This study will evaluate the safety and side effects of vaccine treatment given together with standard radiation and chemotherapy in patients with advanced lung cancer that cannot be operated. The vaccine consists of three parts: 1) a "priming vaccine" called rVCEA(6D)-Tricom, which is made from vaccinia virus; 2) a "boosting vaccine" called fR-CEA(6D)-Tricom, made from fowlpox virus; and 3) sargramostim, or GM-CSF, a protein that boosts the immune system. Human DNA is inserted into the vaccinia and fowlpox viruses to cause production of carcinoembryonic antigen (CEA), a protein that is normally produced by some patient's tumor cells and can be used as a target for the immune system to attack the cancer. Another type of DNA is inserted to cause production of other proteins called Tricom that enhance immune activity.

Patients 18 years of age and older with stage III inoperable lung cancer whose tumors produce CEA and who are tissue type HLA-A2 may be eligible for this study. (HLA type is a genetic marker of the immune system and is tested in a manner similar to blood type testing.) Candidates are screened with a medical history and physical examination, blood and urine tests, electrocardiogram (ECG), computerized tomography (CT) or magnetic resonance imaging (MRI) scans, and a lung function test, if recent studies are not available.

Participants undergo the following procedures:

- Vaccine, Chemotherapy, and Radiation Treatment: Patients receive the priming vaccination on study day 0 and a boosting vaccine every 2 weeks (study days 14, 29, 43, 57 and 70) and then two more boosting vaccines on days 91 and 112. With every vaccination patients also receive an injection of sargramostim to increase the effectiveness of the vaccine. All vaccine and sargramostim doses are given as injections under the skin. In addition to the vaccine treatment, patients have radiation to the tumor on study days 21-25, 28--32, 35-39, 42-46, 49-53, 56-60, and 63-67. Low-dose chemotherapy with paclitaxel and carboplatin are given on days 21, 28, 35, 42, 56, 63, 91, and 112. Dexamethasone, diphenhydramine, and rantinidine or cimetidine are given with the chemotherapy to reduce the drugs' side effects. Patients are monitored closely for treatment side effects with blood and urine tests and with clinic visits every 2 to 3 weeks. They may also have repeat imaging scans to assess the status of their cancer. Patients whose disease does not worsen during treatment and who do not experience serious side effects may continue to receive the boosting vaccine every 3 weeks after day 112.

- Apheresis: Patients undergo apheresis, a procedure for collecting immune cells called lymphocytes, on study days 0, 21, 70, and 133. For this procedure, blood is collected through a needle in an arm vein. The blood circulates through a machine that separates it into its components by spinning, and the lymphocytes are extracted. The rest of the blood is returned to the patient through the same needle. The collected lymphocytes are studied to measure the immune response to treatment.

- Fiberoptic bronchoscopy and lavage: For this procedure to examine the lungs, the patient's mouth and throat are numbed with lidocaine; a sedative may be given for comfort. A thin flexible tube called a bronchoscope is advanced through the nose or mouth into the airways (trachea and bronchi) to examine them carefully. Biopsy specimens are obtained with a biopsy forcep. Saline (salt water) is then injected through the bronchoscope into the air passage, acting as a rinse. A sample of fluid is then withdrawn for microscopic examination. Researchers in the current study will use some of the fluid obtained from the lavage to examine for protein content.

Condition	Treatment or Intervention	Phase
Carcinoma Non-Small Cell Lung	Drug: rV-CEA(6D)/TRICOM  Drug: rF-CEA(6D)/TRICOM  Drug: Recombinant Fowlpox-GM-CSF	Phase I

Further Study Details: 

Expected Total Enrollment:  10

Lung cancer is the leading cause of cancer death in the U.S. Approximately 80% of all lung cancers are non-small cell and 40% of patients will present with stage IIIA or IIIB, which is frequently not amenable to primary surgical treatment. Combined chemotherapy and radiotherapy appear to have improved the outcome for patients with locally advanced, unresectable stage III non-small cell lung cancer (NSCLC). Choy, et al. performed a prospective phase II study using concurrent weekly paclitaxel, carboplatin, and hyperfractionated radiation therapy (paclitaxel/carboplatin/HFX RT) followed by 2 cycles of paclitaxel and carboplatin for locally advanced unresectable NSCLC. At a median follow-up time of 14 months, the median overall survival time was 14.3 months and the median progression-free survival was 8.8 months.

In a series of preclinical experiments, we have shown that radiation can upregulate Fas on tumor cells, which in turn leads to more effective killing of tumor by T cells specific for the tumor-associated antigen (TAA). Moreover, the use of vaccine and radiation was shown to be safe in preclinical models, and in patients in an ongoing clinical trial. Furthermore, the combination of chemotherapy with vaccine has a favorable safety profile, and both preclinical and clinical data suggest that immune responses can be mounted combining vaccine with chemotherapy.

