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 Oropharynx
HYPOTHESIS: Administration of IL-12 will enhance the antitumor activity of cetuximab by activating FcR-positive immune cells that recognize cetuximab-coated tumor cells. The trial combines cetuximab with IL-12 in patients with locally recurrent or unresectable HER1-overexpressing squamous cell carcinoma (SCC) of the oropharynx. Correlative laboratory studies will evaluate the ability of this regimen to activate the innate immune system and relate these events to clinical activity.
RATIONALE: More than 90 percent of oropharyngeal squamous cell carcinomas (SCC) overexpress the epidermal growth factor receptor (EGFR, or HER1). Binding to HER1 by epidermal growth factor (EGF) or transforming growth factor (TGF)-alpha leads to cell cycle progression, reduced cell death (i.e., apoptosis), angiogenesis and metastasis. Tumor HER1 expression correlates with a poor prognosis and resistance to therapy.
Cetuximab is a humanized monoclonal antibody that binds with high affinity to HER1 and shows activity as a single agent in patients with HER1-positive oropharyngeal SCC. When cetuximab binds to HER1 on tumor cells, EGF and TGF-alpha cannot activate the receptor, which reduces proliferation, enhances apoptosis and angiogenesis, inhibits invasiveness and metastasis and down regulates HER1 expression.
This Ohio State-originated clinical trial makes use of the fact that cetuximab and other monoclonal antibody agents possess a binding site in the constant or "Fc" region of the antibody, which is located away from its antigen-binding site. Natural killer cells, monocytes and other innate immune cells bear specialized Fc receptors (FcR) that recognize the antibody's Fc region and enable them to distinguish antibody-coated tumor cells, which they often destroy. Laboratory, preclinical studies and phase I trials indicate that IL-12 can activate FcR-bearing immune cells and enhance their ability to recognize and eliminate antibody-coated tumor cells.
In this trial, we hypothesize that IL-12 will increase the anti-tumor activity of cetuximab in patients with inoperable, HER1-overexpressing oropharyngeal SCC. Our preliminary data strongly indicates that the antitumor activity of IL-12 and cetuximab is dependent on NK cells and their production of IFN-γ, the release of which mobilizes a more effective immune response against cancer cells.
The key objectives of the trial are:
• Identify a safe and tolerable dose of IL-12 in combination with cetuximab.
• Test the ability of IL-12 to enhance response rates to cetuximab in patients who have progressed on a cetuximab-containing regimen.
• Characterize the antitumor mechanism of IL-12 and establish biomarkers that will predict patient responsiveness.
Information gained from this trial should directly apply to other monoclonal antibodies that target HER1 and other oncogenes.
AT A GLANCE
Clinical trial OSU-11010
PI: WILLIAM E. CARSON III, MD, professor of Surgery, associate director
for clinical research and co-leader of the Innate Immunity Program
Eligibility: Patients must be older than 18 years with histologically proven, unresectable, recurrent or metastatic SCC of the oropharynx; one prior systemic therapy is permitted; patients must have progressed on a cetuximab-based regimen or not have responded to it, have an ECOG performance status less than 2, a life expectancy greater than 6 months and normal organ and marrow function.