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A Phase I Clinical, Pharmacokinetic, and Pharmacodynamic Study of Weekly or Every Three Week Ixabepilone and Daily Sunitinib in Patients with Advanced Solid Tumors.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2016 Jul 01; Vol. 22 (13), pp. 3209-17. Date of Electronic Publication: 2016 Feb 10. - Publication Year :
- 2016
-
Abstract
- Purpose: To evaluate the safety, MTD, pharmacokinetics/pharmacodynamics, and early clinical activity of ixabepilone given either weekly or every 3 weeks in combination with daily sunitinib in patients with advanced solid tumors.<br />Experimental Design: Eligible patients received either weekly (schedule A) or every 3 weeks (schedule B) ixabepilone at escalating doses (schedule A: 7.5, 15, or 20 mg/m(2); schedule B: 20, 30, or 40 mg/m(2)), and oral sunitinib (37.5 mg daily), starting on day 8 of cycle 1. Dose-limiting toxicities (DLT) were assessed during cycle 1.<br />Results: The ixabepilone and sunitinib combination was fairly well tolerated. DLTs were observed in 3 subjects (1 in schedule 3A and 2 in schedule 3B). The most common grade 3-4 hematologic and nonhematologic adverse events were leukopenia and fatigue, respectively. Four patients (3 in schedule A) achieved a partial response, while 13 patients had stable disease. Nine of 17 heavily pretreated colorectal cancer patients had clinical benefit. Coadministration of sunitinib with ixabepilone on a weekly (but not every 3 week) schedule was associated with a significant increase in the half-life and a significant decrease in the clearance of ixabepilone. Correlative studies demonstrated a significant association between higher baseline plasma angiogenic activity (PAA) and clinical benefit in schedule A patients. Weekly, but not every 3 weeks, ixabepilone led to a significant decrease in PAA postbaseline.<br />Conclusions: Coadministration of ixabepilone with sunitinib has acceptable toxicity and encouraging clinical activity in heavily pretreated patients, particularly in patients with metastatic colorectal cancer. Clin Cancer Res; 22(13); 3209-17. ©2016 AACR.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Adult
Aged
Angiogenesis Inhibitors pharmacokinetics
Antineoplastic Agents administration & dosage
Antineoplastic Agents adverse effects
Antineoplastic Agents pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Biomarkers, Tumor blood
Drug Administration Schedule
Epothilones administration & dosage
Female
Humans
Indoles administration & dosage
Male
Middle Aged
Neovascularization, Pathologic drug therapy
Pyrroles administration & dosage
Sunitinib
Tubulin Modulators pharmacokinetics
Angiogenesis Inhibitors therapeutic use
Antineoplastic Agents therapeutic use
Epothilones pharmacokinetics
Epothilones therapeutic use
Indoles pharmacokinetics
Indoles therapeutic use
Neoplasms drug therapy
Pyrroles pharmacokinetics
Pyrroles therapeutic use
Tubulin Modulators therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 22
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 26864210
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-15-2184