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

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.

Conditions

• Carcinoma, Squamous Cell of Head and Neck

Interventions

DRUG

Ficlatuzumab

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)

DRUG

Cisplatin

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.

RADIATION

Intensity Modulated Radiotherapy (IMRT)

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.

Sponsors & Collaborators

• AVEO Pharmaceuticals, Inc.

  collaborator INDUSTRY

• Julie E. Bauman, MD, MPH

  lead OTHER

Principal Investigators

• Julie E Bauman, MD, MPH · University of Pittsburgh

Study Design

Allocation

NA

Purpose

OTHER

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2015-09-30

Primary Completion

2016-09-30

Completion

2016-09-30

Countries

• United States

Study Locations