title: A phase I and pharmacokinetic study of afilbercept with FOLFIRI: comparison of Chinese and Caucasian populations.
abstract: Background This study assessed the preliminary safety, pharmacokinetics (PK) and anti-tumor effects of aflibercept in combination with 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) in Chinese patients with previously-treated advanced solid malignancies. Patients and Methods This open-label single-arm Phase I study conducted at two centers in China included adult (≥18 years) patients with metastatic or unresectable solid malignancies who had received ≥1 prior treatment. Patients received aflibercept 4 mg/kg IV on Day 1 followed by FOLFIRI over Days 1 and 2 every 2 weeks, and were assessed for safety, tumor response, PK parameters and immunogenicity. Post-hoc analyses included calculation of progression-free survival (PFS) for patients with colorectal cancer (CRC). Results A total of 20 patients were enrolled. The most common Grade 3/4 adverse events included neutropenia (35%), hypertension (30%), stomatitis (20%) and proteinuria (20%), and no anti-aflibercept antibodies were detected. Six patients achieved a partial response, and in 15 patients with CRC median PFS was 5.95 months (95% CI: 5.29-8.77). Free aflibercept remained in excess of VEGF-bound aflibercept for the majority of the study treatment duration. The mean free aflibercept values for Cmax(64.8 μg/mL) AUC (291 μg.day/mL), CL (0.92 L/day) and Vss(5.9 L) were similar to those measured in Caucasian patients. The addition of aflibercept did not influence the PK of the chemotherapy agents. Conclusion For Chinese patients with pre-treated advanced solid malignancies, 4 mg/kg of aflibercept in combination with FOLFIRI was well-tolerated, demonstrated preliminary anti-tumor activity and had a PK profile consistent with that in Caucasian patients.
authors.affiliation: Affiliated Hospital Cancer Center (307th Hospital of Chinese People's Liberation Army), Academy of Military Medical Sciences, No. 8 East St, Fengtai, Beijing, China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.affiliation: Sanofi R&D China, 2F, No. 108, Jian Guo Lu, Chaoyang District, Beijing, 100022, China.
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Sanofi R&D US, 55 Corporate Dr, Bridgewater, NJ, 08807, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Sun
authors.affiliation: Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Yuexiu, Guangzhou, Guangdong, China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Affiliated Hospital Cancer Center (307th Hospital of Chinese People's Liberation Army), Academy of Military Medical Sciences, No. 8 East St, Fengtai, Beijing, China.
authors.forename: Rongrui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Sanofi R&D France, 3 digue d'Alfortville, 94140, Alfortville, France.
authors.forename: Samira
authors.initials: S
authors.lastname: Ziti-Ljajic
authors.affiliation: Sanofi R&D Asia Pacific, 2F, No. 108, Jian Guo Lu, Chaoyang District, Beijing, 100022, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Shi
authors.affiliation: Sanofi R&D China, 2F, No. 108, Jian Guo Lu, Chaoyang District, Beijing, 100022, China.
authors.forename: Fengying
authors.initials: F
authors.lastname: Xue
authors.affiliation: Sanofi R&D Asia Pacific, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Le Bail
authors.affiliation: Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Yuexiu, Guangzhou, Guangdong, China. xurh@sysucc.org.cn.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Xu
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D044466:Asian People; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D002955:Leucovorin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D011507:Proteinuria / Q000139:chemically induced; D040262:Receptors, Vascular Endothelial Growth Factor / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D013280:Stomatitis / Q000139:chemically induced; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D044465:White People
chemical_list: D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: Aflibercept; Chinese patients; Pharmacokinetics; Phase I study; Safety; Solid tumors