This will be a phase Ib trial where ficlatuzumab will be added to the standard of care for locally advanced HNSCC: cisplatin-IMRT. Biomarkers of HGF/cMet pathway activation that may associate with clinical response will be developed in an expansion cohort. Patients with high or intermediate risk, locally advanced HNSCC will be eligible.
A diagnostic primary tumor block for biomarker correlatives is mandatory for inclusion to this study. A representative paraffin block of the original diagnosis and all repeat biopsies, if available, will be submitted.
The starting dose of ficlatuzumab (dose tier 1) will be 10 mg/kg every 2 weeks, beginning the week prior to cisplatin-IMRT (week -1). Ficlatuzumab will be administered as an IV infusion over 30-60 minutes, for a total of 4 doses.
The starting dose of cisplatin (dose tier 1) will be 40 mg/m2 weekly, beginning concurrent with IMRT during week 1 of study treatment (and one week following the first dose of ficlatuzumab which is administered during week -1 of study treatment). Patients will receive cisplatin once weekly as an IV infusion over 60 minutes, for a total of 7 doses.
Megavoltage energy photon beam irradiation is required. Any treatment planning and delivery system that has been credentialed for head and neck IMRT is acceptable. Immobilization should be performed with a thermoplastic mask to ensure daily reproducibility of setup. Treatment planning CT scans will be required to define tumor, clinical and planning target volumes.The treatment planning CT scan should be acquired with the patient in the same position and immobilization device as for treatment and performed with IV contrast so that major vessels of the neck are easily visualized.
Four dose tiers will be considered for the phase I portion for ficlatuzumab and cisplatin. IMRT will remain consistent for all dose tiers. Under this schema, more than one patient can be enrolled at the same time. However de novo dose escalation cannot occur until 2 patients have completed study treatment without DLT. In the dose-finding phase, a total of 10 patients will be treated if no DLTs are observed or 14 patients if at least one DLT occurs. If no DLTs are observed among the first 10 patients the recommended for phase 2 dose (RP2D) will be set to dose tier 3. If a DLT is observed and 14 patients are treated and observed, the RP2D will be estimated from DLTs across all dose levels by isotonic regression. The observation period for identifying a DLT will be 10 weeks, or 2 weeks following completion of IMRT, whichever comes later. To be considered a DLT, the toxicity must be at least possibly related to ficlatuzumab. An expansion cohort will then proceed at RP2D until 12 patients have been treated at that dose level.
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the following criteria applies:
* Completion of treatment,
* Disease progression,
* Intercurrent illness that prevents further administration of treatment,
* Unacceptable adverse event(s),
* Patient decides to withdraw from the study, or
* General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.
After completing treatment, patients will be followed every 3 months for 2 years, then every 6 months for 3 years, for a total of 5 years from completion of IMRT. Patients removed from study for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.
