Preclinical pharmacokinetics, interspecies scaling, and pharmacokinetics of a Phase I clinical trial of TTAC-0001, a fully human monoclonal antibody against vascular endothelial growth factor 2

PURPOSE: We investigated the safety and pharmacokinetics of a recombinant human monoclonal antibody to vascular endothelial growth factor (rhuMAb VEGF) in patients with cancer. PATIENTS AND METHODS: Cohorts of patients with metastatic cancer having failed prior therapy entered a phase I trial of rhuMAb VEGF administered by a 90-minute intravenous infusion at doses from 0.1 to 10.0 mg/kg on days 0, 28, 35, and 42. Patients underwent pharmacokinetic sampling on day 0 and had serum samples obtained during the subsequent 28 days. Response assessment was carried out on days 49 and 72. RESULTS: Twenty-five patients with a median Eastern Cooperative Oncology Group performance status of 0 were accrued. There were no grade III or IV adverse events definitely related to the antibody. There were three episodes of tumor-related bleeding. Infusions of rhuMAb VEGF were well tolerated without significant toxicity. Grades I and II adverse events possibly or probably related to study drug included asthenia, headache, and nausea. Pharmacokinetics revealed a linear profile with a half-life of 21 days. There were no objective responses, though 12 patients experienced stable disease over the duration of the study. CONCLUSION: rhuMAb VEGF was safely administered without dose-limiting toxicity at doses ranging up to 10 mg/kg. Multiple doses of rhuMAb VEGF were well tolerated, and pharmacokinetic studies indicate that doses of ≥ 0.3 mg/kg have a half-life similar to that of other humanized antibodies. Subsequent trials will explore rhuMAb VEGF alone and in combination chemotherapy.

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Phase I clinical trial with VEGFR2-epitope peptide and gemcitabine for patients with advanced pancreatic cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.2567 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 2567-2567

Author(s):

H. Yamaue ◽

M. Miyazawa ◽

R. Ohsawa ◽

M. Tani ◽

M. Kawai ◽

...

Keyword(s):

Pancreatic Cancer ◽

Clinical Trial ◽

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Phase I ◽

Dose Escalation ◽

Phase I Clinical Trial ◽

Delayed Type Hypersensitivity ◽

Vascular Endothelial ◽

Endothelial Growth Factor

2567 Background: The prognosis of pancreatic cancer patients is one of the most dismal of all cancers. Gemcitabine is a potent anticancer drug for pancreatic cancer, however, one should consider that the clinical benefit of anticancer drugs is limited and other potent therapeutic tool is eagerly awaited. Vascular endothelial growth factor (VEGF) is a glycoprotein which is predominantly related to the neoplastic angiogenesis. VEGF-receptor 2 (VEGFR2; Flk-1 and KDR) is an essential target for tumor angiogenesis. We first identify the epitope peptides of vascular endothelial growth factor receptor 2 (VEGFR2) and confirmed that stimulation using these peptides induces CTLs with potent cytotoxicity in HLA class I-restricted fashion. Methods: We proceeded to Phase I clinical trial using gemcitabine and one of these peptides. Patients were sequentially allocated to cohorts of 6 patients per group receiving 0.5, 1.0, 2.0mg of peptides/body. No intra-patient dose escalation was permitted. The eligibility criteria are: being aged between 20- and 80- year old, expecting the survival more than 3 months after the initiation of this treatment, adequate organ function including bone marrow function, and having HLA-A*2402 (A24) genotype. The enrolled patients received 4 cycles of VEGFR2 peptide sc. and 3 cycles of 1,000 mg/m2 gemcitabine weekly. Results: No patients had grade 3 and 4 toxicity, and dose escalation was succeeded without any DLT. CTL response was observed in 50%, 67%, and 67% of 0.5mg, 1.0mg, and 2.0mg cohort, respectively. The delayed type hypersensitivity of the peptide-injection site was recognized in 83%, 67%, and 100% of 0.5mg, 1.0mg, and 2.0mg cohort, respectively. Therefore, we concluded that MTD should be 2.0mg of peptide. Disease control rate (>SD) was 67% (12/18 patients), and one patient had PR. The median survival time was 8.72 months. Conclusions: These results are promising to proceed the pivotal clinical trial, and the randomized phase II/III trial will start in 2009. No significant financial relationships to disclose.

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