title: A phase I study of intravenous aflibercept with FOLFIRI in Japanese patients with previously treated metastatic colorectal cancer.
abstract: Aflibercept, a recombinant fusion protein, is a potent inhibitor of vascular endothelial growth factor (VEGF)-A, VEGF-B, and the placental growth factor (PlGF). The present study was an open-label, sequential-cohort, dose-escalation trial of intravenous aflibercept administered every 2 weeks in combination with 5-fluorouracil, levofolinate, and irinotecan (FOLFIRI) in patients with previously treated metastatic colorectal cancer (mCRC). We aimed to assess the safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary efficacy of the combination therapy to determine the recommended phase II dose (RPTD) for Japanese patients. Two doses of aflibercept (2.0 and 4.0 mg/kg) were set, and DLTs were evaluated in the first 2 cycles. The subjects comprised 16 patients (n = 3 and 13 for 2.0 and 4.0 mg/kg aflibercept, respectively) who received a total of 149 cycles of aflibercept with FOLFIRI. No DLTs were observed at both doses. The frequent adverse events encountered were leukopenia, neutropenia, anemia, diarrhea, fatigue, decreased appetite, stomatitis, dysphonia, nausea, and epistaxis. The most common grade 3/4 adverse events were neutropenia for both doses and hypertension for the 4.0 mg/kg dose. Free aflibercept exposure increased with the dose, whereas exposure to VEGF-bound aflibercept remained similar at both doses. The response rate and progression-free survival at 4.0 mg/kg was 8.3 % and 7.59 months, respectively. In conclusion, the combination of aflibercept and FOLFIRI was well tolerated at both doses. The RPTD of aflibercept in combination with FOLFIRI for Japanese patients with mCRC was determined to be 4.0 mg/kg every 2 weeks. ClinicalTrials.gov identifier: NCT00921661.
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwashi, Chiba 277-8577, Japan. tyoshino@east.ncc.go.jp
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshino
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Kensei
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.forename: Narikazu
authors.initials: N
authors.lastname: Boku
authors.forename: Nozomu
authors.initials: N
authors.lastname: Machida
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Onozawa
authors.forename: Masako
authors.initials: M
authors.lastname: Asayama
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Fujino
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
mesh_terms: D061605:Administration, Intravenous; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044466:Asian People; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin