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

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.