Clinical trial NCT00048893
Conditions: Breast Neoplasms Metastases, Neoplasm
Keywords: CEA vaccine Metastatic Breast Cancer T- Cell Repertoire High-dose Chemotherapy Breast Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2002-11-01; Completion date: 2011-06-01
Enrollment: 37 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the effectiveness of chemotherapy and a combination of vaccines to treat metastatic breast cancer (breast cancer that has spread beyond the breast) in patients whose cancer cells have a protein called carcinoembryonic antigen (CEA) on their surface. Patients who require surgery or radiation therapy, or both, will receive these treatments as well.

Patients 18 years of age and older with previously untreated metastatic breast cancer may be eligible for this study. Newly diagnosed patients may not have received prior chemotherapy. Patients previously diagnosed with local disease may have received chemotherapy or radiation therapy at least 18 months before entering the current study. Patients may have received hormonal therapy for stage IV disease. Candidates are screened with a medical history and physical examination, blood and urine tests, x-rays, heart and lung tests, and a test to determine the presence of CEA on their tumor cells.

Participants undergo the following procedures:

1. Central venous line: Under local or general anesthesia, an intravenous catheter (plastic tube) is inserted into a major vein in the chest. It is used to give chemotherapy and other medications and to withdraw blood samples.
2. Apheresis: Before beginning treatment and at various times before and after chemotherapy, patients undergo apheresis to collect white blood cells for later re-infusion at the time of immunizations and to evaluate the body's response to the vaccines. For this procedure, blood is collected through the central venous catheter and circulated through a machine that separates the white cells from the rest of the blood. The white cells are removed and frozen for later use. The rest of the blood is returned to the patient through the catheter.
3. First vaccine: Before starting chemotherapy, patients receive one subcutaneous (under the skin) injection of a vaccine called rV-CEA-Tricom, along with subcutaneous injections of granulocyte macrophage colony stimulating factor (GM-CSF) (Sargramostim), a drug that stimulates the bone marrow to release white blood cells and white cell precursors into the bloodstream.
4. Chemotherapy:

   * Taxol (paclitaxel)/Cytoxan (cyclophosphamide): Patients receive three to five cycles of Taxol and Cytoxan. Taxol is given as a continuous 72-hour intravenous (intravenous (IV), through a vein) infusion and Cytoxan is given daily for 3 days, intravenously, over 1 hour. Cycles are 21 to 42 (usually 28) days. After each cycle, patients also receive growth colony stimulating factor (G-CSF) (a drug that helps boost white cells.

Detailed description:
BACKGROUND: Metastatic breast cancer remains to this day a mostly incurable disease, with less than 10% of patients reaching a long-term disease free survival. This study proposes using an immune-depleting chemotherapy as platform for immunotherapy. It is based on the following hypotheses and understanding:

* The combination of dose-intensive followed by immune-depleting chemotherapy provides a platform for subsequent immunotherapy by:

  1. Lengthening the progression-free survival period, thus allowing time for a slow acting therapy such as vaccination to be effective.
  2. Maximally decreasing the patient's tumor burden. This has been shown both in clinical and experimental settings to be desirable if not necessary for immunotherapy to be effective.
  3. Decreasing the tumor burden which may also decrease a tumor-induced immuno-suppressive effect linked to tumor bulk.
  4. Providing tumor antigen exposure following immune depletion in the form of repeated immunizations. This may take advantage of the pattern of immune reconstitution following immune depleting therapy at early time points (antigen-driven peripheral expansion of T-cells) and the renewal of a T-cell repertoire biased towards tumor antigens and anti-tumor responses at later time points.
* Low antigenicity of tumor antigens and immune tolerance may be overcome in a clinically relevant fashion by providing exposure to the tumor antigens (the carcino-embryonic antigen CEA) in a more immunogenic presentation along with added co-stimulatory signal (in the form of two poxvirus-based recombinant vaccines).
* Due to the post immune depletion defects and delay in immune reconstitution, an adequate immune response to vaccines may not occur unless the patients are provided, following immune depletion, with unaltered T-cells in the form of re-infusion of pre-chemotherapy lymphocytes.

