Bench to Bedside: From the Laboratory to the Pharmacy

A Phase I/II Trial of Cetuximab in Combination with Interleukin-12 Administered to Patients with Unresectable Primary or Recurrent Squamous Cell Carcinoma of the Head and Neck

Hypothesis: More than 90 percent of squamous cell carcinomas (SCC) that originate in the oropharynx overexpress the epidermal growth factor receptor (EGFR, or HER1). Cetuximab is an anti-HER1 monoclonal antibody that binds to HER1-overexpressing tumor cells and has activity as a single agent when administered to patients with HER1-positive SCC of the oropharynx. We hypothesize that IL-12 administration will enhance the antitumor activity of cetuximab by activating innate immune cells that recognize antibody-coated tumor cells.

Rationale: This novel protocol exploits the fact that innate immune cells bear specialized receptors for the Fc region on monoclonal antibodies. Evidence suggests that Fc-receptor-dependent mechanisms contribute substantially to the activity of monoclonal antibodies directed against tumor antigens, and that co-administration of immune stimulatory cytokines might enhance their effects. This is particularly true for natural killer (NK) cells.

Once activated, NK cells release cytokines that have antitumor activity and help coordinate innate and specific immune responses. They also release factors that recruit macrophages and T cells to sites of inflammation.

NK cells express an Fc receptor called FcγRIIIa, which enables them to interact with antibody-coated tumor cells and to mediate antibody-dependent cellular cytotoxicity (ADCC) and the secretion of IFN-γ and TNF-α. The presence of IL-12 markedly enhances this antitumor activity. This protocol evaluates whether administration of IL-12 will enhance the antitumor activity of cetuximab in patients with inoperable HER1-overexpressing SCCs of the head and neck.

• The phase I portion of the study will identify a tolerable dose of IL-12 plus cetuximab;
• The phase II study will determine the response rate to the two agents;
• Additional correlative studies will provide information on the antitumor mechanism of IL-12 and establish biomarkers for predicting patient responsiveness.

Along with characterizing the immunologic effects of IL-12 in combination with cetuximab, this study will provide a better understanding of the NK-cell response to antibody-coated tumor cells and of how to improve the regimen’s effectiveness. The information gained from this study should also apply to other monoclonal antibodies currently in use or under development.

William Carson 2At a Glance

Trial no.: identifier: NCT01468896

PI: William E. Carson III, MD

Phone: 614-293-6306

Eligibility: age 18 or older, histologically proven recurrent or metastatic squamous cell carcinoma of the head and neck that is unresectable (patients in the phase II portion of the trial must have measurable disease), ECOG performance status less than 2 (Karnofsky greater than 60%), life expectancy greater than 6 months, normal organ and marrow function, ability to understand and willingness to sign a written informed consent document.

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