A Study of a New Combination and Schedule of Chemotherapy Drugs for the Treatment of Head and Neck Cancer
A Study of a New Combination and Schedule of Chemotherapy Drugs for the Treatment of Head and Neck Cancer
The purpose of this study is to determine the effectiveness and side effects of a new
 combination and schedule of chemotherapy drugs in the treatment of head and neck cancer.
 Patients with advanced or recurrent head and neck cancer, which is untreatable by surgery or
 radiation therapy are eligible for this study. Standard treatment for advanced or recurrent
 head and neck cancer involves the use of chemotherapy.
Approximately 28,900 patients will be diagnosed with squamous cell cancers of the oral cavity
 and pharynx in the year 2002. Of these, an estimated 7,400 patients will present with
 metastases or develop recurrent disease, which is not amenable to surgery or radiation
 therapy. Palliative chemotherapy is thus the only treatment option. Currently, combinations
 of cisplatin and 5-fluorouracil are used as first line treatment strategies, with median
 times to progression of 2.5 to 3 months and median survival rates of 5 to 7 months. The time
 to achieve maximum response with combination therapy is on average 4 months.

 Taxanes, with their unique mechanism of microtubule stabilization, have demonstrated response
 rates similar to standard, first line combination regimens. Several phase II studies have
 evaluated the efficacy of single agent docetaxel in head and neck cancer patients. Cumulative
 response rates were approximately 30%, with higher response rates observed in patients
 receiving no prior chemotherapy. Docetaxel has also been used in combination with cisplatin
 and cisplatin and 5-fluorouracil. Although response rates with such combination regimens were
 superior to the use of single agent docetaxel, grade 3 and 4 toxicities were also more
 prevalent.

 Capecitabine (Xeloda®), a fluoropyrimidine carbamate, is an oral prodrug, which is converted
 in tumor tissues to 5-fluorouracil through multienzymatic activation. Capecitabine (Xeloda®)
 has documented activity in breast and colorectal cancers and is widely administered. Because
 5-fluorouracil has efficacy in the treatment of head and neck cancer, it is reasonable to
 consider that such tumors will respond to capecitabine. To date, there are no published
 trials using capecitabine (Xeloda®) in the treatment of metastatic head and neck cancer
 patients. However, clinical trials are ongoing in the U.S. and Europe with promising results.

 In preclinical models, a synergistic interaction between capecitabine and docetaxel has been
 documented. One possible explanation for the synergy is that docetaxel up-regulates tumor
 levels of thymidine phosphorylase, the enzyme essential for the activation of capecitabine
 and 5'-dFUrd to 5-fluorouracil. Clinically, O'Shaughnessy, et al. recently reported improved
 survival with docetaxel/capecitabine combination therapy in patients with metastatic breast
 cancer, who previously failed anthracycline-containing chemotherapy. In this phase III study,
 patients were stratified according to previous exposure to paclitaxel and then randomized to
 capecitabine (Xeloda®) (1250 mg/m2 twice daily, days 1-14) plus docetaxel (75 mg/m2 day 1,
 repeated every 21 days) versus docetaxel alone. Grade 3 and 4 toxicities were more common in
 the docetaxel/capecitabine combination arm. Capecitabine (Xeloda®) and docetaxel were
 interrupted and the dosages reduced by 25% in patients who experienced a second occurrence of
 a given grade 2 toxicity, or any grade 3 toxicity, suggesting that the starting dosages were
 perhaps too high.

 The role of chemotherapy in metastatic head and neck cancer is limited to palliation of the
 symptoms of disease. Platinum and 5-fluorouracil combinations remain standard first line
 treatment strategies. The taxanes have been shown to have similar efficacy to such first line
 regimens and are often used as salvage treatment for patients with metastatic disease. Given
 that docetaxel has documented clinical efficacy in head and neck cancer and that there are
 preclinical data to suggest synergy with docetaxel and capecitabine, it is reasonable to
 consider using these agents in combination to treat head and neck cancer patients. Moreover,
 capecitabine and docetaxel have distinct mechanisms of action and no overlap of key
 toxicities. A recent phase I/II study by Tonkin, et al. in metastatic breast cancer patients
 demonstrated activity and less toxicity when docetaxel 30 mg/m2/week (day 1 and 8 q21 days)
 was combined with capecitabine 1800 mg/m2/day (14 of 21 days). In another phase I study by
 Nadella, et al. weekly docetaxel (36 mg/m2 ) was combined with 14 days of capecitabine (up to
 1500 mg/m2/day) over a course of 28 days. Antitumor responses were observed in patients with
 breast, colon, and bladder cancers. Hence, we propose this study whereby patients with
 previously treated, metastatic/recurrent head and neck cancer will receive treatment with
 docetaxel and capecitabine.

