Patients with locally advanced (stage III and IV) head and neck cancer are often managed by
      radiotherapy with or without chemotherapy because most of them have unresectable tumor,
      require too extensive surgery, or are medically unfit to go through radical surgery. However,
      the treatment results from conventionally fractionated radiotherapy for locally advanced head
      and neck cancers are poor in terms of local control and survival. Therefore, combinations of
      radiation and chemotherapy have been studied to improve treatment results.

      Sequential radiation-chemotherapy (most given in neo-adjuvant setting) has been studied
      extensively in prospective pilot and large randomized trials. So far, a survival advantage
      over standard radiotherapy has not been demonstrated, but organ preservation has been
      achieved in many patients. Response rates to chemotherapy are high, and decrease in distant
      metastases has been demonstrated in some trials. Despite a high response rate in trials
      comparing neoadjuvant chemotherapy and radiotherapy to radiotherapy alone, improved
      locoregional control (LRC) has not been shown. Concurrent radiation and cisplatin-based
      chemotherapy has shown survival advantage over radiotherapy alone in meta-analysis. However,
      the administration of cisplatin-based chemotherapy is associated with significantly increased
      local and systemic toxic effects, which may preclude many patients from proceeding with
      combined therapy. Therefore, there is a great interest in defining an active regimen that
      does not contain cisplatin.

      An alternative approach to concurrent chemotherapy and radiotherapy has emerged with the
      development of molecular targeted agents. A recently reported randomized phase III study
      demonstrated improved duration of control of locoregional disease and overall survival with
      the addition of the antibody against the epidermal growth factor receptor, cetuximab, to
      definitive radiotherapy in patients with squamous cell carcinoma of the head and neck.
      Importantly, cetuximab administration did not increase radiation-related toxicity.

      The most commonly used chemotherapy other than cisplatin chemotherapy for the treatment of
      advanced head and neck cancer is paclitaxel. There are many studies showing improvement of
      tumor control when paclitaxel was added to the radiotherapy. Paclitaxel poliglumex (PPX,
      CT-2103, Xyotax) is a macromolecule that consists of a biodegradable, water-soluble polymer
      of glutamic acid, a naturally-occurring amino acid, linked to paclitaxel. Preclinical studies
      suggest increased tumor uptake of PPX compared with paclitaxel, resulting in enhanced tumor
      cell kill. PPX may potentiate tumor radiocurability without affecting acute normal tissue
      injury. Moreover, a synergistic increase in tumor cell death was observed when paclitaxel
      poliglumex was administered with cetuximab in a preclinical tumor model.

      The proposed study will assess the rational combination of PPX with radiotherapy and
      cetuximab. This regimen is of great interest and has the potential to improve the therapeutic
      ratio compared with an approach of either cisplatin-based chemoradiotherapy or radiotherapy
      and cetuximab.

      There is also an optional tissue submission component of this study, in which subjects who
      require surgery following their treatment can give permission for a block of tumor tissue
      removed at the time of their surgery to be sent to Cell Therapeutics, Inc. (the manufacturer
      of PPX) for evaluation of PPX accumulation, level of cathepsin B, and estrogen receptor
      expression. This information will be used to correlate the tumor response and survival of
      patients in the future.

      Since the initiation of this study, the relationship of HPV to head and neck cancer has
      become very evident. Our initial results have many more HPV positive subjects, and therefore
      we have added 20 more HPV negative patients to the study, to determine if this status affects
      the outcome.