title: A Phase I Clinical, Pharmacokinetic, and Pharmacodynamic Study of Weekly or Every Three Week Ixabepilone and Daily Sunitinib in Patients with Advanced Solid Tumors.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Department of Medicine, Division of Hematology-Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida. jmerchan2@med.miami.edu montero2@ccf.org.
authors: Alberto J
authors: AJ
authors: Montero
authors: Biostatistics and Bioinformatics Core, Sylvester Comprehensive Cancer Center, Miami, Florida.
authors: Deukwoo
authors: D
authors: Kwon
authors: Department of Medicine, Division of Hematology-Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida.
authors: Aurea
authors: A
authors: Flores
authors: Department of Medicine, Division of Hematology-Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida.
authors: Krisztina
authors: K
authors: Kovacs
authors: Department of Medicine, Division of Hematology-Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida.
authors: Jonathan C
authors: JC
authors: Trent
authors: Department of Medicine, Division of Hematology-Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida.
authors: Pasquale
authors: P
authors: Benedetto
authors: Department of Medicine, Division of Hematology-Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida.
authors: Caio
authors: C
authors: Rocha-Lima
authors: Department of Medicine, Division of Hematology-Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida. jmerchan2@med.miami.edu montero2@ccf.org.
authors: Jaime R
authors: JR
authors: Merchan
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood; D004334:Drug Administration Schedule; D034261:Epothilones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000077210:Sunitinib; D050257:Tubulin Modulators / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D034261:Epothilones; D007211:Indoles; D011758:Pyrroles; D050257:Tubulin Modulators; C430592:ixabepilone; D000077210:Sunitinib