Protocol Number: 99-C-0023

Title:

A Phase I/II Trial of Vaccination with Mutant Ras Peptide-Pulsed Dendritic Cells in the Treatment of HLA A2.1 Positive Patients with Colorectal Cancer

Number:

99-C-0023

Summary:

Ras mutations provide a unique opportunity to study the role of immune manipulation in cancer treatment. Ras mutations are present in 15% of cancers and unlike p53, a limited number of specific DNA base substitutions have been described. Further, since ras mutations are essential for the malignant phenotype, they cannot, theoretically, be down regulated by the tumor to prevent immune detection. We have found that several peptides derived from the mutations commonly found in the ras gene are able to bind to the class I molecule, HLA A2.1. Since at least 40% of colon cancers harbor a ras mutation, we will conduct this trial in patients expressing HLA 2.1 and who have developed colorectal cancers bearing the specific ras mutations which correspond to these peptides. We plan to mature the patient's own cells into dendritic cells which will then serve as an extremely potent delivery system for these peptides. Two groups of patients will be treated, those with metastatic disease and those treated in the adjuvant/locally advanced setting. Patients with measurable metastatic disease will be vaccinated with dendritic cells pulsed with a specific mutant ras peptide followed by interleukin 2. This will allow us to determine the response both of the patient's immune system and of their tumor to vaccination. Patients treated in the adjuvant/locally advanced group will receive peptide pulsed dendritic cells alone. Immunization in the adjuvant/locally advanced setting will allow the patient's immune system to respond optimally to vaccination. We will also examine these patients for an improvement in time to progression. We then plan to use the data we have obtained in the adjuvant/locally advanced setting as pilot data to begin a larger trial.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

ARM I -Adjuvant/Locally Advanced Therapy:

The patient must have had a histologic diagnosis of resected or incompletely resected colorectal cancer with a high risk of recurrence. This may include, but is not limited to: (1) colon cancer-patients with T4 or with any TN2 or N3M0 disease, (2) rectal cancer-patients with T4 or with T3N1, N2, or N3 lesions. Patients with both resectable or unresectable T4 disease following radiation, chemotherapy, and/or surgery will be included in the adjuvant/locally advanced arm.

Patients with completely resected or locally advanced colorectal cancer will be eligible for this study between one and 12 months after completion of conventional therapy. This may include surgery alone (at the patient's request) or adjuvant chemotherapy and/or radiation therapy.

An adequate tumor sample for laboratory analysis for the presence of ras mutations must be available. Patients will only be eligible for this study if the following ras mutations are present: position 12; gly to val, gly to asp, gly to ala, gly to cys, position 13; gly to asp.

HLA A2.1 positivity by serology.

Eastern Cooperative Oncology Group PS 0-1.

Patients with a prior history of non-melanoma skin lesions or cervical carcinoma in situ will be eligible for this study. Patients with a prior history of malignancy, other than the cancer for which they are enrolled in this study, and less than a 50% chance of recurrence within five years are also eligible.

ARM II -Mestastic Disease:

The patient must have a histologic diagnosis of colorectal cancer and radiologic evidence of measurable metastatic disease. Measurable disease will be defined as: Malignant disease measurable in two dimensions by X-ray or physical examination. This may include bone lesions with well demarcated borders. Lesions seen only on bone scan will be considered evaluable rather than measurable disease. Pleural effusions and ascites are not considered measurable disease, but are considered evaluable disease. Changes in the CEA are considered evaluable, but not measurable disease.

An adequate tumor sample for laboratory analysis for the presence of ras mutations must be available. Patients will only be eligible for this study if the following ras mutations are present: position 12; gly to val, gly to asp, gly to ala, gly to cys, position 13; gly to asp.

HLA A2.1 positivity by serology.

Eastern Cooperative Oncology Group PS 0-1.

Patients with a prior history of non-melanoma skin lesions or cervical carcinoma in situ will be eligible for this study. Patients with a prior history of malignancy, other than the cancer for which they are enrolled in this study, and less than a 50% chance of recurrence within five years are also eligible.

EXCLUSION CRITERIA:

ARM I Adjuvant/Locally Advanced Therapy:

Serum total bilirubin greater 2.0 mg/dl and SGOT greater than 2.5 times the upper limit of normal. Serum albumin less than 3. Serum creatinine greater than 2.0 mg/dl. Total lymphocyte count less than 470, granulocytes less than 1000, and platelets less than 100,000/mm(3). Metastases must be excluded in any patients with abnormal liver function tests on ARM I of this study.

HIV positivity, hepatitis B surface antigen positivity, or hepatitis C antibody positivity in the presence of active hepatitis.

A condition, psychiatric or otherwise, that would preclude consistent follow-up or compliance with any component of the study.

Any serious medical conditions that would impair the patient's ability to undergo apheresis.

Pregnant or breast feeding.

No cytotoxic chemotherapy or supraphysiologic steroid therapy within 4 weeks prior to the anticipated vaccine date and no anticipated need for such therapy for at least 2 months following the anticipated vaccination dates. No prior immunologic therapy aimed at manipulating the cellular immune system.

Any serious uncontrolled infection on day 1 of cycle 1 of vaccination.

Patients with an allergy to eggs will not be excluded from this protocol. However, these patients will not be vaccinated against influenza.

ARM II Metastatic Disease:

Ability to meet the above exclusion criteria. Except for the following:

Serum total bilirubin greater than 2.0 mg/dl and SGOT greater than 4 times the upper limit of normal unless due to the presence of disease.

A history of cardiac failure, significant arrhythmias, or significant history of coronary artery disease.

Uncontrolled thyroid disease.

Special Instructions: Currently Not Provided

Keywords:

Immunologic Therapy

Ras Mutations

Adjuvant Therapy

Metastatic Therapy

Cytotoxic T Lymphocytes (CTL)

Dendritic Cells

Mutant Ras

Recruitment Keywords:

None

Conditions:

Colorectal Neoplasm

Neoplasm Metastasis

Investigational Drug(s):

Mutant Ras Peptides

IL-4

GM-CSF

CD40 Ligand

IL-2

Investigational Device(s):

None

Contacts:

CSSC
Clinical Studies Support Center/NCI
164 Rollins Avenue
2nd FLoor
Rockville, MD 20852
Phone: (888) 624-1937
Fax: (301) 881-8239

Electronic Address: ncicssc@mail.nih.gov

Citations:

Ras oncogenes in human cancer: a review

Mutant ras epitopes as targets for cancer vaccines

Ras p21 expression in relation to histopathological variables and prognosis in colorectal adenocarcinoma

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