• Phase I: the maximum tolerated dose of paclitaxel poliglumex in combination with radiotherapy and cetuximab for locally advanced head and neck cancer [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
  
• Phase II: the rate of locoregional control at one year [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  

• The overall response rate (complete and partial response) [ Time Frame: 1 month following treatment and then every 4 months ] [ Designated as safety issue: No ]
  
• The acute and late toxicity profile associated with the study regimen [ Time Frame: 1 month following treatment and then every 4 months ] [ Designated as safety issue: Yes ]
  
• The duration of control of locoregional disease [ Time Frame: 1 month following treatment and then every 4 months ] [ Designated as safety issue: No ]
  
• Overall survival, disease-free survival, and distant relapse rates [ Time Frame: 1 month following treatment and then every 4 months ] [ Designated as safety issue: No ]
  
• Tissue PPX accumulation, level of cathepsin B, and estrogen receptor expression [ Time Frame: At time of locoregional disease progression ] [ Designated as safety issue: No ]
  

Drug: paclitaxel poliglumex
Phase I: 40 mg/m2 IV weekly in Cohort 1 (first 3 subjects), escalating in increments of 10 mg/m2 for Cohorts 2 through 5 (3 subjects each) until the maximum tolerated dose (up to 80 mg/m2 IV weekly) is established; Phase II: MTD mg/m2 IV weekly as established in Phase I (24 additional subjects)
Biological: cetuximab
400 mg/m2 IV loading dose one week prior to starting other study treatments, then 250 mg/m2 IV weekly on same day as paclitaxel poliglumex
Radiation: radiation therapy (IMRT or 3D-CRT)
radiation therapy to the head and neck, consisting of 33 daily fractions of 2.12 Gy for a total of 69.96 Gy, to begin the same day as paclitaxel poliglumex

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.