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

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)447-454
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume67
Issue number2
DOIs
StatePublished - Feb 1 2011

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Kinesin
Pharmacokinetics
Toxicity
Proteins
Maximum Tolerated Dose
Pharmacodynamics
Plasmas
Hypophosphatemia
Safety
Terminology
Hyperbilirubinemia
Cholangiocarcinoma
Hyponatremia
Refractory materials
Tumors
Neutropenia
Embolism
SB 743921
Lymphoma
Appointments and Schedules

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Holen, Kyle D. ; Belani, Chandra P. ; Wilding, George ; Ramalingam, Suresh ; Volkman, Jennifer L. ; Ramanathan, Ramesh K. ; Vasist, Lakshmi S. ; Bowen, Carolyn J. ; Hodge, Jeffrey P. ; Dar, Mohammed M. ; Ho, Peter T.C. / 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. In: Cancer Chemotherapy and Pharmacology. 2011 ; Vol. 67, No. 2. pp. 447-454.
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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.",
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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. / Holen, Kyle D.; Belani, Chandra P.; Wilding, George; Ramalingam, Suresh; Volkman, Jennifer L.; Ramanathan, Ramesh K.; Vasist, Lakshmi S.; Bowen, Carolyn J.; Hodge, Jeffrey P.; Dar, Mohammed M.; Ho, Peter T.C.

In: Cancer Chemotherapy and Pharmacology, Vol. 67, No. 2, 01.02.2011, p. 447-454.

Research output: Contribution to journalArticle

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T1 - 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

AU - Holen, Kyle D.

AU - Belani, Chandra P.

AU - Wilding, George

AU - Ramalingam, Suresh

AU - Volkman, Jennifer L.

AU - Ramanathan, Ramesh K.

AU - Vasist, Lakshmi S.

AU - Bowen, Carolyn J.

AU - Hodge, Jeffrey P.

AU - Dar, Mohammed M.

AU - Ho, Peter T.C.

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N2 - 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.

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