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Phase I trial of ixabepilone administered as three oral doses each separated by 6 hours every 3 weeks in patients with advanced solid tumors

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Summary

Background Ixabepilone, which stabilizes microtubules, has low susceptibility to drug resistance mediated by P-glycoprotein or βIII-tubulin. Materials and Methods This study was designed to determine the maximum tolerated dose (MTD) of oral ixabepilone when administered every 6 h for three doses, every 3 weeks, to patients with refractory advanced cancers. Eighteen patients were treated with escalating doses of ixabepilone: three at cohort 1 (30 mg/dose; 90 mg on Day 1), nine at cohort 2 (40 mg/dose; 120 mg on Day 1), and six at cohort 3 (50 mg/dose; 150 mg on Day 1). Serial plasma samples were collected during cycle 1 for pharmacokinetic (PK) measurements. Results Of the 18 treated patients, eight were male and ten were female. The median age was 59 years, and most had an excellent performance status (KPS 90–100; 61%). There were two dose limiting toxicities (DLT): Grade 4 febrile neutropenia at the 120 mg dose and Grade 4 neutropenic sepsis at the 150 mg dose. Because of the severity and duration of neutropenic sepsis at level 3, level 2 (120 mg) was defined as the MTD and this cohort was expanded to nine patients. High inter-individual variability in plasma drug concentrations was observed during the study, with particularly high levels in two patients with DLT. Conclusions On the basis of this safety profile, the MTD of oral ixabepilone was defined as 120 mg given as three 40 mg doses each separated by 6 h on Day 1 of a 3-week cycle. However, the PK variability observed makes further development of this oral formulation unlikely.

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Acknowledgements

We thank the patients for volunteering to participate in this trial, our clinical research nurses and staff, and the physicians who referred patients for this protocol. The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and scientific expertise. They also wish to acknowledge StemScientific, funded by Bristol-Myers Squibb, for providing writing and editorial support.

Ethical standards

Informed consent was obtained from all patients. The protocol and patient informed consent were approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) at each site before any patients were enrolled at that site.

Conflict of interest

P. L. Clemens, M. Messina, R. Kaleta, and F. Abrahao are employees of Bristol Myers Squibb and were involved in study conduct. There are no other conflicts of interest.

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Authors and Affiliations

  1. Stanford University School of Medicine, Stanford, CA, USA

    Pamela L. Kunz, A. Dimitrios Colevas & Branimir I. Sikic

  2. Lombardi Comprehensive Cancer Center - Georgetown University, Washington, DC, USA

    Aiwu R. He, Michael J. Pishvaian, Jimmy J. Hwang & John L. Marshall

  3. Bristol-Myers Squibb, Princeton, NJ, USA

    Pamela L. Clemens

  4. Bristol-Myers Squibb, Wallingford, CT, USA

    Marianne Messina, Remigiusz Kaleta & Fernanda Abrahao

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  1. Pamela L. Kunz
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Correspondence to Branimir I. Sikic.

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Kunz, P.L., He, A.R., Colevas, A.D. et al. Phase I trial of ixabepilone administered as three oral doses each separated by 6 hours every 3 weeks in patients with advanced solid tumors. Invest New Drugs 30, 2364–2370 (2012). https://doi.org/10.1007/s10637-012-9800-3

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