Phase I dose-escalation study of the safety, tolerability, and pharmacokinetics of aflibercept in combination with S-1 i

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PHASE I STUDIES

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 Toshihiko Doi 1

&

Narikazu Boku 2 & Yusuke Onozawa 3 & Keishiro Takahashi 4 & Osamu Kawaguchi 5 & Atsushi Ohtsu 1

Received: 28 August 2019 / Accepted: 13 December 2019 # The Author(s) 2020

Summary 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 doselimiting 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. Keywords Aflibercept . S-1 . Phase I trial . Japanese . VEGF trap

Introduction 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. Although the

* Toshihiko Doi [email protected] 1

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan

2

Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan

3

Division of Clinical Oncology Shizuoka Cancer Center, Shizuoka, Japan

4

Research & Development, Sanofi K.K., Tokyo, Japan

5

Biostatistics & Programming, Sanofi K.K., Tokyo, Japan

mechanism of angiogenesis is complex, involving multiple signaling pathways, the proangiogenic cytokine, vascular endothelial growth factor A (VEGF-A), is of key importance [2]. VEGF-A is a homodimeric protein which binds to and activates two high-affinity receptors, VEGFR-1 (also known as FLT-

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