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

• Sponsor: Tokyo University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00683085
• Collaborator: Human Genome Center, Institute of Medical Science, University of Tokyo (Other)
• Enrollment: 2
• Location: 1
• Arm: 1
• Duration (Months): 12
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Cancer; Pancreas Neoplasms	Biological: HLA-A*02:01-restricted VEGFR1-derived peptide vaccination	Phase 1/Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: May 1, 2008
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: May 1, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Peptide vaccination 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; 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.; Other Names: VEGFR1-A2-770; TLFWLLLTL

Outcome Measures

Primary Outcome Measures

1. Number of Participants Without Grade 4 Hematological or Grade 3 to 4 Non-hematological Adverse Events [2 months]

   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)

Secondary Outcome Measures

1. Number of Participants With Tumor Regression [2 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Hospital, The Institute of Medical Science, The University of Tokyo	Minato-ku	Tokyo	Japan	108-8639

Sponsors and Collaborators

• Tokyo University
• Human Genome Center, Institute of Medical Science, University of Tokyo

Investigators

• Study Director: Naohide Yamashita, MD, PhD, Director, Research Hospital, Institute of Medical Science, Tokyo University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Ishizaki H, Tsunoda T, Wada S, Yamauchi M, Shibuya M, Tahara H. Inhibition of tumor growth with antiangiogenic cancer vaccine using epitope peptides derived from human vascular endothelial growth factor receptor 1. Clin Cancer Res. 2006 Oct 1;12(19):5841-9.
• Nagayama H, Sato K, Morishita M, Uchimaru K, Oyaizu N, Inazawa T, Yamasaki T, Enomoto M, Nakaoka T, Nakamura T, Maekawa T, Yamamoto A, Shimada S, Saida T, Kawakami Y, Asano S, Tani K, Takahashi TA, Yamashita N. Results of a phase I clinical study using autologous tumour lysate-pulsed monocyte-derived mature dendritic cell vaccinations for stage IV malignant melanoma patients combined with low dose interleukin-2. Melanoma Res. 2003 Oct;13(5):521-30.

• ClinicalTrials.gov Identifier: NCT00683085
• Other Study ID Numbers: IMSUT-PPKVEGFR10201
• First Posted: May 23, 2008
• Last Update Posted: Jul 22, 2011
• Last Verified: Jul 1, 2011

• Keywords provided by , ,: cancer; pancreas; advanced; peptide; vaccination; VEGFR1; HLA; gemcitabine; IFA; Cancer of Pancreas; Neoplasms, Pancreas; Pancreas Cancer
• Additional relevant MeSH terms: Pancreatic Neoplasms

Study Results

Participant Flow

Recruitment Details	Neighboring research hospitals around Tokyo, Japan sent three candidates to our hospital during May, 2008 to March, 2009.
Pre-assignment Detail	Wash out time was four weeks from preceding therapy, and three candidates were evaluated for eligibility. Two cases were compatible to our eligibility, but another candidate was excluded from this study entry because he was not expected to survive more than three months.

Arm/Group Title	Peptide 1 mg Twice Weekly for 8 Weeks With Gemcitabine
Arm/Group Description	HLA-A*0201-restricted VEGFR1-specific peptide, VEGFR1-A02-770(TLFWLLLTL) 1 mg, subcutaneous injection, twice every weeks for eight weeks (total 16 doses) combined with incomplete Freund adjuvant (IFA) and gemcitabine 1,000 mg/m^2 of body surface area
Period Title: Overall Study
STARTED	2
COMPLETED	2
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Peptide 1 mg Twice Weekly for 8 Weeks With Gemcitabine
Arm/Group Description	HLA-A*0201-restricted VEGFR1-specific peptide, VEGFR1-A02-770(TLFWLLLTL) 1 mg, subcutaneous injection, twice every weeks for eight weeks (total 16 doses) combined with incomplete Freund adjuvant (IFA) and gemcitabine 1,000 mg/m^2 of body surface area
Overall Participants	2
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	2 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55 (7.07)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	2 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Without Grade 4 Hematological or Grade 3 to 4 Non-hematological Adverse Events
Description	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)
Time Frame	2 months

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT)

Arm/Group Title	Peptide 1 mg Twice Weekly for 8 Weeks With Gemcitabine
Arm/Group Description	HLA-A*0201-restricted VEGFR1-specific peptide, VEGFR1-A02-770(TLFWLLLTL) 1 mg, subcutaneous injection, twice every weeks for eight weeks (total 16 doses) combined with incomplete Freund adjuvant (IFA) and gemcitabine 1,000 mg/m^2 of body surface area
Measure Participants	2
Number [participants]	1 50%

2. Secondary Outcome

Title	Number of Participants With Tumor Regression
Description	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.
Time Frame	2 months

Outcome Measure Data

Analysis Population Description

intension to treat (ITT)

Arm/Group Title	Peptide 1 mg Twice Weekly for 8 Weeks With Gemcitabine
Arm/Group Description	HLA-A*0201-restricted VEGFR1-specific peptide, VEGFR1-A02-770(TLFWLLLTL) 1 mg, subcutaneous injection, twice every weeks for eight weeks (total 16 doses) combined with incomplete Freund adjuvant (IFA) and gemcitabine 1,000 mg/m^2 of body surface area
Measure Participants	2
Number [participants]	0 0%

Adverse Events

Time Frame	During 2 months after initiation of vaccination
Adverse Event Reporting Description	Serious adverse events include grade 4 hematological or grade 3 to 4 non-hematological adverse events
Arm/Group Title	Peptide 1 mg Twice Weekly for 8 Weeks With Gemcitabine
Arm/Group Description	HLA-A*0201-restricted VEGFR1-specific peptide, VEGFR1-A02-770(TLFWLLLTL) 1 mg, subcutaneous injection, twice every weeks for eight weeks (total 16 doses) combined with incomplete Freund adjuvant (IFA) and gemcitabine 1,000 mg/m^2 of body surface area
All Cause Mortality
	Peptide 1 mg Twice Weekly for 8 Weeks With Gemcitabine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Peptide 1 mg Twice Weekly for 8 Weeks With Gemcitabine
	Affected / at Risk (%)	# Events
Total	1/2 (50%)
Gastrointestinal disorders
Blood in stool	1/2 (50%)	2
Other (Not Including Serious) Adverse Events
	Peptide 1 mg Twice Weekly for 8 Weeks With Gemcitabine
	Affected / at Risk (%)	# Events
Total	2/2 (100%)
Blood and lymphatic system disorders
Hemoglobin	1/2 (50%)	1
Leukocytes	2/2 (100%)	2
Lymphopenia	1/2 (50%)	1
Neutrophils	2/2 (100%)	2
Platelets	1/2 (50%)	1
Skin and subcutaneous tissue disorders
Injection site reaction	2/2 (100%)	2

Limitations/Caveats

Early termination leading to small numbers of subjects analyzed

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.