A Study of a New Combination and Schedule of Chemotherapy Drugs for the Treatment of Head and Neck Cancer

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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: 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. 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.

Official Title
-----------------
A Phase II Trial Evaluating Weekly Docetaxel and Capecitabine in Patients With Metastatic or Advanced, Locally, Recurrent Head and Neck Cancer

Conditions
-----------------
Head and Neck Cancer

Intervention / Treatment
-----------------
* Drug: Docetaxel
* Drug: Capecitabine


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Docetaxel (1000mg PO BID days 5-18 of each Cycle) and Capecitabine (30mg/m2/week IV days 1, 8, &15) | Drug: Docetaxel<br>* Each four-week cycle consists of three infusions through a vein of docetaxel, on days 1, 8, and 15. If the subject's disease has decreased significantly, he/she will continue to receive docetaxel on the every four-week schedule. If the subject's disease has not decreased significantly but there is no evidence the disease is getting worse, he/she will continue on the same treatment until: a) there is evidence that the treatment is no longer working to control the growth of his/her disease, b) He/she experiences unacceptable toxicity, c) his/her disease progresses, or d) he/she chooses to stop therapy.<br>* Other names: US Brand Name: Taxotere;Drug: Capecitabine<br>* Each four-week cycle consists of fourteen days of a medication that the subject will take two times a day orally, on days 5-18. If the subject's disease has decreased significantly, he/she will continue to receive docetaxel on the every four-week schedule. If the subject's disease has not decreased significantly but there is no evidence the disease is getting worse, he/she will continue on the same treatment until: a) there is evidence that the treatment is no longer working to control the growth of his/her disease, b) He/she experiences unacceptable toxicity, c) his/her disease progresses, or d) he/she chooses to stop therapy.<br>* Other names: US Brand Name(s): Xeloda;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate at 4 Months | Disease was assessed by radiologic imaging and RECIST (Response Evaluation Criteria in Solid Tumors) was used to determine response: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Grade III/IV Toxicities Experienced by Participants | The frequency of grade 3 and grade 4 adverse events experienced by all treated participants. | 30 days post treatment | 
| Probability of Progression Free Survival | The estimated 1 year progression free survival. Progression was defined, using RECIST (Response Evaluation Criteria In Solid Tumors Criteria), as a 20% increase in the sum of the longest diameter of target lesions, the development of any new lesion, or the significant clinical deterioration related to the progression of patient's disease. The probability of progression-free survival was presented in a Kaplan-Meier curve to illustrate the distribution of progression time. The median time to progression was determined with a 95% CI (Confidence Interval). | 1 year post treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Squamous cell cancer of the oral cavity and pharynx