The basic vaccination will incorporate a priming vaccination with rV-CEA(6D)/TRICOM followed by serial boosting vaccinations with rF-CEA(6D)/TRICOM. rV- designates recombinant vaccinia and rF- designates recombinant fowlpox. CEA is human carcinoembryonic antigen, which is overexpressed in the majority of human carcinomas. CEA(6D) denotes that the CEA transgene also contains an HLA-A2 enhancer agonist epitope. TRICOM denotes a triad of human T-cell costimulatory molecules (B7.1, ICAM-1, and LFA-3). The majority of NSCLCs express CEA as a target, and patients' tumors will be tested for CEA positivity by IHC to determine eligibility for this protocol. Each vaccination will be given with rF-GM-CSF locally at the same site as the vaccination. This regimen has been tested in two phase I trials [Georgetown University (J. Marshall)-NCI 833 (rV-CEA(6D)/TRICOM, rF-CEA(6D)/TRICOM, and rGM-CSF) and Fox Chase-NCI 1133 (rF-CEA(6D)/TRICOM and rF-GM-CSF)] with no dose limiting toxicities.(1,2) In Marshall's trial, one pathologic complete response (pCR), 5 decreasing CEA, 25 stable disease (SD) (>4 months) were observed. Seven patients were treated for >12 months and 18 for >4 months. CEA-specific T-cell responses were observed in majority of patients tested. This trial demonstrated that the TRICOM vaccines are safe, generate a significant CEA-specific immune response in A2+ patients, and may have significant clinical benefit in patients with advanced cancer.(3) We propose to evaluate the safety and feasibility of combining the standard chemotherapy/radiation therapy for stage III unresectable NSCLC with a CEA/TRICOM vaccine regimen.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
A. Stage III Locally advanced and unresectable non-small cell lung cancer, CEA positive tumor. Tumor that has been shown to express CEA by positive immunohistochemical techniques, using the COL-1 monoclonal CEA antibody (staining of at least 20% of cells will be considered positive).
B. Patients must have histopathological documentation of NSCLC confirmed in the Laboratory of Pathology of the Clinical Center at the National Institutes of Health (NIH) prior to starting this study.
C. 18 years of age or greater.
D. Life expectancy greater than or equal to 6 months.
E. ECOG performance status of 0 - 1.
F. Serum creatinine within institution limits of normal OR creatinine clearance on a 24-hour urine collection of greater than 60 mL/min, total bilirubin less than 1.5 mg/dL and AST less than or equal to twice the institution upper limits of normal.
G. Hematological eligibility parameters (within 16 days of starting therapy):
-Granulocyte count equal to or greater than 1,500/mm (3)
-Platelet count equal to or greater than 100,000/ mm (3)
-Hgb equal to or greater than 10 Gm/dL
-Absolute lymphocyte count equal to or greater than 600/ mm (3).
H. Patient must have recovered from any acute toxicity related to prior therapy, including surgery. (Patients may have had treatment for previous malignancies using chemotherapy or radiation, however prior radiation cannot have been administered to the lung fields and it must be at least three years since they may have received any chemotherapy). Patients may have had prior immune therapy with related vaccinia and fowlpox vaccines or antigen specific peptides, but it must be at least three years since they have received such treatment.
I. All patients must be HLA-A2 positive.
J. Patients must be willing to travel from their home to the NIH for follow-up visits.
K. Patients must understand and sign informed consent that explains the neoplastic nature of their disease, the procedures to be followed, the experimental nature of the treatment, alternative treatments, potential risks and toxicities, and the voluntary nature of participation.
L. Men and women of child-bearing age must agree to use effective birth control or abstinence during protocol treatment and for a period of 4 months after the last vaccination or protocol treatment.
EXCLUSION CRITERIA:
A. Patients should have no evidence of being immunocompromised as defined by: diagnosis of altered immune function, including active or history of eczema, atopic dermatitis, autoimmune disease (autoimmune neutropenia, thrombocytopenia, or hemolytic anemia, HIV, systemic lupus erythematosus, Sjogren syndrome, scleroderma, myasthenia gravis, Goodpasture syndrome, Addison's disease, Hashimoto's thyroiditis, or active Graves' disease), or Chronic Hepatitis infection including B and C.
B. Concurrent steroid use (however, steroid administration using the following will be allowed: topical steroids, inhaled steroid use for mild or moderate asthma, decadron premedication for paclitaxel administration, and short term doses 48-72 hours of decadron to control refractory nausea not responding to other antiemetics, and treatment with systemic corticosteroids for grade 3 or greater radiation pneumonitis ). Although topical steroid steroids are allowed, steroid eye-drops are contraindicated for at least 3 weeks following vaccination in patients receiving vaccinia vaccines.
C. Because of the possibility of auto-inoculation of vaccinia virus, patients with active cases or history of extensive psoriasis, severe acneiform rash, impetigo, varicella zoster, burns, or other traumatic or pruritic skin condition should not be treated. Surgical scars must be healed. Furthermore, patients with a known history of allergy or serious reaction to prior vaccination with vaccinia vaccine will be excluded.
D. The recombinant vaccinia vaccine should not be administered if the following apply to either recipients or, for at least 3 weeks after vaccination, their close household contacts: persons with active or a history of eczema or other eczematoid skin disorders; those with other acute, chronic or exfoliative skin conditions (e.g., atopic dermatitis, burns, impetigo, varicella zoster, severe acne or other open rashes or wounds) until condition resolves; pregnant or nursing women; children under 3 years of age; and immunodeficient or immunosuppressed persons, including HIV infection. Close household contacts are those who share housing or have close physical contact.
E. Patients with known allergy to eggs are not eligible.
F. Other serious intercurrent illness, or other active malignancies (aside from their current lung cancer) within the past 2 years.
G. Patients with evidence of distant metastases.
H. Patients with a history of unstable or newly diagnosed angina pectoris, recent myocardial infarction (within 6 months of enrollment) or New York Heart Assoc. class II-IV congestive heart failure.
I. Pregnant or breast-feeding women.
J. Prior splenectomy.
K. Prior paclitaxel, carboplatin and thoracic radiation treatment for lung cancer.

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  040252; 04-C-0252
Record last reviewed:  November 17, 2004
Last Updated:  November 23, 2004
Record first received:  July 30, 2004
ClinicalTrials.gov Identifier:  NCT00088725
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08