A phase 1 study of SNS-032 (formerly BMS-387032), a potent inhibitor of cyclin-dependent kinases 2, 7 and 9 administered as a single oral dose and weekly infusion in patients with metastatic refractory solid tumors

Elisabeth I. Heath, Keith Bible, Robert E. Martell, Daniel C. Adelman, Patricia M. LoRusso

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Purpose: SNS-032, (formerly BMS-387032) is a potent and selective inhibitor of cyclin-dependent kinases (CDK) 2, 7 and 9. The primary objective of the study was to establish the maximum tolerated dose (MTD), the maximum administered dose (MAD), dose limiting toxicity (DLT), and the recommended phase 2 dose for SNS-032 when administered as a weekly 1-h infusion. The secondary objective was to assess the safety and tolerability of SNS-032 and to evaluate its bioavailability as an oral solution. Methods: Patients with metastatic solid tumors or refractory lymphoma were treated with a starting dose of 4 mg/m 2 intravenously administered over 1-h with a cycle defined as 3 weekly doses of SNS-032 every 21 days. Three patient cohorts were utilized in the dose-escalation schema. Pharmacokinetic studies were performed. For the 13 and 16 mg/m2 dose cohorts, the first dose of cycle 2 was given as an oral solution to estimate the oral bioavailability of the drug in humans. Results: A total of 21 patients were enrolled. Twenty treated patients received a total of 39 cycles of treatment. The most common treatment-related adverse events occurring with greater than 20% incidence were fatigue (25%) and nausea (20%). Following intravenous administration, plasma concentrations declined in a biphasic manner, resulting in mean terminal half-lives between 5 and 10 hours. The mean C max and AUC0-inf increased nearly linearly with dose, ranging from 0.067 to 0.287 μg/ml and 0.103 to 0.553 μg h/ml, respectively. The CL and V ss remained unchanged with increasing dose levels, averaging 38 l/h/m2 and 212 l/m2, respectively. Average oral bioavailability was 19% (range: 4-33%). Three (15%) patients experienced a best response of stable disease. Study enrollment was terminated during dose-escalation due to a change in the development strategy for the study drug. Conclusions: SNS-032 administered as a weekly 1-h infusion was well tolerated, although study enrollment was terminated during dose-escalation and the MTD of SNS-032 administered intravenously on days 1, 8, and 15 of each treatment cycle was not reached. Tumor progression or stable disease was determined to be the best response in all evaluable patients. At the dose levels tested, the oral bioavailability of SNS-032 ranged from 4-33%. The data suggest that oral administration of SNS-032 may be feasible, though the tolerability and bioavailability of the oral formulation would have to be formally assessed.

Original languageEnglish (US)
Pages (from-to)59-65
Number of pages7
JournalInvestigational New Drugs
Volume26
Issue number1
DOIs
StatePublished - Feb 2008

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Cyclin-Dependent Kinase 9
Cyclin-Dependent Kinase 2
Biological Availability
Neoplasms
Maximum Tolerated Dose
N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide
Pharmaceutical Preparations
Intravenous Administration
Nausea
Fatigue
Oral Administration
Lymphoma
Therapeutics

Keywords

  • Cyclin-dependent kinase inhibitor
  • Metastatic refractory solid tumors
  • Phase I

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

A phase 1 study of SNS-032 (formerly BMS-387032), a potent inhibitor of cyclin-dependent kinases 2, 7 and 9 administered as a single oral dose and weekly infusion in patients with metastatic refractory solid tumors. / Heath, Elisabeth I.; Bible, Keith; Martell, Robert E.; Adelman, Daniel C.; LoRusso, Patricia M.

In: Investigational New Drugs, Vol. 26, No. 1, 02.2008, p. 59-65.

