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Cisplatin

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Ficlatuzumab will be administered as an IV infusion over 30-60 minutes, once every two weeks beginning the week prior to cisplatin-IMRT (week -1), for a total of 4 doses.

Cisplatin will be administered as an IV infusion over 60 minutes on Monday, Tuesday, or Wednesday of each treatment week beginning concurrent with IMRT during week 1 of study treatment (and one week following the first dose of ficlatuzumab) for a total of 7 doses.

IMRT: Treatment will be delivered once daily, 5 fractions per week, 35 - 37 fractions, no weekends or holidays over 7 - 8 weeks. All targets will be treated sequentially.

Ficlatuzumab Concentrate for Injection, 20 mg/mL, is formulated in 10 mM histidine buffer pH 5.8. The formulation also includes 142 mM arginine (for isotonicity) and 0.01% polysorbate 80. The product is sterile filtered and aseptically filled into washed and depyrogenated 5 mL glass vials.The product is a clear to slightly opalescent, colorless to slightly yellow, solution.

Ficlatuzumab Concentrate for Injection is to be administered by IV infusion as an admixture with normal saline solution. The admixture solution in an IV bag is connected to an infusion set containing a 0.22 µm low protein-binding in line filter. The filtered admixture solution is clear to slightly opalescent.

Ficlatuzumab is to be stored under refrigerated conditions (2C - 8C)

Ficlatuzumab

Each vial contains 10 mg of DDP, 19 mg of sodium chloride, 100 mg of mannitol, and hydrochloric acid for pH adjustment. One vial is reconstituted with 10 ml of sterile water. The pH range will be 3.5 to 4.5.

Cisplatin will be given as a bolus, infused over 1-2 hours along with appropriate hydration and anti-emetics.

Reconstituted solution of cisplatin is stable for 20 hours when stored at 27°C and should be protected from light if not used within 6 hours. The vials and injection should not be refrigerated. Cisplatin has been shown to react with aluminum needles, producing a black precipitate within 30 minutes.

Immobilization should be performed 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 performed with IV contrast. All tissues to be irradiated must be included in the CT scan.

Targets are defined as primary (requiring a higher dose) and secondary (targets at lower risk requiring a lower dose). The primary target is the PTV3 of the primary tumor and lymph nodes containing clinical or radiographic evidence of metastases. The secondary target is the PTVs consist of an area at intermediate risk (PTV2) and that containing the lowest risk of lymph node involvement (PTV2).

The treatment plan will be based on an analysis of the volumetric dose, including dose volume histogram (DVH) analyses of the PTV and critical normal structures. Inverse planning will be utilized to deliver optimal dose to the PTVs while excluding noninvolved normal tissue.

Intensity Modulated Radiotherapy (IMRT)

Julie E Bauman, MD, MPH

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.

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.

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

A Phase 1b Study of Ficlatuzumab, Cisplatin and Intensity Modulated Radiotherapy (IMRT) in Intermediate or High Risk, Previously Untreated, Locally Advanced Head and Neck Squamous Cell Carcinoma With Biomarker Correlatives

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 ficlatuzumab.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 preliminary clinical efficacy of the combination of ficlatuzumab, cisplatin and IMRT will be described according to CR rate (RECIST 1.1 and Integrated PET/CT criteria), median TTP, LRC, and median OS in: 1) the entire study population; 2) patients treated at RP2D.

All patients will be evaluable for toxicity from the time of their first treatment with ficlatuzumab. The proportion of DLTs in each dosing cohort will be reported, as will the proportion of AEs in accordance with NCI CTCAE v.4 grading criteria

Submission of primary tumor tissue for biomarker correlatives is mandatory to measure tumor protein levels of cMet and HGF prior to study treatment.

The relationship of percent change in the baseline sum diameter of all measurable RECIST lesions to baseline cMet and HGF will be characterized by a linear, or if necessary, generalized linear or nonlinear regression model with appropriate confidence intervals.

Biomarkers in blood will be quantitatively measured and will be evaluated as predictors of tumor response in appropriate generalized linear models. Calculated p values for testing the significance of the prediction models will be adjusted for false discovery by the method of Benjamini and Hochberg.

The peripheral biomarkers related to HGF/c-Met pathway activation will be evaluated. Baseline values and changes in these biomarkers to quantitative response data and PFS will be evaluated. Biomarkers in tumor and blood will be quantitatively measured and will be evaluated as predictors of tumor response in appropriate generalized linear models. Calculated p values for testing the significance of the prediction models will be adjusted for false discovery by the method of Benjamini and Hochberg.

HNSCC is an immunosuppressive disease. Patients demonstrate lower absolute lymphocyte counts than healthy subjects, impaired natural killer (NK) cell activity and poor antigen-presenting function. Mechanistically, HGF inhibits dendritic cell activation. Evaluation of the dendritic cell and T cell phenotypes in baseline biopsies will be evaluated. In addition, longitudinal T cell and NK cell phenotypes in peripheral blood will be analyzed before, during and after exposure to ficlatuzumab.

HNSCC is an immunosuppressive disease. Patients demonstrate lower absolute lymphocyte counts than healthy subjects, impaired natural killer (NK) cell activity and poor antigen-presenting function. Mechanistically, HGF inhibits dendritic cell activation. Evaluation of the dendritic cell and T cell phenotypes in baseline biopsies will be evaluated. In addition, longitudinal T cell and NK cell phenotypes in peripheral blood will be analyzed before, during and after exposure to ficlatuzumab

AVEO Pharmaceuticals, Inc.

Julie E. Bauman, MD, MPH

Director of the Head and Neck Cancer Section and Thyroid Cancer Section in the Division of Hematology-Oncology at the University of Pittsburgh School of Medicine

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Ficlatuzumab, Cisplatin and IMRT in Locally Advanced Head and Neck Squamous Cell Carcinoma	NCT02277184	Carcinoma, Squa...	Ficlatuzumab Cisplatin Intensity Modul...	18 Years -	University of Pittsburgh
Ficlatuzumab, Cisplatin and IMRT in Locally Advanced Head and Neck Squamous Cell Carcinoma	NCT02277184	Carcinoma, Squa...	Ficlatuzumab Cisplatin Intensity Modul...	18 Years -	University of Pittsburgh

Spots Global Cancer Trial Database for poorly differentiated carcinoma of the oropharynx