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Open Access 12-05-2023 | Solid Tumor | Research

A phase Ib study of adavosertib, a selective Wee1 inhibitor, in patients with locally advanced or metastatic solid tumors

Authors: Gerald S Falchook, Jasgit Sachdev, Esteban Rodrigo Imedio, Sanjeev Kumar, Ganesh M Mugundu, Suzanne Jenkins, Juliann Chmielecki, Suzanne Jones, David R Spigel, Melissa Johnson

Published in: Investigational New Drugs | Issue 3/2023

Abstract

Adavosertib selectively inhibits Wee1, which regulates intra-S and G2/M cell-cycle checkpoints. This study investigated dosing schedules for adavosertib monotherapy, determining the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients with advanced solid tumors.

Patients received oral adavosertib qd or bid on a 5/9 schedule (5 days on treatment, 9 days off) in 14-day cycles, or qd on one of two 5/2 schedules (weekly, or for 2 of 3 weeks) in 21-day cycles. Safety, efficacy, and pharmacokinetic analyses were performed.

Sixty-two patients (female, 64.5%; median age, 61.5 years; most common primary tumors: lung [24.2%], ovary [21.0%]) received treatment (qd schedules, n = 50; bid schedules, n = 12) for 1.8 months (median). Median time to maximum adavosertib concentration was 2.2–4.1 h; mean half-life was 5–12 h. Adverse events (AEs) caused dose reductions, interruptions and discontinuations in 17 (27.4%), 25 (40.3%) and 4 (6.5%) patients, respectively. Most common grade ≥ 3 AEs were anemia, neutropenia (each n = 9, 14.5%) and diarrhea (n = 8, 12.9%). Seven (11.3%) patients experienced 10 treatment-related serious AEs (pneumonia n = 2 [3.2%], dehydration n = 2 [3.2%], anemia n = 1 [1.6%], febrile neutropenia n = 1 [1.6%], and thrombocytopenia n = 1 [1.6%]). Overall objective response rate was 3.4% (2/58); disease control rate was 48.4% (30/62); median progression-free survival was 2.7 months.

MTDs were 125 mg (bid 5/9) and 300 mg (qd 5/9 and 5/2 for 2 of 3 weeks); RP2D was 300 mg (qd 5/2 for 2 of 3 weeks). The safety profile was manageable, acceptable, and generally concordant with the known safety profile.

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Watanabe N, Broome M, Hunter T (1995) Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle. EMBO J 14(9):1878–1891CrossRefPubMedPubMedCentral

Dominguez-Kelly R, Martin Y, Koundrioukoff S et al (2011) Wee1 controls genomic stability during replication by regulating the Mus81-Eme1 endonuclease. J Cell Biol 194(4):567–579. https://doi.org/10.1083/jcb.201101047CrossRefPubMedPubMedCentral

Hirai H, Iwasawa Y, Okada M et al (2009) Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Cancer Ther 8(11):2992–3000. https://doi.org/10.1158/1535-7163.MCT-09-0463CrossRefPubMed

Beck H, Nahse-Kumpf V, Larsen MS et al (2012) Cyclin-dependent kinase suppression by WEE1 kinase protects the genome through control of replication initiation and nucleotide consumption. Mol Cell Biol 32(20):4226–4236. https://doi.org/10.1128/MCB.00412-12CrossRefPubMedPubMedCentral

Hirai H, Arai T, Okada M et al (2010) MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol Ther 9(7):514–522. https://doi.org/10.4161/cbt.9.7.11115CrossRefPubMed

Rajeshkumar NV, De Oliveira E, Ottenhof N et al (2011) MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Clin Cancer Res 17(9):2799–2806. https://doi.org/10.1158/1078-0432.CCR-10-2580CrossRefPubMedPubMedCentral

Guertin AD, Li J, Liu Y et al (2013) Preclinical evaluation of the WEE1 inhibitor MK-1775 as single-agent anticancer therapy. Mol Cancer Ther 12(8):1442–1452. https://doi.org/10.1158/1535-7163.MCT-13-0025CrossRefPubMed

Kreahling JM, Gemmer JY, Reed D, Letson D, Bui M, Altiok S (2012) MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells. Mol Cancer Ther 11(1):174–182. https://doi.org/10.1158/1535-7163.MCT-11-0529CrossRefPubMed

Do K, Wilsker D, Ji J et al (2015) Phase I study of single-agent AZD1775 (MK-1775), a WEE1 kinase inhibitor, in patients with refractory solid tumors. J Clin Oncol 33(30):3409–3415. https://doi.org/10.1200/JCO.2014.60.4009CrossRefPubMedPubMedCentral

10.

Liu JF, Xiong N, Campos SM et al (2021) Phase II study of the WEE1 inhibitor adavosertib in recurrent uterine serous carcinoma. J Clin Oncol 39(14):1531–1539. https://doi.org/10.1200/jco.20.03167CrossRefPubMed

11.

