Clinical trial NCT00677287: Histocompatibility Leukocyte Antigen (HLA)-A*2402 Restricted Peptide Vaccine Therapy in Patients With Colorectal Cancer
Official title: Phase I/II Study of Multiple-Vaccine Therapy Using Epitope Peptide Restricted to HLA-A*2402 in Combination With Tegafur/Uracil/Folinate in Treating Patients With Refractory Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Colorectal Cancer
Colon Cancer
Rectal Cancer
Keywords: HLA-A*2402
Peptide Vaccine
RNF43
TOMM34
VEGFR1
VEGFR2
Lead sponsor: Tokyo University
Sponsor class: OTHER
Collaborators: name: Human Genome Center, Institute of Medical Science, University of Tokyo
First posted: 2008-05-14
Enrollment: 14
Sex: ALL
Minimum age (years): 20
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety and time to progression of HLA-A\*2402 restricted epitope peptides RNF43, TOMM34, VEGFR1 and VEGFR2 emulsified with Montanide ISA 51 in combination with Tegafur/Uracil/Folinate chemotherapy.

Detailed description: RNF43 and TOMM34 have been identified as cancer specific molecules especially in colorectal cancer using genome-wide expression profile analysis by cDNA microarray technique. VEGF receptor 1 and 2 are essential targets to tumor angiogenesis, and we identified that peptides derived from these receptors significantly induce the effective tumor specific CTL response in vitro and vivo. According to these findings, in this trial, we evaluate the safety, immunological and clinical response of those peptides. Patients will be vaccinated twice a week for 8 weeks. On each vaccination day, RNF43 peptide (1mg), TOMM34 peptide (1mg), VEGFR1 peptide (1mg) and VEGFR2 peptide (1mg) mixed with Montanide ISA 51 will be administered by subcutaneous injection. The patients will also receive oral chemotherapy (Tegafur/Uracil/Folinate) simultaneously. Repeated cycles of the vaccine and the chemotherapy will be administered until patients develop progressive disease or unacceptable toxicity, whichever occurs first. In the phase I study, we evaluate the safety and tolerability of these peptide vaccine. In the following phase II study, we evaluate the immunological and clinical response of this vaccine therapy.

Eligibility criteria: Inclusion Criteria:

* Advanced or recurrent colorectal cancer
* Resistant against chemotherapy including CPT-11, l-OHP、+/- 5-FU +/- bevacizumab or difficult to continue the chemotherapy due to intolerable side effect(s)
* ECOG performance status 0-2
* Life expectancy \> 3 months
* HLA-A\*2402
* Laboratory values as follows

  * 2000/mm3\<WBC\<15000/mm3
  * Platelet count\>100000/mm3
  * Bilirubin \< 3.0mg/dl
  * Asparate transaminase \< 150IU/L
  * Alanine transaminase \< 150IU/L
  * Creatinine \< 3.0mg/dl
* Able to receive oral Tegafur/Uracil/Folinate therapy
* Able and willing to give valid written informed consent

Exclusion Criteria:

* Pregnancy(woman of childbearing potential:Refusal or inability to use effective means of contraception)
* Breastfeeding
* Active or uncontrolled infection
* Unhealed external wound
* Concurrent treatment with steroids or immunosuppressing agent
* Prior chemotherapy,radiation therapy, or immunotherapy within 4 weeks
* Uncontrolled brain and/or intraspinal lesion(s)
* History of allergy to Tegafur, Uracil, and/or Folinate
* Decision of unsuitableness by principal investigator or physician-in-charge

Primary outcomes:
measure: safety(Phase I:toxicities as assessed by NCI CTCAE version3) and efficacy(Phase II:Feasibility as evaluated by RECIST)
timeFrame: 2 months
Secondary outcomes:
measure: To evaluate immunological responses
timeFrame: 2 months
Other outcomes:
Locations:
city: Minato-ku
country: Japan
facility: The Institute of Medical Science, the University of Tokyo
state: Tokyo
Study officials:
affiliation: Head, Department of Surgery
name: Masaru Shinozaki, MD/PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Uchida N, Tsunoda T, Wada S, Furukawa Y, Nakamura Y, Tahara H. Ring finger protein 43 as a new target for cancer immunotherapy. Clin Cancer Res. 2004 Dec 15;10(24):8577-86. doi: 10.1158/1078-0432.CCR-04-0104.
citation: Shimokawa T, Matsushima S, Tsunoda T, Tahara H, Nakamura Y, Furukawa Y. Identification of TOMM34, which shows elevated expression in the majority of human colon cancers, as a novel drug target. Int J Oncol. 2006 Aug;29(2):381-6.
citation: Niethammer AG, Xiang R, Becker JC, Wodrich H, Pertl U, Karsten G, Eliceiri BP, Reisfeld RA. A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nat Med. 2002 Dec;8(12):1369-75. doi: 10.1038/nm1202-794. Epub 2002 Nov 4.
citation: Li Y, Wang MN, Li H, King KD, Bassi R, Sun H, Santiago A, Hooper AT, Bohlen P, Hicklin DJ. Active immunization against the vascular endothelial growth factor receptor flk1 inhibits tumor angiogenesis and metastasis. J Exp Med. 2002 Jun 17;195(12):1575-84. doi: 10.1084/jem.20020072.
citation: 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. doi: 10.1158/1078-0432.CCR-06-0750.
citation: Wada S, Tsunoda T, Baba T, Primus FJ, Kuwano H, Shibuya M, Tahara H. Rationale for antiangiogenic cancer therapy with vaccination using epitope peptides derived from human vascular endothelial growth factor receptor 2. Cancer Res. 2005 Jun 1;65(11):4939-46. doi: 10.1158/0008-5472.CAN-04-3759.