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

Investigational New Drugs - Tập 38 Số 5 - Trang 1390-1399 - 2020
Toshihiko Doi1, Narikazu Boku2, Yusuke Onozawa3, Keishiro Takahashi4, Osamu Kawaguchi5, Atsushi Ohtsu1
1Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
2Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
3Division of Clinical Oncology, Shizuoka Cancer Center, Shizuoka, Japan
4Research & Development, Sanofi K.K., Tokyo, Japan
5Biostatistics & Programming, Sanofi K.K., Tokyo, Japan

Tóm tắt

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 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.

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Investigational New Drugs

Tập 38 Số 5

1390-1399

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