Abstract
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.
Highlights
The process of angiogenesis plays a crucial role in tumor growth and metastasis [1]
An anti-vascular endothelial growth factor A (VEGF-A) antibody, have shown that targeting this growth factor is effective for the clinical management of metastatic colorectal cancer [6, 7], Invest New Drugs (2020) 38:1390–1399 advanced non-small cell lung cancer [8], metastatic renal cancer [9, 10], and glioblastoma multiforme [11]
Aflibercept is a soluble, decoy receptor construct which incorporates the second immunoglobulin (Ig)-like domain of VEGFR-1 joined to the third Ig-like domain of VEGFR-2, which are fused to the Fc portion of human IgG1 [12, 13]
Summary
The process of angiogenesis plays a crucial role in tumor growth and metastasis [1]. New blood vessels from existing vasculature maintain a source of nutrition and oxygen for the tumor from the host. An anti-VEGF-A antibody, have shown that targeting this growth factor is effective for the clinical management of metastatic colorectal cancer (mCRC) [6, 7], Invest New Drugs (2020) 38:1390–1399 advanced non-small cell lung cancer [8], metastatic renal cancer [9, 10], and glioblastoma multiforme [11]. Aflibercept ( known as ziv-aflibercept in the United States; aflibercept beta in Japan) is a soluble, decoy receptor construct which incorporates the second immunoglobulin (Ig)-like domain of VEGFR-1 joined to the third Ig-like domain of VEGFR-2, which are fused to the Fc portion of human IgG1 [12, 13] This construction allows aflibercept to bind all isoforms of VEGF-A at subpicomolar affinity levels [14]. A phase I study has demonstrated that FOLFIRI plus aflibercept at a dose level of 4 mg/kg every 2 weeks has a manageable toxicity profile, pharmacokinetic (PK) parameters consistent with findings in Caucasian patients, and promising efficacy in Japanese patients with mCRC previously treated with at least one chemotherapy regimen [18]
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