Phase I trial of WEE1 inhibition with chemotherapy and radiotherapy as adjuvant treatment, and a window of opportunity trial with cisplatin in patients with head and neck cancer: the WISTERIA trial protocol

Anthony Kong, James Good, Amanda Kirkham, Joshua Savage, Rhys Mant, Laura Llewellyn, Joanna Parish, Rachel Spruce, Martin Forster, Stefano Schipani, Kevin Harrington, Joseph Sacco, Patrick Murray, Gary Middleton, Christina Yap, Hisham Mehanna, Anthony Kong, James Good, Amanda Kirkham, Joshua Savage, Rhys Mant, Laura Llewellyn, Joanna Parish, Rachel Spruce, Martin Forster, Stefano Schipani, Kevin Harrington, Joseph Sacco, Patrick Murray, Gary Middleton, Christina Yap, Hisham Mehanna

Abstract

Introduction: Patients with head and neck squamous cell carcinoma with locally advanced disease often require multimodality treatment with surgery, radiotherapy and/or chemotherapy. Adjuvant radiotherapy with concurrent chemotherapy is offered to patients with high-risk pathological features postsurgery. While cure rates are improved, overall survival remains suboptimal and treatment has a significant negative impact on quality of life.Cell cycle checkpoint kinase inhibition is a promising method to selectively potentiate the therapeutic effects of chemoradiation. Our hypothesis is that combining chemoradiation with a WEE1 inhibitor will affect the biological response to DNA damage caused by cisplatin and radiation, thereby enhancing clinical outcomes, without increased toxicity. This trial explores the associated effect of WEE1 kinase inhibitor adavosertib (AZD1775).

Methods and analysis: This phase I dose-finding, open-label, multicentre trial aims to determine the highest safe dose of AZD1775 in combination with cisplatin chemotherapy preoperatively (group A) as a window of opportunity trial, and in combination with postoperative cisplatin-based chemoradiation (group B).Modified time-to-event continual reassessment method will determine the recommended dose, recruiting up to 21 patients per group. Primary outcomes are recommended doses with predefined target dose-limiting toxicity probabilities of 25% monitored up to 42 days (group A), and 30% monitored up to 12 weeks (group B). Secondary outcomes are disease-free survival times (groups A and B). Exploratory objectives are evaluation of pharmacodynamic (PD) effects, identification and correlation of potential biomarkers with PD markers of DNA damage, determine rate of resection status and surgical complications for group A; and quality of life in group B.

Ethics and dissemination: Research Ethics Committee, Edgbaston, West Midlands (REC reference 16/WM/0501) initial approval received on 18/01/2017. Results will be disseminated via peer-reviewed publication and presentation at international conferences.

Trial registration number: ISRCTN76291951 and NCT03028766.

Keywords: TITE-CRM; chemoradiation; head and neck squamous cell carcinoma; wee1 inhibitor; window of opportunity study; wisteria.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
Wisteria trial schema. Group A patients were required to have received a minimum treatment of chemotherapy (cisplatin) and AZD1175 in combination to be DLT evaluable. Group B patients were required to have received a minimum of 2 weeks of treatment (half the total scheduled AZD1775 dose) to be DLT evaluable. DLT, dose-limiting toxicity; PD, pharmacodynamic; TITE-CRM, time-to-event continual reassessment method.

