Abstract
Purpose: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of SB-743921 when administered as a 1-h infusion every 21 days to patients with advanced solid tumors or relapsed/refractory lymphoma. Methods: Patients who failed prior standard therapy or those without any standard options were eligible. Fortyfour patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase. An additional 20 patients were enrolled at the recommended phase II dose to obtain additional safety and pharmacokinetic data. The doses evaluated ranged from 2 to 8 mg/m2. The pharmacokinetics of SB-743921 was evaluated at 19 time-points over 48 h following during administration during cycle 1. Toxicity was assessed by the NCI Common Terminology Criteria version 3.0. Response evaluation was performed every 6 weeks. Results: The most common and consistent DLT was neutropenia. Other DLTs observed included hypophosphatemia, pulmonary emboli, SVC syndrome, transaminitis, hyponatremia, and hyperbilirubinemia. The MTD of SB-743921 as a 1-h infusion every 21 days was established as 4 mg/m2. The maximum plasma concentration and area under the plasma concentration time curve appeared to increase proportionally to dose. One durable objective response was seen in a patient with metastatic cholangiocarcinoma who was on treatment 11 months and 6 patients had stable disease for over four cycles. Conclusions: The recommended phase II dose of SB-743921 on this specific schedule of a 1-h infusion every 3 weeks is 4 mg/m2. The promising efficacy and lack of severe toxicities in this study warrant the continued development of SB-743921.
Original language | English (US) |
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Pages (from-to) | 447-454 |
Number of pages | 8 |
Journal | Cancer chemotherapy and pharmacology |
Volume | 67 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2011 |
Keywords
- Kinesin spindle protein
- Mitosis
- Pharmacokinetics
- Phase I
- SB-743921
- Safety
ASJC Scopus subject areas
- Oncology
- Toxicology
- Pharmacology
- Cancer Research
- Pharmacology (medical)