TY - JOUR
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.
N1 - Funding Information:
Acknowledgments The authors thank the patients who participated in this trial; the nurses and nurse practitioners who cared for these patients at The Ohio State University and Montefiore-Einstein Cancer Center; and the staff of the OSU Clinical Trials Processing Laboratory who processed the correlative specimens. This work was supported in part by the P30 CA016058-34 grant (PI: Michael Caligiuri, 12/01/ 2004—11/30/2010) and by funding from Kosan Biosciences, Inc. MV and SM received research funding from Kosan Biosciences, Inc.
PY - 2012/2
Y1 - 2012/2
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.
KW - Epothilone
KW - KOS-1584
KW - Phase I
KW - Solid tumors
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U2 - 10.1007/s00280-011-1724-7
DO - 10.1007/s00280-011-1724-7
M3 - Article
C2 - 21874318
AN - SCOPUS:84856728662
SN - 0344-5704
VL - 69
SP - 523
EP - 531
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 2
ER -