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Phase I clinical, pharmacokinetic, and pharmacodynamic study of KOS-862 (Epothilone D) in patients with advanced solid tumors and lymphoma

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An Erratum to this article was published on 03 January 2012

Summary

Purpose To determine the maximum tolerated dose and safety of the epothilone, KOS-862, in patients with advanced solid tumors or lymphoma. Patients and Methods Patients were treated weekly for 3 out of 4 weeks (Schedule A) or 2 out of 3 weeks (Schedule B) with KOS-862 (16–120 mg/m2). Pharmacokinetic (PK) sampling was performed during cycles 1 and 2; pharmacodynamic (PD) assessment for microtubule bundle formation (MTBF) was performed after the 1st dose, only at or above 100 mg/m2. Results Thirty-two patients were enrolled, and twenty-nine completed ≥1 cycle of therapy. Dose limiting toxicity [DLT] was observed at 120 mg/m2. PK data were linear from 16 to 100 mg/m2, with proportional increases in mean Cmax and AUCtot as a function of dose. Full PK analysis (mean ± SD) at 100 mg/m2 revealed the following: half-life (t ½) = 9.1 ± 2.2 h; volume of distribution (Vz) = 119 ± 41 L/m2; clearance (CL) = 9.3 ± 3.2 L/h/m2. MTBF (n = 9) was seen in 40% of PBMCs within 1 h and in 15% of PBMC at 24-hours post infusion at 100 mg/m2. Tumor shrinkage (n = 2, lymphoma), stable disease >3 months (n = 5, renal, prostate, oropharynx, cholangiocarcinoma, and Hodgkin lymphoma), and tumor marker reductions (n = 1, colorectal cancer/CEA) were observed. Conclusion KOS-862 was well tolerated with manageable toxicity, favorable PK profile, and the suggestion of clinical activity. The maximum tolerated dose was determined to be 100 mg/m2 weekly 3-on/1-off. MTBF can be demonstrated in PBMCs of patients exposed to KOS-862.

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Conflict of Interest Statement

The authors have no conflict of interest to declare.

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Authors and Affiliations

  1. Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10021, USA

    Jason Konner, Rachel N. Grisham, Jae Park, Martee L. Hensley, Paul Sabbatini, David Hyman, David R. Spriggs & Carol Aghajanian

  2. New York University Cancer Institute, New York, NY, USA

    Owen A. O’Connor

  3. Nereus Pharmaceuticals, Inc, San Diego, CA, USA

    Gillian Cropp & Alison L. Hannah

  4. Aeolian Biomed, Lafayette, CA, USA

    Robert Johnson

  5. Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Svetlana Miranov

  6. Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Samuel Danishefsky

  7. Genentech, Inc, 1 DNA Way, South San Francisco, CA, USA

    Jakob Dupont

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  1. Jason Konner
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Correspondence to Jason Konner.

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Supported in part by funds granted by *The American Society of Clinical Oncology Career Development Awards (JD), and by The Damon Runyon-Lilly Clinical Investigator Award (JD). OAO was supported in part by a Leukemia and Lymphoma Society Research Scholar Award.

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Konner, J., Grisham, R.N., Park, J. et al. Phase I clinical, pharmacokinetic, and pharmacodynamic study of KOS-862 (Epothilone D) in patients with advanced solid tumors and lymphoma. Invest New Drugs 30, 2294–2302 (2012). https://doi.org/10.1007/s10637-011-9765-7

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