TY - JOUR
T1 - Adavosertib with Chemotherapy in Patients with Primary Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer
T2 - An Open-Label, Four-Arm, Phase II Study
AU - Moore, Kathleen N.
AU - Chambers, Setsuko K.
AU - Hamilton, Erika P.
AU - Chen, Lee May
AU - Oza, Amit M.
AU - Ghamande, Sharad A.
AU - Konecny, Gottfried E.
AU - Plaxe, Steven C.
AU - Spitz, Daniel L.
AU - Geenen, Jill J.J.
AU - Troso-Sandoval, Tiffany A.
AU - Cragun, Janiel M.
AU - Rodrigo Imedio, Esteban
AU - Kumar, Sanjeev
AU - Mugundu, Ganesh M.
AU - Lai, Zhongwu
AU - Chmielecki, Juliann
AU - Jones, Suzanne F.
AU - Spigel, David R.
AU - Cadoo, Karen A.
N1 - Funding Information:
K.N. Moore reports grants and personal fees from AstraZeneca during the conduct of the study. K.N. Moore also reports grants and personal fees from Genentech/Roche, Immunogen, Clovis, Tesaro, Pfizer, and OncoMed; grants from Lilly; personal fees from Janssen, Aravive, VBL Therapeutics, Samumed, Eisai, GSK, Vavotar, and Tarveda outside the submitted work. E.P. Hamilton reports grants from OncoMed, Genentech/Roche, Zymeworks, Rgenix, ArQule, Clovis, Silverback Therapeutics, Millenium, Acerta, Sermonix, Torque, Black Diamond, Karyopharm, Infinity Pharmaceuticals, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana-Farber Cancer Hospital, Hutchinson Med-iPharma, MedImmune, Seagen, Puma Biotechnology, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Takeda, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Polyphor, Immunogen, Plexxicon, Amgen, Akesobio Australia, and Shattuck Labs, as well as other support from Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, and Seagen during the conduct of the study. A.M. Oza reports grants, non-financial support, and other support from AstraZeneca outside the submitted work. S.A. Ghamande reports grants from AstraZeneca during the conduct of the study, as well as personal fees from GSK and Eisai outside the submitted work. G.E. Konecny reports being a speaker for AstraZeneca, Clovis, and GSK, as well as research funding from Lilly and Merck. S.C. Plaxe reports grants from AstraZeneca during the conduct of the study, as well as other support from AstraZeneca outside the submitted work. D.L. Spitz reports personal fees from Sarah Cannon Research during the conduct of the study. E. Rodrigo Imedio reports other support from AstraZeneca during the conduct of the study, as well as other support from BioNTech SE outside the submitted work. Z. Lai reports employment and ownership of stock with AstraZeneca. J. Chmielecki reports personal fees and other support from AstraZeneca during the conduct of the study, as well as personal fees and other
Funding Information:
The study was funded by AstraZeneca, which participated in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The authors would like to thank all participating patients and their families. Manuscript drafting was conducted by Sarah Cannon Development Innovations and Ben Drever, PhD, of AMICULUM, with funding from AstraZeneca.
Publisher Copyright:
© 2022 American Association for Cancer Research Inc.. All rights reserved.
PY - 2022/1/1
Y1 - 2022/1/1
N2 - Purpose: This study assessed the efficacy, safety, and pharmacokinetics of adavosertib in combination with four chemotherapy agents commonly used in patients with primary platinum-resistant ovarian cancer. Patients and Methods: Women with histologically or cytologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled between January 2015 and January 2018 in this open-label, four-arm, multicenter, phase II study. Patients received adavosertib (oral capsules, 2 days on/5 days off or 3 days on/4 days off) in six cohorts from 175 mg once daily to 225 mg twice daily combined with gemcitabine, paclitaxel, carboplatin, or pegylated liposomal doxorubicin. The primary outcome measurement was overall response rate. Results: Three percent of patients (3/94) had confirmed complete response and 29% (27/94) had confirmed partial response. The response rate was highest with carboplatin plus weekly adavosertib, at 66.7%, with 100% disease control rate, and median progressionfree survival of 12.0 months. The longest median duration of response was in the paclitaxel cohort (12.0 months). The most common grade ≥3 adverse events across all cohorts were neutropenia [45/94 (47.9%) patients], anemia [31/94 (33.0%)], thrombocytopenia [30/94 (31.9%)], and diarrhea and vomiting [10/94 (10.6%) each]. Conclusions: Adavosertib showed preliminary efficacy when combined with chemotherapy. The most promising treatment combination was adavosertib 225 mg twice daily on days 1-3, 8-10, and 15-17 plus carboplatin every 21 days. However, hematologic toxicity was more frequent than would be expected for carboplatin monotherapy, and the combination requires further study to optimize the dose, schedule, and supportive medications.
AB - Purpose: This study assessed the efficacy, safety, and pharmacokinetics of adavosertib in combination with four chemotherapy agents commonly used in patients with primary platinum-resistant ovarian cancer. Patients and Methods: Women with histologically or cytologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled between January 2015 and January 2018 in this open-label, four-arm, multicenter, phase II study. Patients received adavosertib (oral capsules, 2 days on/5 days off or 3 days on/4 days off) in six cohorts from 175 mg once daily to 225 mg twice daily combined with gemcitabine, paclitaxel, carboplatin, or pegylated liposomal doxorubicin. The primary outcome measurement was overall response rate. Results: Three percent of patients (3/94) had confirmed complete response and 29% (27/94) had confirmed partial response. The response rate was highest with carboplatin plus weekly adavosertib, at 66.7%, with 100% disease control rate, and median progressionfree survival of 12.0 months. The longest median duration of response was in the paclitaxel cohort (12.0 months). The most common grade ≥3 adverse events across all cohorts were neutropenia [45/94 (47.9%) patients], anemia [31/94 (33.0%)], thrombocytopenia [30/94 (31.9%)], and diarrhea and vomiting [10/94 (10.6%) each]. Conclusions: Adavosertib showed preliminary efficacy when combined with chemotherapy. The most promising treatment combination was adavosertib 225 mg twice daily on days 1-3, 8-10, and 15-17 plus carboplatin every 21 days. However, hematologic toxicity was more frequent than would be expected for carboplatin monotherapy, and the combination requires further study to optimize the dose, schedule, and supportive medications.
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U2 - 10.1158/1078-0432.CCR-21-0158
DO - 10.1158/1078-0432.CCR-21-0158
M3 - Article
C2 - 34645648
AN - SCOPUS:85122960633
SN - 1078-0432
VL - 28
SP - 36
EP - 44
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -