Phase i dose escalation study of KOS-1584, a novel epothilone, in patients with advanced solid tumors

Elaine T. Lam, Sanjay Goel, Larry J. Schaaf, Gillian F. Cropp, Alison L. Hannah, Yiqing Zhou, Barbara McCracken, Brandi I. Haley, Robert G. Johnson, Sridhar Mani, Miguel A. Villalona-Calero

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Purpose: First-in-man study of KOS-1584, a second generation epothilone. Methods: Patients with advanced solid malignancies received KOS-1584 every 3 weeks until disease progression. Using a modified Fibonacci dose escalation scheme, one patient was enrolled at each dose level until the first instance of grade 2 toxicity. Thereafter, a standard 3 + 3 design was utilized. Results: Sixty-six patients in 14 cohorts were dosed from 0.8 to 48 mg/m 2. Diarrhea, arthralgias, and encephalopathy were dose-limiting toxicities (DLTs) at doses ≥36 mg/m 2. At the recommended phase II dose (RP2D), the most common adverse effects were peripheral neuropathy (low grade), fatigue, arthralgias/myalgias, and diarrhea (31, 6%). The incidence of neutropenia was low. The overall clearance, volume of distribution, and half-life of KOS-1584 were 11 ± 6.17 L/h/m 2, 327 ± 161 L/m 2, and 21.9 ± 8.75 h, respectively. The half-life for the seco-metabolite (KOS-1891) was 29.6 ± 13.8 h. KOS-1584 exhibited linear pharmacokinetics. A dose-dependent increase in microtubulin bundle formation was observed at doses ≥27 mg/m 2. Two patients achieved partial responses and 24 patients had stable disease (SD). Conclusions: The RP2D of KOS-1584 is 36 mg/m 2. The lack of severe neurologic toxicity, diarrhea, neutropenia, or hypersensitivity reactions; favorable pharmacokinetic profile; and early evidence of activity support further evaluation.

Original languageEnglish (US)
Pages (from-to)523-531
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume69
Issue number2
DOIs
StatePublished - Feb 2012

Fingerprint

Epothilones
Tumors
Toxicity
Diarrhea
Pharmacokinetics
Arthralgia
Neoplasms
Neutropenia
Half-Life
Myalgia
Brain Diseases
Peripheral Nervous System Diseases
Metabolites
Nervous System
Fatigue
Disease Progression
Hypersensitivity
KOS-1584
Fatigue of materials
Incidence

Keywords

  • Epothilone
  • KOS-1584
  • Phase I
  • Solid tumors

ASJC Scopus subject areas

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

Cite this

Phase i dose escalation study of KOS-1584, a novel epothilone, in patients with advanced solid tumors. / Lam, Elaine T.; Goel, Sanjay; Schaaf, Larry J.; Cropp, Gillian F.; Hannah, Alison L.; Zhou, Yiqing; McCracken, Barbara; Haley, Brandi I.; Johnson, Robert G.; Mani, Sridhar; Villalona-Calero, Miguel A.

In: Cancer Chemotherapy and Pharmacology, Vol. 69, No. 2, 02.2012, p. 523-531.

Research output: Contribution to journalArticle

Lam, ET, Goel, S, Schaaf, LJ, Cropp, GF, Hannah, AL, Zhou, Y, McCracken, B, Haley, BI, Johnson, RG, Mani, S & Villalona-Calero, MA 2012, 'Phase i dose escalation study of KOS-1584, a novel epothilone, in patients with advanced solid tumors', Cancer Chemotherapy and Pharmacology, vol. 69, no. 2, pp. 523-531. https://doi.org/10.1007/s00280-011-1724-7
Lam, Elaine T. ; Goel, Sanjay ; Schaaf, Larry J. ; Cropp, Gillian F. ; Hannah, Alison L. ; Zhou, Yiqing ; McCracken, Barbara ; Haley, Brandi I. ; Johnson, Robert G. ; Mani, Sridhar ; Villalona-Calero, Miguel A. / Phase i dose escalation study of KOS-1584, a novel epothilone, in patients with advanced solid tumors. In: Cancer Chemotherapy and Pharmacology. 2012 ; Vol. 69, No. 2. pp. 523-531.
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abstract = "Purpose: First-in-man study of KOS-1584, a second generation epothilone. Methods: Patients with advanced solid malignancies received KOS-1584 every 3 weeks until disease progression. Using a modified Fibonacci dose escalation scheme, one patient was enrolled at each dose level until the first instance of grade 2 toxicity. Thereafter, a standard 3 + 3 design was utilized. Results: Sixty-six patients in 14 cohorts were dosed from 0.8 to 48 mg/m 2. Diarrhea, arthralgias, and encephalopathy were dose-limiting toxicities (DLTs) at doses ≥36 mg/m 2. At the recommended phase II dose (RP2D), the most common adverse effects were peripheral neuropathy (low grade), fatigue, arthralgias/myalgias, and diarrhea (31, 6{\%}). The incidence of neutropenia was low. The overall clearance, volume of distribution, and half-life of KOS-1584 were 11 ± 6.17 L/h/m 2, 327 ± 161 L/m 2, and 21.9 ± 8.75 h, respectively. The half-life for the seco-metabolite (KOS-1891) was 29.6 ± 13.8 h. KOS-1584 exhibited linear pharmacokinetics. A dose-dependent increase in microtubulin bundle formation was observed at doses ≥27 mg/m 2. Two patients achieved partial responses and 24 patients had stable disease (SD). Conclusions: The RP2D of KOS-1584 is 36 mg/m 2. The lack of severe neurologic toxicity, diarrhea, neutropenia, or hypersensitivity reactions; favorable pharmacokinetic profile; and early evidence of activity support further evaluation.",
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T1 - Phase i dose escalation study of KOS-1584, a novel epothilone, in patients with advanced solid tumors

AU - Lam, Elaine T.

AU - Goel, Sanjay

AU - Schaaf, Larry J.

AU - Cropp, Gillian F.

AU - Hannah, Alison L.

AU - Zhou, Yiqing

AU - McCracken, Barbara

AU - Haley, Brandi I.

AU - Johnson, Robert G.

AU - Mani, Sridhar

AU - Villalona-Calero, Miguel A.

PY - 2012/2

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N2 - Purpose: First-in-man study of KOS-1584, a second generation epothilone. Methods: Patients with advanced solid malignancies received KOS-1584 every 3 weeks until disease progression. Using a modified Fibonacci dose escalation scheme, one patient was enrolled at each dose level until the first instance of grade 2 toxicity. Thereafter, a standard 3 + 3 design was utilized. Results: Sixty-six patients in 14 cohorts were dosed from 0.8 to 48 mg/m 2. Diarrhea, arthralgias, and encephalopathy were dose-limiting toxicities (DLTs) at doses ≥36 mg/m 2. At the recommended phase II dose (RP2D), the most common adverse effects were peripheral neuropathy (low grade), fatigue, arthralgias/myalgias, and diarrhea (31, 6%). The incidence of neutropenia was low. The overall clearance, volume of distribution, and half-life of KOS-1584 were 11 ± 6.17 L/h/m 2, 327 ± 161 L/m 2, and 21.9 ± 8.75 h, respectively. The half-life for the seco-metabolite (KOS-1891) was 29.6 ± 13.8 h. KOS-1584 exhibited linear pharmacokinetics. A dose-dependent increase in microtubulin bundle formation was observed at doses ≥27 mg/m 2. Two patients achieved partial responses and 24 patients had stable disease (SD). Conclusions: The RP2D of KOS-1584 is 36 mg/m 2. The lack of severe neurologic toxicity, diarrhea, neutropenia, or hypersensitivity reactions; favorable pharmacokinetic profile; and early evidence of activity support further evaluation.

AB - Purpose: First-in-man study of KOS-1584, a second generation epothilone. Methods: Patients with advanced solid malignancies received KOS-1584 every 3 weeks until disease progression. Using a modified Fibonacci dose escalation scheme, one patient was enrolled at each dose level until the first instance of grade 2 toxicity. Thereafter, a standard 3 + 3 design was utilized. Results: Sixty-six patients in 14 cohorts were dosed from 0.8 to 48 mg/m 2. Diarrhea, arthralgias, and encephalopathy were dose-limiting toxicities (DLTs) at doses ≥36 mg/m 2. At the recommended phase II dose (RP2D), the most common adverse effects were peripheral neuropathy (low grade), fatigue, arthralgias/myalgias, and diarrhea (31, 6%). The incidence of neutropenia was low. The overall clearance, volume of distribution, and half-life of KOS-1584 were 11 ± 6.17 L/h/m 2, 327 ± 161 L/m 2, and 21.9 ± 8.75 h, respectively. The half-life for the seco-metabolite (KOS-1891) was 29.6 ± 13.8 h. KOS-1584 exhibited linear pharmacokinetics. A dose-dependent increase in microtubulin bundle formation was observed at doses ≥27 mg/m 2. Two patients achieved partial responses and 24 patients had stable disease (SD). Conclusions: The RP2D of KOS-1584 is 36 mg/m 2. The lack of severe neurologic toxicity, diarrhea, neutropenia, or hypersensitivity reactions; favorable pharmacokinetic profile; and early evidence of activity support further evaluation.

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