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.
OBJECTIVE
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/m(2). 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/m(2). 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/m(2). The promising efficacy and lack of severe toxicities in this study warrant the continued development of SB-743921.
Holen
Kyle D
KD
University of Wisconsin Carbone Cancer Center, K4/528, 600 Highland Ave., Madison, WI 53792-5666, USA. kdh@medicine.wisc.edu
Belani
Chandra P
CP
Wilding
George
G
Ramalingam
Suresh
S
Volkman
Jennifer L
JL
Ramanathan
Ramesh K
RK
Vasist
Lakshmi S
LS
Bowen
Carolyn J
CJ
Hodge
Jeffrey P
JP
Dar
Mohammed M
MM
Ho
Peter T C
PT
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use*; D002867:Chromones / Q000494:pharmacology* / Q000627:therapeutic use*; D004066:Digestive System Diseases / Q000139:chemically induced; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D011655:Pulmonary Embolism / Q000139:chemically induced / Q000401:mortality; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D002867:Chromones; D004791:Enzyme Inhibitors; C470243:KIF11 protein, human; C557279:SB 743921; D016547:Kinesins
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