Trial Information

A Phase I/II Study of Radiation Therapy, Paclitaxel Poliglumex and Cetuximab in Advanced Head and Neck Cancer

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.