Human Leukocyte Antigen-A*02:01-restricted Tumor Vessel Specific Peptide Vaccination for Advanced Pancreatic Cancer

Study Overview
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Brief Summary
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Pancreatic cancer is the fourth leading cause of cancer death in the United States, and no combination therapy is far superior to gemcitabine alone. Vascular endothelial growth factor receptor type 1 (VEGFR1) is expressed on the tumor vessels and a candidate of tumor vessel-specific peptide vaccination strategy to induce T cell immune response. We conducted the study to confirm the safety and efficacy of combined modality intervention using conventional dose of gemcitabine with peptide vaccination targeting tumor-vessel specific VEGFR1 in case of advanced/inoperable or therapy-resistant pancreatic cancer patients. Gemcitabine 1,000 mg/m^2 (body surface area) will be administered on day 1, day 8, day 15, day 29, day 36, and day 43, respectively. VEGFR1-derived HLA-A*02:01-restricted peptide (VEGFR1-A02-770; TLFWLLLTL) emulsified with Montanide ISA51 will be subcutaneously injected twice weekly for 8 weeks (total 16 doses).

Detailed Description
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HLA-A*02:01-restricted VEGFR1-specific cytotoxic T lymphocyte (CTL) responses were obtained from HLA-A2/Kd transgenic murine model. HLA-A*02:01-restricted VEGFR1-specific CTL clones were also obtained from peripheral blood mononuclear cells of healthy volunteer donors. These CTL clones showed potent anti-tumor CTL responses in HLA class Ⅰ-restricted manner in vitro. Vaccination of HLA-A*02:01-restricted VEGFR1-specific peptide to A2/Kd transgenic mice markedly suppress the tumor-induced angiogenesis and tumor growth in vivo.

Official Title
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Phase I/II Trial of Human Leukocyte Antigen (HLA)-A*02:01-restricted Vascular Endothelial Growth Factor Receptor 1 (VEGFR1)-Derived Peptide Vaccination Combined With Conventional Dose of Gemcitabine for Advanced Pancreatic Cancer

Conditions
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Pancreatic Cancer, Pancreas Neoplasms

Intervention / Treatment
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* Biological: HLA-A*02:01-restricted VEGFR1-derived peptide vaccination


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Heterozygote or homozygote of HLA-A*02:01 allele Inoperable or recurrent pancreatic cancer with or without any prior therapy Difficult to continue the prior therapy due to treatment-related toxicities ECOG performance status 0-2 Evaluable primary or metastatic lesion with RECIST v.1.0 criteria Clearance period from prior therapy more than 4 weeks Life expectancy more than 3 months Laboratory values as follows 2,000/μL< WBC <15,000/μL Platelet count >100,000/μL AST <150 IU/L ALT <150 IU/L Total bilirubin <3.0 mg/dl Serum creatinine <3.0 mg/dl Exclusion Criteria: Pregnancy (refusal or inability to use effective contraceptives) Breastfeeding Active or uncontrolled infection Systemic use of corticosteroids or immunosuppressants Uncontrollable brain metastasis and/or meningeal infiltration Unhealed external wound Possibilities of complicated paralytic ileus or interstitial pneumonitis Decision of not eligible determined by principal investigator or attending doctor

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Peptide vaccination<br>VEGFR1-derived HLA-A*02:01-restricted peptide (VEGFR1-A2-770; TLFWLLLTL)was vaccinated twice weekly for 8 weeks (total 16 doses) combined with conventional dose (1,000 mg/m^2 body surface area) of gemcitabine 6 doses for advanced stage pancreatic cancer to confirm the safety and efficacy of this type of peptide. | Biological: HLA-A*02:01-restricted VEGFR1-derived peptide vaccination<br>* VEGFR1-derived HLA-A*02:01-restricted peptide (VEGFR1-A2-770; TLFWLLLTL)was vaccinated twice weekly for 8 weeks (total 16 doses) combined with conventional dose (1,000 mg/m^2 body surface area) of gemcitabine 6 doses for advanced stage pancreatic cancer to confirm the feasibility and efficacy of this type of peptide.<br>* Other names: VEGFR1-A2-770; TLFWLLLTL;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Without Grade 4 Hematological or Grade 3 to 4 Non-hematological Adverse Events | Number of participants without grade 4 hematological or grade 3 other adverse events were caslculated based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v.3) | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Tumor Regression | Sum of diameters of primary pancreatic tumor or metastatic tumors (target lesions) before and after vaccination were measured by computed tomography. Sum of tumors' size diameters decrease more than 30% after vaccination was diagnosed as response according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 guidelines. | 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HLA, cancer, pancreas, advanced, peptide, vaccination, VEGFR1, gemcitabine, IFA, Cancer of Pancreas, Neoplasms, Pancreas, Pancreas Cancer