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div>Secondary objectives were the characterization of OS and PFS and the kinetics of neurotoxicity. Cisplatin and cyclophosphamide, with differing and potentially synergistic mechanisms of action, were combined with dose-intensified paclitaxel. 13-16 Paclitaxel stabilizes microtubule assembly 3-mercaptopyruvate sulfurtransferase 17 and slows the repair of DNA lesions, including cisplatin adducts and cyclophosphamide cross-links. 16, 18 We defined the maximum tolerated dose of paclitaxel as 250 mg/m2 given as a 24-hour infusion with flexible filgrastim support 19 and determined its safety when combined with cyclophosphamide 750 mg/m2 and cisplatin 75 mg/m2. 20 Administration of the triplet to patients with advanced stage EOC led to an 89% clinical response rate and a 61% surgical response rate (microscopic and pathologic) in a single-institution study of patients with EOC. 20 That phase 2 study defined the activity and tolerability of this dose-intense paclitaxel combination. The study was approved by the institutional review boards at the Selinexor nmr National Cancer Institute (NCI) and Massachusetts General Hospital (MGH). Eligibility criteria included women with untreated, newly diagnosed, International Federation of Gynecology and Obstetrics stage III/IV EOC; initiation of therapy within 6 weeks of staging laparotomy; creatinine clearance ��60 mL/minute; good end-organ function; an Eastern Cooperative Oncology Group performance status between 0 and 2; and informed consent. Patients were excluded for a prior history of invasive cancer, myocardial infarction, or unstable dysrhythmia within 6 months of study entry or for gastrointestinal bleeding within 1 month of entry. Agents were provided by the Cancer Therapy Evaluation Program, NCI. NCI patients received their first cycle in the hospital and received subsequent cycles as outpatients, whereas MGH patients received all cycles in the hospital. The premedication, treatment, and dose modification schema are shown in Tables 1 and 2. Cisplatin was limited to 6 cycles to minimize the risk of allergic reactions www.selleckchem.com and cumulative neurotoxicity. Cyclophosphamide and paclitaxel were continued in patients who required >6 cycles to achieve the best clinical response and after surgical reassessment. Subsequent cycles were initiated if nonhematologic toxicity was grade and if their absolute granulocyte count was ��1500 cells/mm3. Drug compliance and toxicity were assessed at each visit and were graded using NCI Common Toxicity Criteria version 1.0 (CTC v1.0). Proprioception, vibration, and pinprick sensory modalities; deep tendon reflexes; Romberg maneuver; and tandem gait were evaluated in each cycle. The paclitaxel dose was modified for objective clinical findings with functional impairment consistent with CTC v1.0 grade 3 neurologic toxicity.</div>