 To reduce the potential for toxicity, we will use a modification of the Nadella regimen.
 Docetaxel will be administered weekly at a dosage of 30 mg/m2 for 3 out of every 4 weeks and
 capecitabine will be administered at a flat dosage of 2000 mg per day (1000 mg p.o. b.i.d.)
 for two weeks out of every 4 weeks. The justification for using a flat dosage of capecitabine
 versus a calculated dosage is based on pharmacokinetic data that show no change in clearance
 of capecitabine with changes in BSA. We plan to use a fixed dose of 2000 mg qd (1000 mg q am
 and 1000 mg q pm). Fixed dosing of capecitabine is convenient and feasible, as shown in a
 prior University of Michigan study in breast cancer patients. In another study Schott, et al.
 informally piloted the combination of weekly docetaxel 36 mg/m2 and 1500 mg twice daily (3000
 mg/day) x 14 days capecitabine in metastatic breast cancer patients, and found it to be
 without unexpected or untoward side effects. Additionally, to take advantage of the time
 course of upregulation of TP in the preclinical models, the capecitabine dose will be given
 on days 5-18. In a flat dosing scheme, the Nadella regimen would have administered an average
 dose of 2125 mg qd for 14 days, assuming an average BSA of 1.7 m2. We plan to round this
 dosage downward to 2000 mg per day x 14 days; therefore, our regimen will use a slightly
 lower dosage of capecitabine. We feel that our proposed slightly lowered dose (closer to
 Nadella phase I dosing vs. Tonkin) of capecitabine is justified for the following reasons:

 1. The Nadella study was performed in a group of patients with solid tumor malignancies
 that were refractory to conventional therapy or for whom no effective therapy existed.
 ECOG performance status (PS) was 1 or 2 in 5/17 (30%) patients, 10/17 patients had
 received 2 or more lines of previous chemotherapy, and 7/17 patients had received
 previous radiotherapy. Based on data from previous treatment of head and neck cancer
 patients at the University of Michigan, the patient population to be enrolled in this
 trial is expected to be 60% PS 0 and 40% PS 1, and some will have received prior
 chemotherapy and/or radiotherapy. Like the Nadella patient population, a majority of our
 patients have been pretreated and are of poorer health.

 2. Dose interruptions and modifications are built into the protocol so that appropriate
 changes in treatment can be made in patients with Grade I or II toxicity, before the
 toxicity becomes Grade III or greater. Since the docetaxel is given weekly, and the
 capecitabine is administered daily, if patients are experiencing toxicity within a
 cycle, the dose of either can be held or modified.
Inclusion Criteria:

 -  Patients must have documented advanced, locally recurrent, or metastatic head and neck
 carcinoma, which is untreatable by surgical resection or radiation therapy.

 -  Prior chemotherapy for advanced/metastatic disease is allowed (1 regimen only).

 -  Patients must be taxane-naïve (no prior docetaxel or paclitaxel).

 -  Patients who have received chemoradiation as a primary therapy for advanced head and
 neck cancer are eligible.

 -  Patients must have measurable or evaluable disease. Pre-study imaging for disease
 assessment must be done within 28 days of registration.

 -  Patients with brain metastases are eligible if they have been stable for at least six
 weeks post-radiation therapy.

 -  Aged 18 years or older

 -  Performance status of 0-2 by Zubrod criteria.

 -  Life expectancy of at least 12 weeks.

 -  Hematologic: absolute neutrophil count (ANC) equal to or > 1,500/mm3; hemoglobin equal
 to or > 8.0 g/dl; platelets equal to or > 100,000/mm3.

 -  Total bilirubin must be within normal institutional limits (WNL).

 -  Transaminases (AST/SGOT and ALT/SGPT) may be up to 2.5 X the institutional upper limit
 of normal (ULN) if alkaline phosphatase is less than ULN, or alkaline phosphatase may
 be up to 4 X ULN if transaminases are less than ULN.

 -  A calculated creatinine clearance of > 50 ml/min

 -  Women of childbearing potential must have a negative pregnancy test at baseline, prior
 to receiving any study drug. (Pregnant or lactating patients are excluded.)

 -  Patients of reproductive potential must practice effective contraception while on
 study and for at least six months after receiving the last dose of study drug.

 -  All patients must sign an informed consent prior to enrollment.

 -  No prior history of malignancy, except for adequately treated skin cancer or in situ
 cervical carcinoma or any other cancer in complete remission for at least two years.

 Exclusion Criteria:

 -  Patients with congestive heart failure, second or third degree heart block or recent
 myocardial infarction within 12 months from registration are not eligible.

 -  Peripheral neuropathy equal to or greater than grade 2.

 -  Patients with a history of severe hypersensitivity reaction to drugs formulated with
 polysorbate 80.

 -  Use of standard chemotherapy or investigational agents for treatment of head and neck
 cancer within 28 days of 1st dose of study drug.

 -  Any medical or psychiatric illness which, in the opinion of the principal
 investigator, would compromise the patient's ability to tolerate this treatment
 regimen.

 -  Prior unanticipated severe reaction to fluoropyrimidine therapy or known
 hypersensitivity to 5-fluorouracil.

 -  Pregnant or lactating women, women of childbearing potential with either a positive
 pregnancy test (PPT) at baseline, or sexually active females not using a reliable
 contraceptive method while on study and for at least six months after chemotherapy.
 (Postmenopausal women must have been amenorrheic for at least 12 months to be
 considered of non-childbearing potential.)

 -  Sexually active patients not using a reliable contraceptive method while on study and
 for at least six months after chemotherapy.

 -  Patients with malabsorption syndromes will be excluded. Administration of capecitabine
 through feeding tubes is permitted.

 -  Serious concurrent infections.

 -  Any other serious uncontrolled medical or surgical conditions that the investigator
 feels might compromise study participation.