Yurda, Marta
AU - Beijnen, Jos H
AU - Huitema, Alwin D R
AU - Witteveen, Petronella O
AU - Steeghs, Neeltje
AU - van Haaften, Gijs
AU - van Vugt, Marcel A T M
AU - de Ridder, Jeroen
AU - Opdam, Frans L
N1 - Funding Information:
The authors would like to thank all patients, their families and the entire study team at the Netherlands Cancer Institute, Utrecht University Medical Center and University Medical Center Groningen. We would like to acknowledge the NKI- AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for supplying NKI-AVL Biobank material and lab support. Drug and funding support for this study was provided by AstraZeneca and research support by KWF Dutch Cancer Society.
Funding Information:
The authors would like to thank all patients, their families and the entire study team at the Netherlands Cancer Institute, Utrecht University Medical Center and University Medical Center Groningen. We would like to acknowledge the NKI- AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for supplying NKI-AVL Biobank material and lab support. Drug and funding support for this study was provided by AstraZeneca and research support by KWF Dutch Cancer Society.
Publisher Copyright:
© 2023 Elsevier Inc.
PY - 2023/7
Y1 - 2023/7
N2 - OBJECTIVE: In the first part of this phase II study (NCT01164995), the combination of carboplatin and adavosertib (AZD1775) was shown to be safe and effective in patients with TP53 mutated platinum-resistant ovarian cancer (PROC). Here, we present the results of an additional safety and efficacy cohort and explore predictive biomarkers for resistance and response to this combination treatment.METHODS: This is a phase II, open-label, non-randomized study. Patients with TP53 mutated PROC received carboplatin AUC 5 mg/ ml·min intravenously and adavosertib 225 mg BID orally for 2.5 days in a 21-day cycle. The primary objective is to determine the efficacy and safety of carboplatin and adavosertib. Secondary objectives include progression-free survival (PFS), changes in circulating tumor cells (CTC) and exploration of genomic alterations.RESULTS: Thirty-two patients with a median age of 63 years (39-77 years) were enrolled and received treatment. Twenty-nine patients were evaluable for efficacy. Bone marrow toxicity, nausea and vomiting were the most common adverse events. Twelve patients showed partial response (PR) as best response, resulting in an objective ORR of 41% in the evaluable patients (95% CI: 23%-61%). The median PFS was 5.6 months (95% CI: 3.8-10.3). In patients with tumors harboring CCNE1 amplification, treatment efficacy was slightly but not significantly better.CONCLUSIONS: Adavosertib 225 mg BID for 2.5 days and carboplatin AUC 5 could be safely combined and showed anti-tumor efficacy in patients with PROC. However, bone marrow toxicity remains a point of concern, since this is the most common reason for dose reductions and dose delays.
AB - OBJECTIVE: In the first part of this phase II study (NCT01164995), the combination of carboplatin and adavosertib (AZD1775) was shown to be safe and effective in patients with TP53 mutated platinum-resistant ovarian cancer (PROC). Here, we present the results of an additional safety and efficacy cohort and explore predictive biomarkers for resistance and response to this combination treatment.METHODS: This is a phase II, open-label, non-randomized study. Patients with TP53 mutated PROC received carboplatin AUC 5 mg/ ml·min intravenously and adavosertib 225 mg BID orally for 2.5 days in a 21-day cycle. The primary objective is to determine the efficacy and safety of carboplatin and adavosertib. Secondary objectives include progression-free survival (PFS), changes in circulating tumor cells (CTC) and exploration of genomic alterations.RESULTS: Thirty-two patients with a median age of 63 years (39-77 years) were enrolled and received treatment. Twenty-nine patients were evaluable for efficacy. Bone marrow toxicity, nausea and vomiting were the most common adverse events. Twelve patients showed partial response (PR) as best response, resulting in an objective ORR of 41% in the evaluable patients (95% CI: 23%-61%). The median PFS was 5.6 months (95% CI: 3.8-10.3). In patients with tumors harboring CCNE1 amplification, treatment efficacy was slightly but not significantly better.CONCLUSIONS: Adavosertib 225 mg BID for 2.5 days and carboplatin AUC 5 could be safely combined and showed anti-tumor efficacy in patients with PROC. However, bone marrow toxicity remains a point of concern, since this is the most common reason for dose reductions and dose delays.
UR - http://www.scopus.com/inward/record.url?scp=85162234298&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2023.05.063
DO - 10.1016/j.ygyno.2023.05.063
M3 - Article
C2 - 37236033
SN - 0090-8258
VL - 174
SP - 239
EP - 246
JO - Gynecologic Oncology
JF - Gynecologic Oncology
ER -