Phase I study of aflibercept in combination with docetaxel in Japanese patients with advanced solid malignancies.

Angiogenesis is a hallmark of cancer development. This study sought to determine the recommended dose of aflibercept, a recombinant fusion protein targeting VEGF-A, VEGF-B and placental growth factor (PlGF), combined with docetaxel in Japanese patients with advanced solid malignancies. This phase I study was planned to include 12 patients following a 3 + 3 algorithm to determine the maximum tolerated dose of aflibercept combined with docetaxel in patients with metastatic or unresectable solid tumors (trial registration: NCT00545246). Docetaxel (75 mg/m2 every 3 weeks or 60 mg/m2 after protocol amendment) was combined with escalating doses of aflibercept (2, 4 and 6 mg/kg every 4 weeks). Free and VEGF-bound aflibercept were measured to assess free aflibercept in excess of the VEGF-bound form. At the starting dose of the combination, 3 of 6 patients treated experienced febrile neutropenia. After reducing the docetaxel dose to 60 mg/m2 in step 2 and permitting therapeutic granulocyte colony-stimulating factor (G-CSF) use, 2 of 3 patients in both cohorts experienced febrile neutropenia. Five patients (42%) had a partial response and 4 patients had stable disease (33%). Free aflibercept in excess of the VEGF-bound form was not maintained at this dose level. The dose limiting toxicity (DLT) of aflibercept combined with docetaxel was febrile neutropenia, which occurred in 2 of 3 Japanese patients at the lowest aflibercept dose level (2 mg/kg) combined with docetaxel (60 mg/m2) and therapeutic G-CSF use. A recommended dose for further studies was not determined because of the DLT at the starting dose.

Isatuximab monotherapy in relapsed/refractory multiple myeloma: A Japanese, multicenter, phase 1/2, safety and efficacy study.

Isatuximab, an anti-CD38 monoclonal antibody, targets cells that strongly express CD38 including malignant plasma cells. This open-label, single-arm, multicenter, phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). In Phase 1, patients were sequentially assigned to receive isatuximab once weekly (QW) in cycle 1 (4 weeks) and every 2 weeks (Q2W) in subsequent cycles. Cohort 1 (n = 3) received 10 mg/kg QW/Q2W; cohort 2 (n = 5) received 20 mg/kg QW/Q2W. No dose-limiting toxicities occurred; the recommended dose for the single-arm phase 2 study (n = 28) was 20 mg/kg QW/Q2W. The overall safety profile was consistent with the current knowledge of isatuximab. The most common adverse events were infusion reactions (42.9%; 12/28); all were grade 1/2 and generally occurred during the first infusion. The overall response rate with 20 mg/kg QW/Q2W isatuximab was 36.4% (12/33); patients with high-risk cytogenetic abnormalities had comparable results. In phase 2, the median progression-free survival was 4.7 (95% confidence interval, 3.75 to not reached) months. Median overall survival was not reached. Isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM including high-risk cytogenetic patients. This trial is registered at ClinicalTrials.gov as NCT02812706.

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.

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.