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Published in: Journal of Neuro-Oncology 2/2010

01-11-2010 | Clinical Study – Patient Study

A phase I/II trial and pharmacokinetic study of ixabepilone in adult patients with recurrent high-grade gliomas

Authors: David M. Peereboom, Jeffrey G. Supko, Kathryn A. Carson, Tracy Batchelor, Surasak Phuphanich, Glenn Lesser, Tom Mikkelson, Joy Fisher, Serena Desideri, Xiaoying He, Stuart A. Grossman, The New Approaches to Brain Tumor Therapy (NABTT) Consortium

Published in: Journal of Neuro-Oncology | Issue 2/2010

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Abstract

Ixabepilone is an epothilone, a novel class of non-taxane microtubule stabilizing agents. A phase I/II and pharmacokinetic trial of ixabepilone was conducted in patients with recurrent high-grade gliomas. Adult patients received ixabepilone as a 1-h infusion daily for 5 days every 3 weeks. A modified continual reassessment method was used to escalate doses, beginning at 5.0 mg/m2, in patients stratified by use or non-use of enzyme inducing antiepileptic drugs (EIAED). In the phase I study, the maximum tolerated dose (MTD) and pharmacokinetics of ixabepilone were determined for each group. The phase II study used a two-stage design to evaluate response rate. Secondary endpoints were survival and 6-month progression free survival. In the phase I trial, 38 patients (median age 54 years) were enrolled. The MTD was 6.8 mg/m2 for patients not taking EIAEDs and 9.6 mg/m2 for those taking EIAEDs. The dose limiting toxicities in both groups were hematologic. Twenty-three patients (median age 54 years) were enrolled in the first stage of the phase II trial. No objective responses were observed. Median overall survival was 5.8 (95% CI, 5.0–8.6) months and 6-month PFS rate was 4% (95% CI, 0–22%). The overall mean total body clearance for ixabepilone was significantly higher (P = 0.003) in patients receiving EIAEDs (36 ± 11 l/h/m2) than those not (24 ± 9.2 l/h/m2). Patients on EIAEDs had a substantially higher MTD likely due to induction of cytochrome P450. Ixabepilone had no activity in patients with recurrent high-grade gliomas.
Literature
1.
go back to reference Landis SH, Murray T, Bolden S, Wingo PA (1999) Cancer statistics. Cancer J Clin 49:8–31CrossRef Landis SH, Murray T, Bolden S, Wingo PA (1999) Cancer statistics. Cancer J Clin 49:8–31CrossRef
2.
go back to reference Gerth K, Bedorf N, Hofle G, Irschik H, Reichenbach H (1996) Epothilons A and B: antifungal and cytotoxic compounds from sorangium cellulosum (myxobacteria) production, physico-chemical and biological properties. J Antibiot 49:560–563PubMed Gerth K, Bedorf N, Hofle G, Irschik H, Reichenbach H (1996) Epothilons A and B: antifungal and cytotoxic compounds from sorangium cellulosum (myxobacteria) production, physico-chemical and biological properties. J Antibiot 49:560–563PubMed
3.
go back to reference Bollag DM, McQueney PA, Zhu J et al (1995) Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res 55:2325–2333PubMed Bollag DM, McQueney PA, Zhu J et al (1995) Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res 55:2325–2333PubMed
4.
go back to reference Kowalski RJ, Giannakakou P, Hamel E (1997) Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (taxol(R)). J Biol Chem 272:2534–2541CrossRefPubMed Kowalski RJ, Giannakakou P, Hamel E (1997) Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (taxol(R)). J Biol Chem 272:2534–2541CrossRefPubMed
5.
go back to reference Lee FY, Borzilleri R, Fairchild CR et al (2001) BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res 7:1429–1437PubMed Lee FY, Borzilleri R, Fairchild CR et al (2001) BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res 7:1429–1437PubMed
6.
go back to reference Muhlradt PF, Sasse F (1997) Epothilone B stabilizes microtubuli of macrophages like taxol without showing taxol-like endotoxin activity. Cancer Res 57:3344–3346PubMed Muhlradt PF, Sasse F (1997) Epothilone B stabilizes microtubuli of macrophages like taxol without showing taxol-like endotoxin activity. Cancer Res 57:3344–3346PubMed
7.
