A Study of a New Combination and Schedule of Chemotherapy Drugs for the Treatment of Head and Neck Cancer
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase II Trial Evaluating Weekly Docetaxel and Capecitabine in Patients With Metastatic or Advanced, Locally, Recurrent Head and Neck Cancer|
- Overall Response Rate at 4 Months [ Time Frame: 4 months ] [ Designated as safety issue: No ]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.
- Frequency of Grade III/IV Toxicities Experienced by Participants [ Time Frame: 30 days post treatment ] [ Designated as safety issue: Yes ]The frequency of grade 3 and grade 4 adverse events experienced by all treated participants.
- Probability of Progression Free Survival [ Time Frame: 1 year post treatment ] [ Designated as safety issue: No ]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).
|Study Start Date:||November 2002|
|Study Completion Date:||July 2010|
|Primary Completion Date:||August 2008 (Final data collection date for primary outcome measure)|
Experimental: Arm 1
Docetaxel (1000mg PO BID days 5-18 of each Cycle) and Capecitabine (30mg/m2/week IV days 1, 8, &15)
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.
Other Name: US Brand Name: TaxotereDrug: Capecitabine
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.
Other Name: US Brand Name(s): Xeloda
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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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00148122
|United States, Michigan|
|University of Michigan Comprehensive Cancer Center|
|Ann Arbor, Michigan, United States, 48109|
|Principal Investigator:||Francis Worden, M.D.||University of Michigan Cancer Center|