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

Purpose: The WEE1 tyrosine kinase regulates G2/M transition and maintains genomic stability, particularly in p53-deficient tumors which require DNA repair after genotoxic therapy. There is a need to exploit the role of WEE1 inhibition in head and neck squamous cell carcinoma (HNSCC) mostly driven by tumor-suppressor loss. This completed phase I clinical trial represents the first published clinical experience using the WEE1 inhibitor, AZD1775, with cisplatin and docetaxel. Experimental Design: We implemented an open-label phase I clinical trial using a 3+3 dose-escalation design for patients with Stage III/IVB HNSCC with borderline-resectable or unresectable disease, who were candidates for definitive chemoradiation. AZD1775 was administered orally twice a day over 2.5 days on the first week, then in combination with cisplatin (25mg/m 2) and docetaxel (35mg/m 2) for three weeks. The primary outcome measure was adverse events to establish maximum-tolerated-dose (MTD). Secondary measures included response, pharmacokinetics, pharmacodynamics, and genomic data. Results: The MTD for AZD1775 was established at 150mg orally twice per day for 2.5 days. RECISTv1.1 responses were seen in 5 of 10 patients; histological adjustment revealed 3 additional responders. The only drug-limiting toxicity was Grade-3 diarrhea. The PK C8hr target of 240nM was achieved on Day 4 at all three doses tested. Pharmacodynamic analysis revealed a reduction in pY15-Cdk and increases in gH2AX, CC3 and RPA32/RPA2 were noted in responders vs. non-responders. Conclusions:The triplet combination of AZD1775, cisplatin and docetaxel is safe and tolerable. Preliminary results show promising anti-tumor efficacy in advanced HNSCC, meriting further investigation at the recommended phase 2 dose.

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