go back to reference Muldoon LL, Soussain C, Jahnke K et al (2007) Chemotherapy delivery issues in central nervous system malignancy: a reality check. J Clin Oncol 25:2295–2305CrossRefPubMed Muldoon LL, Soussain C, Jahnke K et al (2007) Chemotherapy delivery issues in central nervous system malignancy: a reality check. J Clin Oncol 25:2295–2305CrossRefPubMed
8.
go back to reference Chamberlain MC, Kormanik P (1999) Salvage chemotherapy with taxol for recurrent anaplastic astrocytomas. J Neurooncol 43:71–78CrossRefPubMed Chamberlain MC, Kormanik P (1999) Salvage chemotherapy with taxol for recurrent anaplastic astrocytomas. J Neurooncol 43:71–78CrossRefPubMed
9.
go back to reference Chang SM, Kuhn JG, Robins HI et al (2001) A phase II study of paclitaxel in patients with recurrent malignant glioma using different doses depending upon the concomitant use of anticonvulsants: a North American brain tumor consortium report. Cancer 91:417–422CrossRefPubMed Chang SM, Kuhn JG, Robins HI et al (2001) A phase II study of paclitaxel in patients with recurrent malignant glioma using different doses depending upon the concomitant use of anticonvulsants: a North American brain tumor consortium report. Cancer 91:417–422CrossRefPubMed
10.
go back to reference Prados MD, Schold SC, Spence AM et al (1996) Phase II study of paclitaxel in patients with recurrent malignant glioma. J Clin Oncol 14:2316–2321PubMed Prados MD, Schold SC, Spence AM et al (1996) Phase II study of paclitaxel in patients with recurrent malignant glioma. J Clin Oncol 14:2316–2321PubMed
11.
go back to reference Peterson JK, Tucker C, Favours E et al (2005) In vivo evaluation of ixabepilone (BMS247550), a novel epothilone B derivative, against pediatric cancer models. Clin Cancer Res 11:6950–6958CrossRefPubMed Peterson JK, Tucker C, Favours E et al (2005) In vivo evaluation of ixabepilone (BMS247550), a novel epothilone B derivative, against pediatric cancer models. Clin Cancer Res 11:6950–6958CrossRefPubMed
12.
go back to reference Goel S, Cohen M, Cömezoglu SN et al (2008) The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone: a first in class epothilone B analogue in late-phase clinical development. Clin Cancer Res 14:2701–2709CrossRefPubMed Goel S, Cohen M, Cömezoglu SN et al (2008) The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone: a first in class epothilone B analogue in late-phase clinical development. Clin Cancer Res 14:2701–2709CrossRefPubMed
13.
go back to reference Vecht CJ, Wagner GL, Wilms EB (2003) Interactions between antiepileptic and chemotherapeutic drugs. Lancet Neurol 2:404–409CrossRefPubMed Vecht CJ, Wagner GL, Wilms EB (2003) Interactions between antiepileptic and chemotherapeutic drugs. Lancet Neurol 2:404–409CrossRefPubMed
14.
go back to reference Abraham J, Agrawal M, Bakke S et al (2003) Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days. J Clin Oncol 21:1866–1873CrossRefPubMed Abraham J, Agrawal M, Bakke S et al (2003) Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days. J Clin Oncol 21:1866–1873CrossRefPubMed
15.
go back to reference Aghajanian C, Burris HA III, Jones S et al (2007) Phase I study of the novel epothilone analog ixabepilone (BMS-247550) in patients with advanced solid tumors and lymphomas. J Clin Oncol 25:1082–1088CrossRefPubMed Aghajanian C, Burris HA III, Jones S et al (2007) Phase I study of the novel epothilone analog ixabepilone (BMS-247550) in patients with advanced solid tumors and lymphomas. J Clin Oncol 25:1082–1088CrossRefPubMed
16.
go back to reference Larkin JM, Kaye SB (2007) Potential clinical applications of epothilones: a review of phase II studies. Ann Oncol 18:28–34CrossRef Larkin JM, Kaye SB (2007) Potential clinical applications of epothilones: a review of phase II studies. Ann Oncol 18:28–34CrossRef
17.
go back to reference Piantadosi S, Fisher JD, Grossman S (1998) Practical implementation of a modified continual reassessment method for dose-finding trials. Cancer Chemother Pharmacol 41:429–436CrossRefPubMed Piantadosi S, Fisher JD, Grossman S (1998) Practical implementation of a modified continual reassessment method for dose-finding trials. Cancer Chemother Pharmacol 41:429–436CrossRefPubMed
18.
