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A Phase I/II Study of Active Immunotherapy With CEA(6D)VRP Vaccine(AVX701)in Patients With Advanced or Metastatic Malignancies Expressing CEA or Stage III Colon Cancer

Phase 1/Phase 2
18 Years
Not Enrolling
Colorectal Cancer, Breast Cancer, Lung Cancer, Pancreatic Cancer, Colon Cancer

Thank you

Trial Information

A Phase I/II Study of Active Immunotherapy With CEA(6D)VRP Vaccine(AVX701)in Patients With Advanced or Metastatic Malignancies Expressing CEA or Stage III Colon Cancer

CEA represents an attractive target antigen for immunotherapy since it is over expressed in
nearly all colorectal cancers and pancreatic cancers, and is also expressed by some lung and
breast cancers, and uncommon tumors such as medullary thyroid cancer, but is not expressed
in other cells of the body except for low-level expression in gastrointestinal epithelium
[1]. That CEA is a potential target for T cell mediated immune responses in humans is
demonstrated by the observation that CEA contains epitopes that may be recognized in an MHC
restricted fashion by T cells [2-11]. Specifically, there is support for the existence of
human cytolytic T cells (CTLs) that recognize CEA epitopes that bind to MHC molecules HLA-
A2, A3, and A24. For the most part, these T cells have been generated by in vitro cultures
using antigen-presenting cells pulsed with the epitope of interest to stimulate peripheral
blood mononuclear cells. In addition, T cell lines have been generated after stimulation
with CEA latex beads, CEA protein-pulsed plastic adherent peripheral blood mononuclear
cells, or DCs sensitized with CEA RNA. T cells have also been generated from patients
immunized with a vaccinia vector encoding CEA immunogen (discussed below). Using
high-performance liquid chromatography mass-spectrometry-based approaches, HLA A2-presented
peptides from CEA have been identified in primary gastrointestinal tumors [12]. Of the HLA
A2 restricted epitopes of CEA, CAP-1, a nine amino acid sequence, has been shown to
stimulate CTLs from cancer patients immunized with vaccinia-CEA. Cap-1(6D) is a peptide
analog of CAP-1. Its sequence includes a heteroclitic (nonanchor position) mutation,
resulting in an amino acid change from Asn to Asp, to enhance recognition by the T-cell
receptor without any change in binding to HLA A2. Compared with the non mutated CAP-1
epitope, Cap-1(6D) has been shown to enhance the sensitization of CTLs by 100 to 1,000 times
[3, 5, 13]. CTL lines could be elicited from peripheral blood mononuclear cells of healthy
volunteers by in vitro sensitization to the Cap-1(6D) peptide but not to the CAP-1 peptide.
These cell lines can lyse human tumor cells expressing endogenous CEA.

Inclusion Criteria:

Cohorts 1-4 only:

- Histologically confirmed diagnosis of metastatic malignancy due to a tumor expressing

- The tumor must express CEA as defined by immunohistochemical staining, CEA blood
level, or a tumor known to be universally CEA positive.

- Must have received treatment with standard therapy having a possible overall survival
benefit or refused such therapy.

- Must have received and progressed through at least one line of palliative
chemotherapy for colorectal, breast, lung, or pancreatic cancer. For other
malignancies, if a first line therapy with survival or palliative benefit exists, it
should have been administered and there should have been progressive disease.

Cohort 5 Only:

- Histologically confirmed colon cancer (rectal cancer excluded). Since colon cancer
is nearly universally CEA positive, CEA staining is not required.

- Documented stage III colon cancer with no evidence of disease.

- One to six months following standard post-operative adjuvant treatment, which should
have consisted of 5-fluorouracil and folinic acid or capecitabine with or without
oxaliplatin for 4-6 months)

All Cohorts:

- Karnofsky performance status ≥ 70%.

- Estimated life expectancy > 6 months and not expected to require further systemic
chemotherapy for at least 3 months.

- Age ≥ 18 years.

- Adequate hematologic function (WBC ≥ 3000/microliter, hemoglobin ≥ 9 g/dL, and
platelets ≥ 100,000/microliter).

- Adequate renal and hepatic function, (serum creatinine < 1.5 mg/dL, bilirubin ≤ 1.5
mg/dL, and ALT and AST ≤ 2.5 x upper limit of normal).

- Patients who have received CEA-targeted immunotherapy, if treatment was discontinued
at least 3 months before enrollment.

- Patients who are taking medications that do not have a known history of
immunosuppression are eligible for this trial.

- Ability to understand and provide signed informed consent.

- Ability to return to Duke University Medical Center for adequate follow-up, as
required by protocol.

Exclusion Criteria:

- Concurrent cytotoxic chemotherapy or radiation therapy (must be at least 3 months
between any prior CEA-targeted immunotherapy and study treatment and at least 4 weeks
between any other prior therapy and study treatment).

- Patients with previously resected brain metastases will be permitted if a CT or MRI
scan shows no metastasis within 1 month before enrollment.

- History of autoimmune disease.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

determine the safety of immunization with CEA(6D) VRP

Outcome Time Frame:

2.5 years

Safety Issue:


Principal Investigator

Michael Morse, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University


United States: Institutional Review Board

Study ID:




Start Date:

September 2007

Completion Date:

May 2010

Related Keywords:

  • Colorectal Cancer
  • Breast Cancer
  • Lung Cancer
  • Pancreatic Cancer
  • Colon Cancer
  • CEA
  • CEA-expressing malignancies
  • Metastatic malignancies
  • VRP Vaccine
  • Alphavirus replicons
  • Molecular therapeutics
  • Stage III colon cancer
  • Breast Neoplasms
  • Neoplasms
  • Colonic Neoplasms
  • Colorectal Neoplasms
  • Lung Neoplasms
  • Pancreatic Neoplasms



Duke University Medical CenterDurham, North Carolina  27710