A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose
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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.
Patients who failed prior standard therapy or those without any standard options were eligible. Forty-four 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.
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.
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.
KeywordsSB-743921 Phase I Pharmacokinetics Kinesin spindle protein Mitosis Safety
- 6.Stein MN, Tan A, Taber K, Fernandez R, Agrawal NG, Vandendries E, Hsu K, Walker A, Holen K, Wilding G (2007) Phase I clinical and pharmacokinetic (PK) trial of the kinesin spindle protein (KSP) inhibitor MK-0731 in patients with solid tumors. In: 2007 ASCO annual meeting proceedings Part I. J Clin Oncol 25(18S):2007 (June 20 Supplement; abstr 2548)Google Scholar
- 7.Infante JR, Spratlin JL, Kurzrock R, Eckhardt SG, Burris HA, Puchalski TA, Li J, Wu K, Ochs J, Herbst RS (2008) Clinical, pharmacokinetic (PK), pharmacodynamic findings in a phase I trial of weekly (wkly) intravenous AZD4877 in patients with refractory solid tumors. J Clin Oncol 26:2008 (May 20 suppl; abstr 2501)Google Scholar
- 8.Stephenson JJ, Lewis N, Martin JC, Ho A, Li J, Wu K, Pace L, Eder JP, Schwartz GK (2008) Phase I multicenter study to assess the safety, tolerability, and pharmacokinetics of AZD4877 administered twice weekly in adult patients with advanced solid malignancies. J Clin Oncol 26:2008 (May 20 suppl; abstr 2516)Google Scholar