go back to reference Shah VP, Midha KK, Dighe S et al (1991) Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. Conference report. Eur J Drug Metab Pharmacokinet 16:249–255 Shah VP, Midha KK, Dighe S et al (1991) Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. Conference report. Eur J Drug Metab Pharmacokinet 16:249–255
19.
go back to reference Lacey LF, Keene ON, Pritchard JF, Bye A (1997) Common noncompartmental pharmacokinetic variables: are they normally or log-normally distributed? J Biopharm Stat 7:171–178CrossRefPubMed Lacey LF, Keene ON, Pritchard JF, Bye A (1997) Common noncompartmental pharmacokinetic variables: are they normally or log-normally distributed? J Biopharm Stat 7:171–178CrossRefPubMed
20.
go back to reference Mizuta E, Tsubotani A (1985) Preparation of mean drug concentration–time curves in plasma. A study on the frequency distribution of pharmacokinetic parameters. Chem Pharm Bull 33:1620–1632PubMed Mizuta E, Tsubotani A (1985) Preparation of mean drug concentration–time curves in plasma. A study on the frequency distribution of pharmacokinetic parameters. Chem Pharm Bull 33:1620–1632PubMed
21.
go back to reference Beumer JH, Garner RC, Cohen MB et al (2007) Human mass balance study of the novel anticancer agent ixabepilone using accelerator mass spectrometry. Invest New Drugs 25:327–334CrossRefPubMed Beumer JH, Garner RC, Cohen MB et al (2007) Human mass balance study of the novel anticancer agent ixabepilone using accelerator mass spectrometry. Invest New Drugs 25:327–334CrossRefPubMed
22.
go back to reference Zhou S, Yung Chan S, Cher Goh B et al (2005) Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. Clin Pharmacokinet 44:279–304CrossRefPubMed Zhou S, Yung Chan S, Cher Goh B et al (2005) Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. Clin Pharmacokinet 44:279–304CrossRefPubMed
23.
go back to reference Glantz MJ, Cole BF, Forsyth PA et al (2000) Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the quality standards subcommittee of the American academy of neurology. Neurology 54:1886–1893PubMed Glantz MJ, Cole BF, Forsyth PA et al (2000) Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the quality standards subcommittee of the American academy of neurology. Neurology 54:1886–1893PubMed
24.
go back to reference Tanaka E (1999) Clinically significant pharmacokinetic drug interactions between antiepileptic drugs. J Clin Pharm Ther 24:87–92CrossRefPubMed Tanaka E (1999) Clinically significant pharmacokinetic drug interactions between antiepileptic drugs. J Clin Pharm Ther 24:87–92CrossRefPubMed
25.
go back to reference Chang SM, Kuhn J, Wen P et al (2004) Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs. Invest New Drugs 22:427–435CrossRefPubMed Chang SM, Kuhn J, Wen P et al (2004) Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs. Invest New Drugs 22:427–435CrossRefPubMed
26.
go back to reference Cloughesy TF, Kuhn J, Robins HI et al (2005) Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: a North American brain tumor consortium study. J Clin Oncol 23:6647–6656CrossRefPubMed Cloughesy TF, Kuhn J, Robins HI et al (2005) Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: a North American brain tumor consortium study. J Clin Oncol 23:6647–6656CrossRefPubMed
27.
go back to reference Fetell MR, Grossman SA, Fisher JD et al (1997) Preirradiation paclitaxel in glioblastoma multiforme: efficacy, pharmacology, and drug interactions. New approaches to brain tumor therapy central nervous system consortium. J Clin Oncol 15:3121–3128PubMed Fetell MR, Grossman SA, Fisher JD et al (1997) Preirradiation paclitaxel in glioblastoma multiforme: efficacy, pharmacology, and drug interactions. New approaches to brain tumor therapy central nervous system consortium. J Clin Oncol 15:3121–3128PubMed
28.
go back to reference Galanis E, Buckner JC, Maurer MJ et al (2005) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a north central cancer treatment group study. J Clin Oncol 23:5294–5304CrossRefPubMed Galanis E, Buckner JC, Maurer MJ et al (2005) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a north central cancer treatment group study. J Clin Oncol 23:5294–5304CrossRefPubMed
29.