Castedo M, Perfettini J, Roumier T, Andreau K, Medema R, Kroemer G (2004) Cell death by mitotic catastrophe: a molecular definition. Oncogene 23(16):2825–2837. https://doi.org/10.1038/sj.onc.1207528CrossRefPubMed

12.

Patel MR, Falchook GS, Wang JS-Z et al (2019) Open-label, multicenter, phase I study to assess safety and tolerability of adavosertib plus durvalumab in patients with advanced solid tumors. J Clin Oncol 37(Suppl):abstract2562CrossRef

13.

Leijen S, van Geel R, Pavlick A et al (2016) 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 34(36):4371–4380. https://doi.org/10.1200/JCO.2016.67.5991CrossRefPubMedPubMedCentral

14.

Hamilton E, Falchook GS, Wang JS et al Phase Ib study of adavosertib in combination with olaparib in patients with refractory solid tumors: dose escalation. American Association for Cancer Research Annual Meeting, Atlanta, GA, USA, March 29–April 3, 2019; abstract CT025

15.

Bauer TM, Moore K, Rader JS et al (2019) Open-label, multicenter, phase ib study to assess safety, tolerability and efficacy of adavosertib monotherapy in patients with advanced solid tumors: expansion cohorts.Cancer Res79(13 Suppl):abstract CT012

16.

Takebe N, Naqash AR, O’Sullivan Coyne G et al (2021) Safety, Antitumor Activity, and Biomarker Analysis in a phase I trial of the once-daily Wee1 inhibitor adavosertib (AZD1775) in patients with Advanced Solid Tumors. Clin Cancer Res 27(14):3834–3844. https://doi.org/10.1158/1078-0432.Ccr-21-0329CrossRefPubMedPubMedCentral

17.

Eisenhauer E, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. https://doi.org/10.1016/j.ejca.2008.10.026CrossRefPubMed

18.

AstraZeneca (2015) AstraZeneca global policy bioethics. https://www.astrazeneca.com/content/dam/az/our-company/Documents/Bioethics-Policy.pdf. Accessed 23 July 2021

19.

Clark TA, Chung JH, Kennedy M et al (2018) Analytical Validation of a hybrid capture-based next-generation sequencing clinical assay for genomic profiling of cell-free circulating tumor DNA. J Mol Diagn 20(5):686–702. https://doi.org/10.1016/j.jmoldx.2018.05.004CrossRefPubMedPubMedCentral

20.

US Department of Health and Human Services, Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER) (2002) Guidance for industry. Food-effect bioavailability and fed bioequivalence studies. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070241.pdf

21.

Lheureux S, Cristea MC, Bruce JP et al (2021) Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 397(10271):281–292. https://doi.org/10.1016/s0140-6736(20)32554-xCrossRefPubMed

22.

Moore KN, Chambers SK, Hamilton EP et al (2022) Adavosertib with Chemotherapy in patients with primary platinum-resistant ovarian, fallopian tube, or peritoneal Cancer: an Open-Label, Four-Arm, phase II study. Clin Cancer Res 28(1):36–44. https://doi.org/10.1158/1078-0432.Ccr-21-0158CrossRefPubMed

23.

Westin SN, Coleman RL, Fellman BM et al (2021) EFFORT: EFFicacy of adavosertib in parp ResisTance: a randomized two-arm non-comparative phase II study of adavosertib with or without olaparib in women with PARP-resistant ovarian cancer. J Clin Oncol 39(15suppl):5505. https://doi.org/10.1200/JCO.2021.39.15_suppl.5505CrossRef

24.

Yap TA, Ngoi N, Dumbrava EE et al (2022) NCI10329: phase ib Sequential Trial of Agents against DNA Repair (STAR) study to investigate the sequential combination of the poly (ADP-Ribose) polymerase inhibitor (PARPi) olaparib (ola) and WEE1 inhibitor (WEE1i) adavosertib (ada) in patients (pts) with DNA damage response (DDR)-aberrant advanced tumors, enriched for BRCA1/2 mutated and CCNE1 amplified cancers. Eur J Cancer 174:S7. https://doi.org/10.1016/S0959-8049(22)00822-XCrossRef

25.

Någård M, Ah-See ML, So K et al (2020) Effect of food on the pharmacokinetics of the WEE1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors. Cancer Chemother Pharmacol 86(1):97–108. https://doi.org/10.1007/s00280-020-04101-4CrossRefPubMedPubMedCentral

Title: A phase Ib study of adavosertib, a selective Wee1 inhibitor, in patients with locally advanced or metastatic solid tumors
Authors: Gerald S Falchook
Jasgit Sachdev
Esteban Rodrigo Imedio
Sanjeev Kumar
Ganesh M Mugundu
Suzanne Jenkins
Juliann Chmielecki
Suzanne Jones
David R Spigel
Melissa Johnson
Publication date: 12-05-2023
Publisher: Springer US
Keyword: Solid Tumor
Published in: Investigational New Drugs / Issue 3/2023
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-023-01371-6

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