WEE1 Inhibitor MK-1775, Docetaxel, and Cisplatin Before Surgery in Treating Patients With Borderline Resectable Stage III-IVB Squamous Cell Carcinoma of the Head and Neck

Head and Neck Squamous Cell Carcinoma Clinical Trial

Official title: A Phase I Clinical Trial of AZD1775 in Combination With Neoadjuvant Weekly Docetaxel and Cisplatin Prior to Surgery in Squamous Cell Carcinoma of the Head and Neck (HNSCC)

Status Completed

Clinical Trial Summary

This phase I trial studies the side effects and the best dose of WEE1 inhibitor MK-1775 when given together with docetaxel and cisplatin in treating patients with stage III-IVB squamous cell carcinoma of the head and neck that may or may not be able to be removed by surgery (borderline resectable). WEE1 inhibitor MK-1775 may block the growth of tumor cells by blocking some of enzymes that are needed for tumor growth and may also help docetaxel and cisplatin work better by making tumor cells more sensitive to the drug. Drugs used in chemotherapy, such as docetaxel and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving WEE1 inhibitor MK-1775 with docetaxel and cisplatin before surgery may kill more tumor cells and shrink the tumor, allowing patients to undergo surgery to remove it.

Clinical Trial Description

PRIMARY OBJECTIVES:

I. To evaluate the safety profile and determine a maximum tolerated dose (MTD) dose of AZD1775 (WEE1 inhibitor MK-1775) in combination with weekly cisplatin and docetaxel as a neoadjuvant approach in locally advanced borderline resectable and/or surgically unresectable with high nodal burden (e.g., >= N2b disease) and judged appropriate for non-surgical definitive therapy.

II. To determine the pharmacokinetics (PK) of the combination of single doses of AZD1775 with fixed weekly dosing of docetaxel and cisplatin given on a three out of four week cycle.

III. To evaluate pharmacodynamic (PD) biomarkers of AZD1775 drug effect in head and neck squamous cell carcinoma (HNSCC) cancers, and in particular p53 mutated HNSCC patients.

SECONDARY OBJECTIVES;

I. To evaluate the preliminary activity and efficacy of the combination in terms of objective response rate in patients with borderline resectable and unresectable HNSCC and in particular, in p53 mutated HNSCC patients.

II. The rate of resectability for borderline unresectable patients will be noted post neoadjuvant therapy.

III. The rate of unresectable patients who underwent definitive therapy via chemoradiation.

IV. Progression-free survival will be noted as part of the preliminary efficacy determination of this study.

VI. During all parts of the study, patients will be monitored carefully for the development of adverse experiences and will be monitored for clinical and/or radiographic evidence of disease progression according to usual standards of clinical practice.

TERTIARY OBJECTIVES:

I. To gain mechanistic understanding of the link between p53 mutation status and disruption of immunoglobulin heavy constant gamma 2 (G2M) regulation deregulation.

II. To confirm kinase inhibition in tumor primary cultures as well as in patient tumor-derived xenografted (PDX) mice extracts, downstream signaling consequences (WEE1 G2 checkpoint kinase [WEE1]; WEE1's target, cyclin-dependent kinase 1 [CDC2]), and mechanisms of p53 synthetic lethality which sensitize cancer cells to genotoxic therapy.

OUTLINE: This is a dose-escalation study of WEE1 inhibitor MK-1775.

Patients receive WEE1 inhibitor MK-1775 orally (PO) twice daily (BID) on days 2-4, 9-11, and 16-18, and day -7 prior to course 1, day 1 for PD assessment. Patients also receive cisplatin intravenously (IV) on days 1 (or up to two days after last dose of WEE1 inhibitor MK-1775 lead-in is completed), 8 (or 7 days after first chemotherapy dose), and 15, and docetaxel IV on days 1, 8, and 15. Patients experiencing progressive disease undergo surgical resection. Patients not deemed surgically resectable proceed to chemoradiation as clinically indicated. Patients experiencing stable disease or partial response may receive 2 additional courses of treatment every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 4 years. ;

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Squamous Cell
• Head and Neck Squamous Cell Carcinoma
• Squamous Cell Carcinoma of Head and Neck

• NCT number: NCT02508246
• Study type: Interventional
• Source: University of Washington
• Status: Completed
• Phase: Phase 1
• Start date: July 22, 2015
• Completion date: April 26, 2018