A Study of a New Combination and Schedule of Chemotherapy Drugs for the Treatment of Head and Neck Cancer
|First Submitted Date ICMJE||September 2, 2005|
|First Posted Date ICMJE||September 7, 2005|
|Results First Submitted Date||February 13, 2014|
|Results First Posted Date||March 28, 2014|
|Last Update Posted Date||April 17, 2014|
|Start Date ICMJE||November 2002|
|Primary Completion Date||August 2008 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Overall Response Rate at 4 Months [ Time Frame: 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.
|Original Primary Outcome Measures ICMJE||Not Provided|
|Change History||Complete list of historical versions of study NCT00148122 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||A Study of a New Combination and Schedule of Chemotherapy Drugs for the Treatment of Head and Neck Cancer|
|Official Title ICMJE||A Phase II Trial Evaluating Weekly Docetaxel and Capecitabine in Patients With Metastatic or Advanced, Locally, Recurrent Head and Neck Cancer|
|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.|
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:
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Head and Neck Cancer|
|Study Arms||Experimental: Arm 1
Docetaxel (1000mg PO BID days 5-18 of each Cycle) and Capecitabine (30mg/m2/week IV days 1, 8, &15)
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||July 2010|
|Primary Completion Date||August 2008 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years and older (Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00148122|
|Other Study ID Numbers ICMJE||UMCC 2-33
Legacy IRBMED 2002-747 ( Other Identifier: University of Michigan IRBMED )
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Francis (Frank) Worden, University of Michigan Cancer Center|
|Study Sponsor ICMJE||University of Michigan Cancer Center|
|Collaborators ICMJE||Not Provided|
|PRS Account||University of Michigan Cancer Center|
|Verification Date||March 2014|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP