Ficlatuzumab and Cetuximab in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC)

Summary

The epidermal growth factor receptor (EGFR) is both oncogene and prognostic biomarker in head and neck squamous cell carcinoma (HNSCC). EGFR's functional importance in HNSCC resulted in development of the first molecularly targeted strategy, the anti-EGFR monoclonal antibody cetuximab. Given the lack of therapeutic options for patients with recurrent/metastatic HNSCC after failure of cetuximab, there is strong scientific interest in understanding resistance in order to identify new therapies for this population. A possible resistance mechanism to anti-EGFR therapy in HNSCC is primary or compensatory activation of alternate growth factor receptors including c-Met. The MET oncogene encodes c-Met, an RTK bound exclusively by the ligand, hepatocyte growth factor (HGF). The HGF/c-Met signaling pathway converges with the EGFR network at both the PI3K/Akt and MAPK nodes. Laboratory data suggest the ability for reciprocal compensation between EGFR and c-Met. We hypothesize that HGF/c-Met pathway inhibition may overcome resistance to cetuximab in patients with HNSCC, such as those with clinical cetuximab resistance.

Ficlatuzumab (AV-299) is a humanized HGF-inhibitory immunoglobulin G1 (IgG1) monoclonal antibody. The primary objective of this phase 1b study is to find the recommended phase II dose (RP2D) of the combination of ficlatuzumab and cetuximab in patients with recurrent/metastaticHNSCC. The dose-finding study design will follow a Narayana k-in-a-row design with k set to 2 to target a 33% rate of dose-limiting toxicity (DLT). In the dose-finding phase, a total of 8 patients will be treated if no DLTs are observed or 14 patients if at least one DLT occurs. An expansion cohort will then proceed at RP2D until 12 patients have been treated at that dose level with the combination of ficlatuzumab and cetuximab. We will evaluate biomarkers of HGF/cMet pathway activation in baseline tissue, plasma and immune cells for a preliminary relationship with clinical activity.

Conditions

• Carcinoma, Squamous Cell of Head and Neck
• Squamous Cell Carcinoma of the Head and Neck
• Squamous Cell Carcinoma, 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 (2o C- 8oC)

DRUG

Cetuximab

Cetuximab is supplied as a 50-mL, single-use vial containing 100 mg of cetuximab at a concentration of 2 mg/mL in phosphate buffered saline. The solution should be clear and colorless and may contain a small amount of easily visible white amorphous cetuximab particulates. Cetuximab can be administered via infusion pump or syringe pump, it must not be administered as an IV push or bolus. Cetuximab must be administered with the use of a low protein binding 0.22-micrometer in-line filter. Maximum infusion rate should not exceed 5 mL/min. Store vials under refrigeration at 2C to 8C (36F to 46F). DO NOT FREEZE. Following the cetuximab infusion, a one-hour observation period is recommended.

Sponsors & Collaborators

• AVEO Pharmaceuticals, Inc.

  collaborator INDUSTRY

• James J Lee

  lead OTHER

Principal Investigators

• James Ohr, DO · Attending Physician, UPMC Hillman Cancer Center

Study Design

Allocation

NA

Purpose

OTHER

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2015-08-31

Primary Completion

2016-06-30

Completion

2018-02-28

Countries

• United States

Study Locations