Research output: Contribution to journalArticle

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title = "A phase 1 study of SNS-032 (formerly BMS-387032), a potent inhibitor of cyclin-dependent kinases 2, 7 and 9 administered as a single oral dose and weekly infusion in patients with metastatic refractory solid tumors",
abstract = "Purpose: SNS-032, (formerly BMS-387032) is a potent and selective inhibitor of cyclin-dependent kinases (CDK) 2, 7 and 9. The primary objective of the study was to establish the maximum tolerated dose (MTD), the maximum administered dose (MAD), dose limiting toxicity (DLT), and the recommended phase 2 dose for SNS-032 when administered as a weekly 1-h infusion. The secondary objective was to assess the safety and tolerability of SNS-032 and to evaluate its bioavailability as an oral solution. Methods: Patients with metastatic solid tumors or refractory lymphoma were treated with a starting dose of 4 mg/m 2 intravenously administered over 1-h with a cycle defined as 3 weekly doses of SNS-032 every 21 days. Three patient cohorts were utilized in the dose-escalation schema. Pharmacokinetic studies were performed. For the 13 and 16 mg/m2 dose cohorts, the first dose of cycle 2 was given as an oral solution to estimate the oral bioavailability of the drug in humans. Results: A total of 21 patients were enrolled. Twenty treated patients received a total of 39 cycles of treatment. The most common treatment-related adverse events occurring with greater than 20{\%} incidence were fatigue (25{\%}) and nausea (20{\%}). Following intravenous administration, plasma concentrations declined in a biphasic manner, resulting in mean terminal half-lives between 5 and 10 hours. The mean C max and AUC0-inf increased nearly linearly with dose, ranging from 0.067 to 0.287 μg/ml and 0.103 to 0.553 μg h/ml, respectively. The CL and V ss remained unchanged with increasing dose levels, averaging 38 l/h/m2 and 212 l/m2, respectively. Average oral bioavailability was 19{\%} (range: 4-33{\%}). Three (15{\%}) patients experienced a best response of stable disease. Study enrollment was terminated during dose-escalation due to a change in the development strategy for the study drug. Conclusions: SNS-032 administered as a weekly 1-h infusion was well tolerated, although study enrollment was terminated during dose-escalation and the MTD of SNS-032 administered intravenously on days 1, 8, and 15 of each treatment cycle was not reached. Tumor progression or stable disease was determined to be the best response in all evaluable patients. At the dose levels tested, the oral bioavailability of SNS-032 ranged from 4-33{\%}. The data suggest that oral administration of SNS-032 may be feasible, though the tolerability and bioavailability of the oral formulation would have to be formally assessed.",
keywords = "Cyclin-dependent kinase inhibitor, Metastatic refractory solid tumors, Phase I",
author = "Heath, {Elisabeth I.} and Keith Bible and Martell, {Robert E.} and Adelman, {Daniel C.} and LoRusso, {Patricia M.}",
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pages = "59--65",
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T1 - A phase 1 study of SNS-032 (formerly BMS-387032), a potent inhibitor of cyclin-dependent kinases 2, 7 and 9 administered as a single oral dose and weekly infusion in patients with metastatic refractory solid tumors

AU - Heath, Elisabeth I.

AU - Bible, Keith

AU - Martell, Robert E.

AU - Adelman, Daniel C.

AU - LoRusso, Patricia M.

PY - 2008/2

Y1 - 2008/2

N2 - Purpose: SNS-032, (formerly BMS-387032) is a potent and selective inhibitor of cyclin-dependent kinases (CDK) 2, 7 and 9. The primary objective of the study was to establish the maximum tolerated dose (MTD), the maximum administered dose (MAD), dose limiting toxicity (DLT), and the recommended phase 2 dose for SNS-032 when administered as a weekly 1-h infusion. The secondary objective was to assess the safety and tolerability of SNS-032 and to evaluate its bioavailability as an oral solution. Methods: Patients with metastatic solid tumors or refractory lymphoma were treated with a starting dose of 4 mg/m 2 intravenously administered over 1-h with a cycle defined as 3 weekly doses of SNS-032 every 21 days. Three patient cohorts were utilized in the dose-escalation schema. Pharmacokinetic studies were performed. For the 13 and 16 mg/m2 dose cohorts, the first dose of cycle 2 was given as an oral solution to estimate the oral bioavailability of the drug in humans. Results: A total of 21 patients were enrolled. Twenty treated patients received a total of 39 cycles of treatment. The most common treatment-related adverse events occurring with greater than 20% incidence were fatigue (25%) and nausea (20%). Following intravenous administration, plasma concentrations declined in a biphasic manner, resulting in mean terminal half-lives between 5 and 10 hours. The mean C max and AUC0-inf increased nearly linearly with dose, ranging from 0.067 to 0.287 μg/ml and 0.103 to 0.553 μg h/ml, respectively. The CL and V ss remained unchanged with increasing dose levels, averaging 38 l/h/m2 and 212 l/m2, respectively. Average oral bioavailability was 19% (range: 4-33%). Three (15%) patients experienced a best response of stable disease. Study enrollment was terminated during dose-escalation due to a change in the development strategy for the study drug. Conclusions: SNS-032 administered as a weekly 1-h infusion was well tolerated, although study enrollment was terminated during dose-escalation and the MTD of SNS-032 administered intravenously on days 1, 8, and 15 of each treatment cycle was not reached. Tumor progression or stable disease was determined to be the best response in all evaluable patients. At the dose levels tested, the oral bioavailability of SNS-032 ranged from 4-33%. The data suggest that oral administration of SNS-032 may be feasible, though the tolerability and bioavailability of the oral formulation would have to be formally assessed.

AB - Purpose: SNS-032, (formerly BMS-387032) is a potent and selective inhibitor of cyclin-dependent kinases (CDK) 2, 7 and 9. The primary objective of the study was to establish the maximum tolerated dose (MTD), the maximum administered dose (MAD), dose limiting toxicity (DLT), and the recommended phase 2 dose for SNS-032 when administered as a weekly 1-h infusion. The secondary objective was to assess the safety and tolerability of SNS-032 and to evaluate its bioavailability as an oral solution. Methods: Patients with metastatic solid tumors or refractory lymphoma were treated with a starting dose of 4 mg/m 2 intravenously administered over 1-h with a cycle defined as 3 weekly doses of SNS-032 every 21 days. Three patient cohorts were utilized in the dose-escalation schema. Pharmacokinetic studies were performed. For the 13 and 16 mg/m2 dose cohorts, the first dose of cycle 2 was given as an oral solution to estimate the oral bioavailability of the drug in humans. Results: A total of 21 patients were enrolled. Twenty treated patients received a total of 39 cycles of treatment. The most common treatment-related adverse events occurring with greater than 20% incidence were fatigue (25%) and nausea (20%). Following intravenous administration, plasma concentrations declined in a biphasic manner, resulting in mean terminal half-lives between 5 and 10 hours. The mean C max and AUC0-inf increased nearly linearly with dose, ranging from 0.067 to 0.287 μg/ml and 0.103 to 0.553 μg h/ml, respectively. The CL and V ss remained unchanged with increasing dose levels, averaging 38 l/h/m2 and 212 l/m2, respectively. Average oral bioavailability was 19% (range: 4-33%). Three (15%) patients experienced a best response of stable disease. Study enrollment was terminated during dose-escalation due to a change in the development strategy for the study drug. Conclusions: SNS-032 administered as a weekly 1-h infusion was well tolerated, although study enrollment was terminated during dose-escalation and the MTD of SNS-032 administered intravenously on days 1, 8, and 15 of each treatment cycle was not reached. Tumor progression or stable disease was determined to be the best response in all evaluable patients. At the dose levels tested, the oral bioavailability of SNS-032 ranged from 4-33%. The data suggest that oral administration of SNS-032 may be feasible, though the tolerability and bioavailability of the oral formulation would have to be formally assessed.

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KW - Metastatic refractory solid tumors

KW - Phase I

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