go back to reference Gilbert MR, Supko JG, Batchelor T et al (2003) Phase I clinical and pharmacokinetic study of irinotecan in adults with recurrent malignant glioma. Clin Cancer Res 9:2940–2949PubMed Gilbert MR, Supko JG, Batchelor T et al (2003) Phase I clinical and pharmacokinetic study of irinotecan in adults with recurrent malignant glioma. Clin Cancer Res 9:2940–2949PubMed
30.
go back to reference Grossman SA, Hochberg F, Fisher J et al (1998) Increased 9-aminocamptothecin dose requirements in patients on anticonvulsants. NABTT CNS consortium the new approaches to brain tumor therapy. Cancer Chemother Pharmacol 42:118–126CrossRefPubMed Grossman SA, Hochberg F, Fisher J et al (1998) Increased 9-aminocamptothecin dose requirements in patients on anticonvulsants. NABTT CNS consortium the new approaches to brain tumor therapy. Cancer Chemother Pharmacol 42:118–126CrossRefPubMed
31.
go back to reference Phuphanich S, Baker SD, Grossman SA et al (2005) Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: a dose escalation and pharmacologic study. Neuro Oncol 7:177–182CrossRefPubMed Phuphanich S, Baker SD, Grossman SA et al (2005) Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: a dose escalation and pharmacologic study. Neuro Oncol 7:177–182CrossRefPubMed
32.
go back to reference Prados MD, Lamborn KR, Chang S et al (2006) Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. Neuro Oncol 8:67–78CrossRefPubMed Prados MD, Lamborn KR, Chang S et al (2006) Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. Neuro Oncol 8:67–78CrossRefPubMed
33.
go back to reference Reardon DA, Egorin MJ, Quinn JA et al (2005) Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol 23:9359–9368CrossRefPubMed Reardon DA, Egorin MJ, Quinn JA et al (2005) Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol 23:9359–9368CrossRefPubMed
34.
go back to reference Reardon DA, Quinn JA, Vredenburgh JJ et al (2006) Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res 12:860–868CrossRefPubMed Reardon DA, Quinn JA, Vredenburgh JJ et al (2006) Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res 12:860–868CrossRefPubMed
35.
go back to reference Luo G, Cunningham M, Kim S et al (2002) CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos 30:795–804CrossRefPubMed Luo G, Cunningham M, Kim S et al (2002) CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos 30:795–804CrossRefPubMed
36.
go back to reference Raucy JL (2003) Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab Dispos 31:533–539CrossRefPubMed Raucy JL (2003) Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab Dispos 31:533–539CrossRefPubMed
37.
go back to reference Faucette SR, Wang H, Hamilton GA et al (2004) Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos 32:348–358CrossRefPubMed Faucette SR, Wang H, Hamilton GA et al (2004) Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos 32:348–358CrossRefPubMed
38.
go back to reference Mani S, McDaid H, Hamilton A et al (2004) Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors. Clin Cancer Res 10:1289–1298CrossRefPubMed Mani S, McDaid H, Hamilton A et al (2004) Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors. Clin Cancer Res 10:1289–1298CrossRefPubMed
39.
go back to reference Gadgeel SM, Wozniak A, Boinpally RR et al (2005) Phase I clinical trial of BMS-247550, a derivative of epothilone B, using accelerated titration 2B design. Clin Cancer Res 11:6233–6239CrossRefPubMed Gadgeel SM, Wozniak A, Boinpally RR et al (2005) Phase I clinical trial of BMS-247550, a derivative of epothilone B, using accelerated titration 2B design. Clin Cancer Res 11:6233–6239CrossRefPubMed
Metadata
Title
A phase I/II trial and pharmacokinetic study of ixabepilone in adult patients with recurrent high-grade gliomas
Authors
David M. Peereboom
Jeffrey G. Supko
Kathryn A. Carson
Tracy Batchelor
Surasak Phuphanich
Glenn Lesser
Tom Mikkelson
Joy Fisher
Serena Desideri
Xiaoying He
Stuart A. Grossman
The New Approaches to Brain Tumor Therapy (NABTT) Consortium
Publication date
01-11-2010
Publisher
Springer US
Published in
Journal of Neuro-Oncology / Issue 2/2010
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-010-0190-0

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