References

    1. Jemal A, Siegel R, Ward E, et al. . Cancer statistics, 2009. CA Cancer J Clin 2009;59:225–49. 10.3322/caac.20006
    1. Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med 2008;359:1143–54. 10.1056/NEJMra0707975
    1. Bernier J, Domenge C, Ozsahin M, et al. . Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945–52. 10.1056/NEJMoa032641
    1. Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Sem Rad Onc 2015;25:11–17.
    1. Kang H, Kiess A, Chung CH. Emerging biomarkers in head and neck cancer in the era of genomics. Nat Rev Clin Oncol 2015;12:11–26. 10.1038/nrclinonc.2014.192
    1. Olivier M, Hollstein M, Hainaut P. Tp53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2010;2:a001008 10.1101/cshperspect.a001008
    1. Petitjean A, Achatz MIW, Borresen-Dale AL, et al. . Tp53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene 2007;26:2157–65. 10.1038/sj.onc.1210302
    1. Dillon MT, Good JS, Harrington KJ. Selective targeting of the G2/M cell cycle checkpoint to improve the therapeutic index of radiotherapy. Clin Oncol 2014;26:257–85. 10.1016/j.clon.2014.01.009
    1. Hirai H, Iwasawa Y, Okada M, et al. . Small-Molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumour cells to DNA-damaging agents. Mol Can Ther 2009;8:2992–3000.
    1. Van Linden AA, Baturin D, Ford JB, et al. . Inhibition of Wee1 sensitizes cancer cells to antimetabolite chemotherapeutics in vitro and in vivo, independent of p53 functionality. Mol Cancer Ther 2013;12:2675–84.
    1. Magnussen GI, Holm R, Emilsen E, et al. . High expression of Wee1 is associated with poor disease-free survival in malignant melanoma: potential for targeted therapy. BMJ Cancer 2013;13:288.
    1. Mir SE, De Witt Hamer PC, Krawczyk PM, et al. . In silico analysis of kinase expression identifies Wee1 as a gatekeeper against mitotic catastrophe in glioblastoma. Cancer Cell 2010;18:244–57. 10.1016/j.ccr.2010.08.011
    1. Wu Z, Doondeea JB, Gholami AM, et al. . Quantitative chemical proteomics reveals new potential drug targets in head and neck cancer. Mol Cell Proteomics 2011;10:M111:M111.011635 10.1074/mcp.M111.011635
    1. Hirai H, Iwasawa Y, Okada 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. 10.1158/1535-7163.MCT-09-0463
    1. Bridges KA, Hirai H, Buser CA, et al. . MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clin Cancer Res 2011;17:5638–48. 10.1158/1078-0432.CCR-11-0650
    1. Do K, Doroshow JH, Kummar S. Wee1 kinase as a target for cancer therapy. Cell Cycle 2013;12:3159–64. 10.4161/cc.26062
    1. Osman AA, Monroe MM, Ortega Alves MV, et al. . Wee-1 kinase inhibition overcomes cisplatin resistance associated with high-risk TP53 mutations in head and neck cancer through mitotic arrest followed by senescence. Mol Cancer Ther 2015;14:608–19. 10.1158/1535-7163.MCT-14-0735-T
    1. Caretti V, Hiddingh L, Lagerweij T, et al. . Wee1 kinase inhibition enhances the radiation response of diffuse intrinsic pontine gliomas. Mol Cancer Ther 2013;12:141–50. 10.1158/1535-7163.MCT-12-0735
    1. Sarcar B, Kahali S, Prabhu AH, et al. . Targeting radiation-induced G(2) checkpoint activation with the Wee-1 inhibitor MK-1775 in glioblastoma cell lines. Mol Cancer Ther 2011;12:2405–14.
    1. Karnak D, Engelke CG, Parsels LA, et al. . Combined inhibition of Wee1 and PARP1/2 for radiosensitization in pancreatic cancer. Clin Cancer Res 2014;20:5085–96. 10.1158/1078-0432.CCR-14-1038
    1. Guertin AD, Li J, Liu Y, et al. . Preclinical evaluation of the Wee1 inhibitor MK-1775 as single-agent anticancer therapy. Mol Cancer Ther 2013;12:1442–52. 10.1158/1535-7163.MCT-13-0025
    1. Méndez E, Rodriguez CP, Kao MC, et al. . A phase I clinical trial of AZD1775 in combination with neoadjuvant Weekly docetaxel and cisplatin before definitive therapy in head and neck squamous cell carcinoma. Clin Cancer Res 2018;24:2740–8. 10.1158/1078-0432.CCR-17-3796
    1. Zhong L, Zhang C, Ren G, et al. . Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally advanced resectable oral squamous cell carcinoma. J Clin Oncol 2012;30:1–12.
    1. Perrone F, Bossi P, Cortelazzi B, et al. . Tp53 mutations and pathologic complete response to neoadjuvant cisplatin and fluorouracil chemotherapy in resected oral cavity squamous cell carcinoma. J Clin Oncol 2010;28:761–6. 10.1200/JCO.2009.22.4170
    1. O’Quigley J, Pepe M, Fisher L. Continual reassessment method. Biometrics 1990;46:33–48.
    1. Cheung YK. Dose finding by the continual reassessment method. New York: Chapman & Hall/CRC Press, 2011.
    1. Cheung YK, Chappell R. Sequential designs for phase I clinical trials with late-onset toxicities. Biometrics 2000;56:1177–82. 10.1111/j.0006-341x.2000.01177.x
    1. Yap C, Craddock C, Quigley JO, et al. . Comparing the implementation of a modified continual reassessment method to a 3+3 design in a phase I acute myeloid leukaemia trial. Clin Trials 2013;10:75.
    1. Do K, Wilsker D, Ji J, KT D, Balasubramanian P, et al. . Phase I study of single-agent AZD1775 (MK-1775), a Wee1 kinase inhibitor, in patients with refractory solid tumors. J Clin Oncol 2015;33:3409–15. 10.1200/JCO.2014.60.4009
    1. Schellens JH, Leijen S, Shapiro G, et al. . Update on a phase I pharmacologic and pharmacodynamic study of MK1775, a WEE1 tyrosine kinase inhibitor in monotherapy and combination with gemcitabine, cisplatin or carboplatin in patents with advance solid tumour. ASCO, 2011. Available:
    1. Homma A, Inamura N, Oridate N, et al. . Concomitant Weekly cisplatin and radiotherapy for head and neck cancer. Jpn J Clin Oncol 2011;41:980–6. 10.1093/jjco/hyr086
    1. Traynor AM, Richards GM, Hartig GK, et al. . Comprehensive IMRT plus Weekly cisplatin for advanced head and neck cancer: the University of Wisconsin experience. Head Neck 2010;32:599–606. 10.1002/hed.21224
    1. Jagdis A, Laskin J, Hao D, et al. . Dose delivery analysis of Weekly versus 3-weekly cisplatin concurrent with radiation therapy for locally advanced nasopharyngeal carcinoma (NPC). Am J Clin Oncol 2014;37:63–9. 10.1097/COC.0b013e31826b9b1a
    1. Aaronson NK, Ahmedzai S, Bergman B, et al. . The European organization for research and treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365–76. 10.1093/jnci/85.5.365
    1. Bjordal K, de Graeff A, Fayers PM, et al. . A 12 country field study of the EORTC QLQ-C30 (version 3.0) and the head and neck cancer specific module (EORTC QLQ-H&N35) in head and neck patients. EORTC Quality of Life Group. Eur J Cancer 2000;36:1796–807. 10.1016/s0959-8049(00)00186-6
    1. Chen AY, Frankowski R, Bishop-Leone J, et al. . The development and validation of a dysphagia-specific quality-of-life questionnaire for patients with head and neck cancer: the M. D. Anderson dysphagia inventory. Arch Otolaryngol Head Neck Surg 2001;127:870–6.
    1. National Cancer Institute Common terminology criteria for adverse events (CTCAE) (version 4.0). Available:

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