cles. Patients were taken off protocol for either progression of disease, adverse events from the treatments, or noncompliance. The protocol was approved by the Protocol Sunitinib Sutent Review and Monitoring Committee and the Institutional Review Board at New York University School of Medicine, being activated in August 2000, and completed in November 2005. Written informed consent was obtained from each patient. Drug delivery and toxicity. This was an open label, single center, nonrandomized, dose escalating phase I study with the subsequent phase II study at RPTD. At the four dose levels tested, cycles were given every 21 days. Cisplatin at 40 mg/m2 per cycle for dose levels 1 3 was administered as an intravenous infusion on day 1 of each treatment course. At dose level 4, cisplatin was increased to 50 mg/m2.
The infusion was accompanied by hydration and antiemetic medications including HT3 antagonists. Capecitabine was given at 2,500 mg/m2/day in two divided doses, initially for 5 days, for 10 days, and for 14 days. Therefore, the total dose/cycle increased from 12,500 mg/m2 to 25,000 mg/m2 and to 35,000 mg/m2. In this 33 dose escalation design, the MTD consisted of the level where after expansion to six patients, no more than two had dose limiting toxicities. DLTs were grade 3 nonhematologic adverse events that occurred during cycle 1 and grade 4 non hematologic adverse events that occurred anytime during the treatment course. They were defined by utilizing the National Cancer Institute Common Toxicity Criteria, version 2.0. The maximum cumulative dose of cisplatin was limited to 500 mg/m2.
For patients achieving partial responses or complete responses, or those who did not progress and did not experience serious toxicities after at least six cycles, prolonged administration of single agent capecitabine at 2,000 mg/m2/day, in two divided doses for days 1 14 in a 3 week cycle, would be given for a minimum duration of 6 months. RPTD was defined as the dose level below the MTD. At the level of the established RPTD, an additional 20 patients would be enrolled, with emphasis given to accruing patients with gastric and other upper gastrointestinal primary sites. No provisions were made to escalate beyond dose level 4, since this dose level was considered a suitable RPTD given that both agents were therapeutically active in respective single agent dose and schedules.
All toxicities were evaluated based on NCI Common Toxicity Criteria version 2.0. Patients were removed from the protocol if they experienced any DLTs, if they missed two consecutive cycles or if a cycle was delayed for more than 20 days. For PPE, the following grading was utilized, grade 1, erythema only, grade 2, erythema with numbness, pain or any symptoms that affect activities of daily living, grade 3, moist desquamation, blisters or ulcers or lesions which are so painful that activities of daily living cannot be performed. For any significant non hematological toxicities such as PPE, mucositis or diarrhea, improvement of symptoms to at least grade 1 was required prior to resuming another cycle of chemotherapy. Treatment was held for ANC 1,500/l and for platelet count 100,000/l. The dose of subsequent capecitabine and cisplatin were determined by the nadir of neutrophils and/or platelets. For