Clinical trial NCT00179309
Conditions: Breast Cancer
Keywords: CEA MUC-1 Immunotherapy GM-CSF Vaccine Breast Cancer Metastatic Breast Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2005-09-01; Completion date: 2013-10-01
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will test whether giving a combination of a vaccine together with docetaxel is more effective against breast cancer than docetaxel alone. The Food and Drug Administration has approved docetaxel to treat many cancers, including breast cancer. The vaccine consists of three parts: 1) a "priming vaccine" called PANVAC (PAN (all) VAC (vaccine)) trademark \[TM\]-V, which is made from vaccinia virus; 2) a "boosting vaccine" called PANVAC\[TM\]-F, made from fowlpox virus; and 3) sargramostim, or granulocyte macrophage colony stimulating factor (GM-CSF), a protein that may help boost the immune system. Human genes are inserted into the vaccinia and fowlpox viruses to cause production of carcinoembryonic antigen (CEA) and mucin 1 (MUC-1)-two proteins that are often produced by cancer cells and can be used as a target for the immune system to attack the cancer. Another type of deoxyribonucleic acid (DNA) is inserted to cause production of other proteins that enhance immune activity.

Patients 18 years of age or older with metastatic breast cancer (disease that has spread beyond the original site) and whose cancer produces CEA or mucin 1 (MUC-1) protein may be eligible for this study. Patients must have antigen type human leukocyte antigen A2 (HLA-A2). They may have received adjuvant docetaxel treatment at least 3 months before entering this study, prior hormonal therapy and up to three chemotherapy regimens. Candidates are screened with a medical history and physical examination, blood and urine tests, electrocardiogram, and computerized tomography (CT) or magnetic resonance imaging scans.

Participants are randomly assigned to one of two treatment groups - docetaxel alone or docetaxel plus vaccine - as follows:

Docetaxel Alone

All patients receive docetaxel. The drug is infused through a vein over 30 to 60 minutes once a week for 3 consecutive weeks with 1 week off drug. Patients also take dexamethasone 12 hours and 1 hour before and 12 hours after the docetaxel to help prevent fluid retention (edema) that docetaxel may cause.

Docetaxel Plus Vaccine

Participants receive the priming vaccination followed by monthly boosting vaccinations, along with the weekly docetaxel therapy. With every vaccination, patients also receive an injection of sargramostim to increase the number of immune cells at the vaccination site. Sargramostim injections are given the day of vaccination and daily for the next 3 days. All vaccine and sargramostim doses are given as injections under the skin, usually in the thigh. Patients are observed in the clinic for 1 hour after each injection.

Patients have blood tests every four weeks to monitor drug side effects and before every vaccination to check blood counts. A bone scan or CT scan (or both) is done every 2 to 3 months to check the response to treatment.

Patients may continue receiving treatment as long as their disease does not worsen and they can tolerate the treatment without significant side effects. Patients assigned to receive docetaxel alone whose disease progresses after 3 months on the drug may choose to receive the vaccine or come off the study to receive other treatment options. Patients are monitored with yearly telephone calls for up to 15 years.

Detailed description:
Background:

Weekly docetaxel therapy is currently used as a standard treatment for patients with metastatic breast cancer.

Although many patients initially respond to this form of therapy, the majority will eventually develop disease progression and die from their disease.

We have explored the use of combining pox vector vaccines with docetaxel. In a recent clinical trial, men with prostate cancer were given both the vaccine and docetaxel without any significant toxicity and the docetaxel did not diminish immune responses to the vaccine.

Objectives:

To evaluate progression free survival comparing PANVAC + docetaxel vs. docetaxel alone in patients with metastatic breast cancer.

To evaluate overall survival comparing PANVAC + docetaxel vs. docetaxel alone in patients with metastatic breast cancer.

To evaluate in both arms cluster of differentiation 8 (CD8+) T cell responses directed against carcinoembryonic antigen (CEA) and mucin (MUC-1) in human leukocyte antigen 2 (HLA-A2), A3, and A24 positive patients by interferon-gamma enzyme linked immunosorbent spot (ELISPOT) assay.

Eligibility:

Metastatic breast cancer (either male or female) with evidence of metastatic disease (must have radiographic evidence of disease) and life expectancy of at least 4 months.

Patients may have received unlimited prior hormonal therapy or chemotherapy, but no prior docetaxel for metastatic disease.

Hematological eligibility parameters within 16 days of starting therapy:

Granulocyte count greater than or equal to 1,500/mm\^3, Platelet count greater than or equal to 100,000/mm\^3, hemoglobin (Hgb) greater than or equal to 8 Gm/dL.

Design:

A randomized Phase II study evaluating the role of combining docetaxel with PANVAC\[TM\]-V (recombinant vaccinia containing the genes encoding for CEA, MUC-1, lymphocyte function-associated antigen 3 (LFA-3), intercellular adhesion molecule 1 (ICAM-1) and B7.1) and PANVAC\[TM\]-F (recombinant fowlpox containing the genes encoding for CEA, MUC-1, LFA-3, ICAM-1 and B7.1) vs. docetaxel alone to determine if the addition of the vaccine can prolong the time to disease progression as well as overall survival in patients with metastatic breast cancer.

Patients randomized to docetaxel alone may receive sequential therapy with PANVAC\[TM\]-V and PANVAC\[TM\]-F at time of disease progression.

In patients randomized to the concurrent therapy, PANVAC\[TM\]-V will be administered to patients 3 weeks prior to the start of chemotherapy as the initial vaccine.

The immune responses to CEA and MUC-1 will then be boosted by administration of PANVAC\[TM\]-F.

Sargramostim or granulocyte macrophage colony stimulating factor (GM-CSF) will be administered with each vaccine inoculation for four consecutive days only for patients treated at the National cancer Institute (NCI).

Arms: arm 1: Patients receive vaccinia-carcinoembryonic antigen (CEA)- mucin-1 (MUC-1)- triad of costimulatory molecules (TRICOM) vaccine subcutaneously (SC) once and sargramostim, or granulocyte macrophage colony stimulating factor (GM-CSF) SC once daily for 4 days in week -2. Patients also receive fowlpox-CEA-MUC-1-TRICOM vaccine SC once and GM-CSF SC once daily for 4 days in weeks 1, 5, and 9. Patients also receive docetaxel intravenous (IV) over 30 minutes once weekly in weeks 1-3, 5-7, and 9-11. After week 12, patients with no disease progression continue with docetaxel once weekly for 3 weeks followed by 1 week of rest and fowlpox-CEA-MUC-1-TRICOM vaccine plus GM-CSF every 4 weeks until disease progression. arm 2: Patients receive docetaxel as in arm I. After week 12, patients with disease progression discontinue docetaxel and receive vaccinia-carcinoembryonic antigen (CEA)- mucin 1(MUC-1)-triad of costimulatory molecules (TRICOM) vaccine, fowlpox-CEA-MUC-1-TRICOM vaccine, and sargramostim, or granulocyte macrophage colony stimulating factor (GM-CSF) as in arm I until further disease progression. Patients with no disease progression after week 12 continue with docetaxel as in arm I until disease progression.
Interventions: intervention 1: Docetaxel intervention 2: PANVAC-V intervention 3: PANVAC-F intervention 4: Sargramostim
Intervention descriptions: intervention 1: 35 mg/m\^2 intravenous 30-60 minutes once a week for 3 consecutive weeks with 1 week off drug. intervention 2: 2 x 10\^8 PFU intervention 3: 1 x 10\^9 PFU intervention 4: Given subcutaneously under the skin, usually in the thigh on the day of vaccination and daily for the next 3 days.

Protocol documents: