Ficlatuzumab, Cisplatin and IMRT in Locally Advanced Head and Neck Squamous Cell Carcinoma

Study Summary

Head and neck squamous cell carcinoma (HNSCC) is the most common cancer arising in the upper aerodigestive tract, and is the sixth leading incident cancer worldwide. Despite advances in multimodality therapy, 5-year overall survival (OS) is 40-60%, and has increased only incrementally in the past two decades. The current standard of care for primary nonsurgical management of locally advanced HNSCC is concurrent cisplatin-radiotheray, which significantly improved OS, progression-free survival, and locoregional control compared with radiotherapy alone in the landmark Intergroup trial 0126. The MET proto-oncogene encodes c-Met, a heterodimeric growth factor receptor bound exclusively by its ligand, hepatocyte growth factor (HGF). In the laboratory, activation of the HGF/c-Met pathway is associated with resistance to cisplatin and radiotherapy in HNSCC. We hypothesize that the addition of an HGF/c-Met pathway inhibitor to cisplatin-radiotherapy may improve outcomes in HNSCC. Ficlatuzumab (AV-299) is a humanized HGF-inhibitory IgG1 monoclonal antibody. The primary objective of this study is to establish the recommended phase II dose (RP2D) of the combination of ficlatuzumab, cisplatin and intensity-modulated radiotherapy (IMRT), in patients with locally advanced HNSCC. The dose-finding study design will follow a Narayana k-in-a-row design with k set to 3 to target a 33% DLT rate. In the dose-finding phase, a total of either 10 or 14 patients will be treated. If no DLTs are observed among 10 patients, the highest dose tier will be declared the RP2D. Otherwise the RP2D will be estimated from DLTs across all dose levels by isotonic regression. The secondary objective is to estimate biomarker association with preliminary clinical response. We will evaluate biomarkers of HGF/cMet pathway activation in tumor tissue, plasma, and immune cells.

Primary Outcome

A dose escalation/de-escalation plan will be conducted according to an adaptive Narayana k-in-a-row design.We will select the dose of ficlatuzumab that is close to but does not exceed a 33% dose limiting toxicity (DLT) rate when administered with a fixed standard dose of cisplatin and IMRT. The observation period for identifying a DLT will be 10 weeks, or 2 weeks following completion of IMRT, whichever comes later. Note: to be considered a DLT, the toxicity must be at least possibly related to f

Interventions

• DRUG Cisplatin
• RADIATION Intensity Modulated Radiotherapy (IMRT)
• DRUG Ficlatuzumab