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
Mené sur des patients atteints d'un carcinome épidermoïde de la tête et du cou de stade III/IVB, cet essai de phase I évalue la dose maximale tolérée, les caractéristiques pharmacocinétiques et pharmacodynamiques, l'efficacité, du point de vue du taux de réponse, et la toxicité d'un traitement néoadjuvant dispensé de façon hebdomadaire à base d'un composé appelé AZD1775, un inhibiteur de WEE1, en combinaison avec docétaxel et cisplatine, avant une chimioradiothérapie définitive
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.