Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 2, pp 447–454 | Cite as

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

  • Kyle D. Holen
  • Chandra P. Belani
  • George Wilding
  • Suresh Ramalingam
  • Jennifer L. Volkman
  • Ramesh K. Ramanathan
  • Lakshmi S. Vasist
  • Carolyn J. Bowen
  • Jeffrey P. Hodge
  • Mohammed M. Dar
  • Peter T. C. Ho
Original Article

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. 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.

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.

Keywords

SB-743921 Phase I Pharmacokinetics Kinesin spindle protein Mitosis Safety 

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Kyle D. Holen
    • 1
  • Chandra P. Belani
    • 2
  • George Wilding
    • 1
  • Suresh Ramalingam
    • 2
  • Jennifer L. Volkman
    • 1
  • Ramesh K. Ramanathan
    • 2
  • Lakshmi S. Vasist
    • 3
    • 4
  • Carolyn J. Bowen
    • 3
    • 4
  • Jeffrey P. Hodge
    • 3
    • 4
  • Mohammed M. Dar
    • 3
    • 4
  • Peter T. C. Ho
    • 3
    • 4
  1. 1.University of Wisconsin Carbone Cancer CenterMadisonUSA
  2. 2.University of Pittsburgh Cancer InstitutePittsburghUSA
  3. 3.GlaxoSmithKline R&DResearch Triangle ParkUSA
  4. 4.GlaxoSmithKline R&DCollegevilleUSA

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