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

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.

• Authors: 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
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 69 Issue 2 Pg. 523-31 (Feb 2012) ISSN: 1432-0843 [Electronic] Germany
• PMID: 21874318 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Epothilones
• KOS-1584
• Tubulin Modulators

Topics

• Adult
• Aged
• Aged, 80 and over
• Area Under Curve
• Arthralgia (chemically induced)
• Diarrhea (chemically induced)
• Dose-Response Relationship, Drug
• Epothilones (adverse effects, chemistry, pharmacokinetics, therapeutic use)
• Fatigue (chemically induced)
• Female
• Humans
• Male
• Metabolic Clearance Rate
• Middle Aged
• Molecular Structure
• Neoplasms (drug therapy, metabolism, pathology)
• Peripheral Nervous System Diseases (chemically induced)
• Treatment Outcome
• Tubulin Modulators (adverse effects, chemistry, therapeutic use)