Phase I dose-escalation study of the safety, tolerability, and pharmacokinetics of aflibercept in combination with S-1 in Japanese patients with advanced solid malignancies

Autor: Yusuke Onozawa, Narikazu Boku, Toshihiko Doi, Atsushi Ohtsu, Keishiro Takahashi, Osamu Kawaguchi
Rok vydání: 2020
Předmět:
Adult
Male
0301 basic medicine
Antimetabolites
Antineoplastic
medicine.medical_specialty
Pleural effusion
Recombinant Fusion Proteins
Urology
Angiogenesis Inhibitors
Antibodies
Phase I trial
03 medical and health sciences
0302 clinical medicine
Asian People
Pharmacokinetics
Phase I Studies
Neoplasms
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
Pharmacology (medical)
Infusions
Intravenous
Aged
Tegafur
Aflibercept
Pharmacology
Proteinuria
business.industry
Standard treatment
Incidence (epidemiology)
S-1
Middle Aged
medicine.disease
Drug Combinations
Oxonic Acid
Receptors
Vascular Endothelial Growth Factor
Treatment Outcome
030104 developmental biology
Oncology
Tolerability
030220 oncology & carcinogenesis
Toxicity
Japanese
Female
medicine.symptom
business
VEGF trap
medicine.drug
Zdroj: Investigational New Drugs
ISSN: 1573-0646
0167-6997
Popis: SummaryBackground Aflibercept, a recombinant fusion protein binding VEGF-A, VEGF-B and placental growth factor, inhibits tumor growth by blocking angiogenesis. The aim of this phase I dose-escalation study was to determine the recommended phase II dose (RP2D) of aflibercept in combination with S-1 in Japanese patients with solid tumors. Patients and methods Sequential cohorts of 3–6 patients with metastatic or unresectable solid tumors, who had failed at least one prior line of standard treatment or who were not suitable for such treatment, were to receive escalating doses of aflibercept every 2 weeks, starting at 2 mg/kg, combined with S-1 at 40 mg/m2 twice daily (80 mg/m2/day; 4 weeks on/2 weeks off). Dose-escalation was to be based on the incidence of dose-limiting toxicity (DLT). Blood samples were collected for pharmacokinetic analysis. Results At the first dose level (aflibercept 2 mg/kg plus S-1) 1 of 6 patients experienced a DLT (grade 4 proteinuria). The aflibercept dose was consequently escalated to 4 mg/kg; 1 of 3 patients treated at this dose level had a DLT (grade 2 pleural effusion), and another patient experienced grade 3 reversible posterior leukoencephalopathy syndrome after the DLT assessment period. Additional patients were therefore enrolled into the first dose level to explore safety and tolerability. The study was subsequently terminated prematurely. The maximum tolerated dose was not reached and the RP2D was not determined in Japanese patients. Conclusions The tolerability and safety of aflibercept 2 mg/kg in combination with S-1 was confirmed in Japanese patients with advanced solid tumors.
Databáze: OpenAIRE
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