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.

Abstract

Background 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.

• Authors: Toshihiko Doi, Narikazu Boku, Yusuke Onozawa, Keishiro Takahashi, Osamu Kawaguchi, Atsushi Ohtsu
• Journal: Investigational new drugs (Invest New Drugs) Vol. 38 Issue 5 Pg. 1390-1399 (10 2020) ISSN: 1573-0646 [Electronic] United States
• PMID: 31907738 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antibodies
• Antimetabolites, Antineoplastic
• Drug Combinations
• Recombinant Fusion Proteins
• S 1 (combination)
• Tegafur
• aflibercept
• Oxonic Acid
• Receptors, Vascular Endothelial Growth Factor

Topics

• Adult
• Aged
• Angiogenesis Inhibitors (administration & dosage, adverse effects, blood, pharmacokinetics)
• Antibodies (blood)
• Antimetabolites, Antineoplastic (administration & dosage, adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacokinetics)
• Asian People
• Drug Combinations
• Female
• Humans
• Infusions, Intravenous
• Male
• Middle Aged
• Neoplasms (blood, drug therapy, metabolism)
• Oxonic Acid (administration & dosage, adverse effects)
• Receptors, Vascular Endothelial Growth Factor (administration & dosage, blood)
• Recombinant Fusion Proteins (administration & dosage, adverse effects, blood, pharmacokinetics)
• Tegafur (administration & dosage, adverse effects)
• Treatment Outcome