Adavosertib with Chemotherapy in Patients with Primary Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer: An Open-Label, Four-Arm, Phase II Study.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 01 2022
01 01 2022
Historique:
received:
18
01
2021
revised:
08
06
2021
accepted:
06
10
2021
pubmed:
15
10
2021
medline:
14
1
2022
entrez:
14
10
2021
Statut:
ppublish
Résumé
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. 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. 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 progression-free 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]. 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.
Identifiants
pubmed: 34645648
pii: 1078-0432.CCR-21-0158
doi: 10.1158/1078-0432.CCR-21-0158
doi:
Substances chimiques
Pyrazoles
0
Pyrimidinones
0
Platinum
49DFR088MY
Carboplatin
BG3F62OND5
adavosertib
K2T6HJX3I3
Paclitaxel
P88XT4IS4D
Banques de données
ClinicalTrials.gov
['NCT02272790']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Comment
Langues
eng
Sous-ensembles de citation
IM
Pagination
36-44Commentaires et corrections
Type : CommentOn
Informations de copyright
©2021 American Association for Cancer Research.
Références
NCCN Clinical Practice Guidelines in Oncology: ovarian cancer version 2. 2018.
Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24:vi24–32.
Davis A, Tinker AV, Friedlander M. “Platinum resistant” ovarian cancer: what is it, who to treat and how to measure benefit?. Gynecol Oncol. 2014;133:624–31.
Luvero D, Milani A, Ledermann JA. Treatment options in recurrent ovarian cancer: latest evidence and clinical potential. Ther Adv Med Oncol. 2014;6:229–39.
Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32:1302–8.
Merck KGaA, Darmstadt, Germany, and Pfizer provide update on avelumab in platinum-resistant/refractory ovarian cancer. 2018.
Columbus G. Avelumab misses primary endpoints in phase III ovarian cancer trial. 2018.
Liu J, Matulonis UA. New strategies in ovarian cancer: translating the molecular complexity of ovarian cancer into treatment advances. Clin Cancer Res. 2014;20:5150–6.
Colombo N, Conte PF, Pignata S, Raspagliesi F, Scambia G. Bevacizumab in ovarian cancer: focus on clinical data and future perspectives. Crit Rev Oncol Hematol. 2016;97:335–48.
Konecny GE, Kristeleit RS. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. Br J Cancer. 2016;115:1157–73.
Sandhu SK, Schelman WR, Wilding G, Moreno V, Baird RD, Miranda S, et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2013;14:882–92.
Moore K, Secord AA, Geller MA, Miller DS, Cloven NG, Fleming GF. QUADRA: a phase 2, open-label, single-arm study to evaluate niraparib in patients (pts) with relapsed ovarian cancer (ROC) who have received ≥3 prior chemotherapy regimens. J Clin Oncol. 2018;36.
Ahmed AA, Etemadmoghadam D, Temple J, Lynch AG, Riad M, Sharma R, et al. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J Pathol. 2010;221:49–56.
Aarts M, Sharpe R, Garcia-Murillas I, Gevensleben H, Hurd MS, Shumway SD, et al. Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1. Cancer Discov. 2012;2:524–39.
Hirai H, Iwasawa Y, Okada M, Arai T, Nishibata T, Kobayashi M, et al. Small-molecule inhibition of WEE1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Cancer Ther. 2009;8:2992–3000.
Leijen S, van Geel RM, Pavlick AC, Tibes R, Rosen LAbdul Razak AR, et al. Phase I study evaluating WEE1 inhibitor AZD1775 as monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors. J Clin Oncol. 2016;34:4371–80.
Lewis CW, Jin Z, Macdonald D, Wei W, Qian XJ, Choi WS, et al. Prolonged mitotic arrest induced by WEE1 inhibition sensitizes breast cancer cells to paclitaxel. Oncotarget. 2017;8:73705–22.
Hirai H, Arai T, Okada M, Nishibata T, Kobayashi M, Sakai N, et al. MK-1775, a small molecule WEE1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol Ther. 2010;9:514–22.
Bridges KA, Hirai H, Buser CA, Brooks C, Liu H, Buchholz TA, et al. MK-1775, a novel WEE1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clin Cancer Res. 2011;17:5638–48.
Rajeshkumar NV, De Oliveira E, Ottenhof N, Watters J, Brooks D, Demuth T, et al. MK1775, a potent WEE1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Clin Cancer Res. 2011;17:2799–806.
Oza AM, Estevez-Diz M, Grischke E-M, Hall M, Marmé F, Provencher D, et al. A biomarker-enriched, randomized phase II trial of adavosertib (AZD1775) plus paclitaxel and carboplatin for women with platinum-sensitive TP53-mutant ovarian cancer. Clin Cancer Res. 2020;26:4767–76.
Leijen S, van Geel RM, Sonke GS, de Jong D, Rosenberg EH, Marchetti S, et al. 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. J Clin Oncol. 2016;34:4354–61.
Lheureux S, Cristea MC, Bruce JP, Garg S, Cabanero M, Mantia-Smaldone G, et al. Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2021;397:281–92.
Markman M, Blessing J, Rubin SC, Connor J, Hanjani P, Waggoner S. Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a Gynecologic Oncology Group study. Gynecol Oncol. 2006;101:436–40.
Gabizon AA. Stealth liposomes and tumour targeting: one step further in the quest for the magic bullet. Clin Cancer Res. 2001;7:223–5.
Park HJ, Bae JS, Kim KM, Moon YJ, Park S-H, Ha SH. The PARP inhibitor olaparib potentiates the effect of the DNA damaging agent doxorubicin in osteosarcoma. J Exp Clin Cancer Res. 2018;37:107.
Någård M, Ah-See M-L, So K, Strauss J, Wise-Draper T, Safran H, et al. Phase I study to assess the effect of adavosertib (AZD1775) on the pharmacokinetics of substrates of CYP1A2, CYP2C19 and CYP3A4 in patients with advanced solid tumors. Cancer Res. 2020;80.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 2010.
Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer. 2011;21:419–23.
Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31:1023–31.
Williams LL, Fudge M, Burnett LS, Jones HW. Salvage carboplatin therapy for advanced ovarian cancer after first-line treatment with cisplatin. Am J Clin Oncol. 1992;15:331–6.
Kavanagh J, Tresukosol D, Edwards C, Freedman R, Gonzalez de Leon C, Fishman A, et al. Carboplatin reinduction after taxane in patients with platinum-refractory epithelial ovarian cancer. J Clin Oncol. 1995;13:1584–8.
Naumann RW, Coleman RL. Management strategies for recurrent platinum-resistant ovarian cancer. Drugs. 2011;71:1397–412.
Markman M, Webster K, Zanotti K, Kulp B, Peterson G, Belinson J. Phase 2 trial of single-agent gemcitabine in platinum-paclitaxel refractory ovarian cancer. Gynecol Oncol. 2003;90:593–6.
D'Agostino G, Amant F, Berteloot P, Scambia G, Vergote I. Phase II study of gemcitabine in recurrent platinum-and paclitaxel-resistant ovarian cancer. Gynecol Oncol. 2003;88:266–9.
Benson AB, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA Jr, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004;22:2918–26.
Colombo N, Sessa C, du Bois A, Ledermann J, McCluggage WG, McNeish I, et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Ann Oncol. 2019;30:672–705.
Trillsch F, Mahner S, Hilpert F, Davies L, García-Martínez E, Kristensen G, et al. Prognostic and predictive effects of primary versus secondary platinum resistance for bevacizumab treatment for platinum-resistant ovarian cancer in the AURELIA trial. Ann Oncol. 2016;27:1733–9.
Bauer TM, Jones SF, Greenlees C, Cook C, Jewsbury PJ, Mugundu G, et al. A phase Ib, open-label, multi-center study to assess the safety, tolerability, pharmacokinetics, and anti-tumor activity of AZD1775 monotherapy in patients with advanced solid tumors: expansion cohorts. J Clin Oncol. 2016;34.
Ayhan A, Kuhn E, Wu RC, Ogawa H, Bahadirli-Talbott A, Mao T-L, et al. CCNE1 copy-number gain and overexpression identify ovarian clear cell carcinoma with a poor prognosis. Modern Pathol. 2017;30:297–303.