The late recovery of thymic function (18 to 24 months) with reappearance of naive T-cells may play a determinant role in the prevention of later disease progression. It is the rationale for a late series of immunizations.

ELIGIBILITY: Patients with metastatic breast cancer untreated with chemotherapy or radiation in the previous 18 months with CEA positivity in either the tumor or the serum.

OBJECTIVES: The primary objectives are to evaluate biologically this immunization strategy by assessing CEA specific T-cell responses as well as clinically by comparing the patient event free survival (EFS) to our historical control (protocol 96-C-0104) in which patients have received the same conventional therapy but no immunization

DESIGN: Before any chemotherapy patients will be immunized with one of two tumor-specific, recombinant, poxvirus-based deoxyribonucleic acid (DNA) Tricom vaccines and sensitized lymphocytes will be cryopreserved. Patients will then receive conventional induction therapy with Paclitaxel, Cyclophosphamide and Doxorubicin, surgery and / or radiation as indicated for local control, then immune depleting chemotherapy with Fludarabine \& Cyclophosphamide. Following immune depletion, patients will receive 9 immunization boosts over the next 30 months. Patients whose disease progress through the vaccination schedule, may, under certain circumstances, receive further vaccinations under a more intensive schedule (monthly).

Interventions: intervention 1: recombinant fowlpox-CEA(6D)/TRICOM vaccine intervention 2: recombinant vaccinia-CEA(6D)/TRICOM vaccine intervention 3: filgrastim intervention 4: sargramostim intervention 5: cyclophosphamide intervention 6: doxorubicin hydrochloride intervention 7: fludarabine phosphate intervention 8: paclitaxel intervention 9: Mesna
Intervention descriptions: intervention 1: 4 x 10\^8 pfu given monthly subcutaneously for three doses in the first series and three doses on each of the intermediate and late re-immunizations (total 9 doses). intervention 2: rV-CEA (6D)/Tricom concomitantly with sargramostim (rGM-CSF). 1.2 x 10\^8 pfu x 1 dose subcutaneously. intervention 3: 5 mcg/kg/day subcutaneously intervention 4: 100 mcg daily for 4 consecutive days at the same site as the rF-CEA (6D)/Tricom vaccine. The first dose will be given with the vaccine. intervention 5: First induction chemotherapy: 2700 mg/m\^2 per cycle (900 mg/m\^2 per day intravenous over 1 hour for 3 consecutive days, days 1-3).

Second induction: 600 mg/m\^2 per cycle (600 mg/m\^2 intravenous over 1 hour day 1.

Immune depleting chemotherapy: 2400 mg/m\^2 per cycle (600 mg/m\^2 per day intravenous over 1 hour for 4 consecutive days, days 1-4). intervention 6: 60 mg/m\^2 per cycle (60 mg/m\^2 slow intravenous push day 1). intervention 7: 120 mg/m\^2 (30 mg/m\^2 per day intravenous over 30 minutes for 4 consecutive days (days 1-4)). intervention 8: 160 mg/m\^2 per cycle (53.3 mg/m\^2 per day by continuous intravenous infusion over 24 hours for 3 consecutive days 1-3). intervention 9: Percent equals fraction of total daily cyclophosphamide dose. Initial: 20% of cyclophosphamide dose given intravenously (IV) mixed with cyclophosphamide.

3 hours post completion of cyclophosphamide: 20% intravenously (IV) or 40% by mouth (PO) 6 hours post completion of cyclophosphamide: 20% intravenously (IV) or 40% by mouth (PO) 9 hours post completion of cyclophosphamide: 20% intravenously (IV) or 40% by mouth (PO)

Protocol documents: