Paclitaxel, Cyclophosphamide & Doxorubicin, Autologous Dendritic Cells & Surgery in Stage II/III Breast Cancer (Women)

University of Nebraska

Status and phase

Completed

Phase 2

Conditions

Breast Cancer

Treatments

Drug: doxorubicin hydrochloride

Procedure: adjuvant therapy

Drug: tamoxifen citrate

Genetic: reverse transcriptase-polymerase chain reaction

Procedure: neoadjuvant therapy

Genetic: gene expression analysis

Procedure: conventional surgery

Biological: therapeutic autologous dendritic cells

Drug: aromatase inhibition therapy

Genetic: protein expression analysis

Other: immunohistochemistry staining method

Other: laboratory biomarker analysis

Radiation: radiation therapy

Other: immunoenzyme technique

Procedure: biopsy

Drug: paclitaxel

Drug: cyclophosphamide

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00499083

0072-06-FB

P30CA036727 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

RATIONALE: Drugs used in chemotherapy, such as paclitaxel, cyclophosphamide, and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Injecting the patient's dendritic cells directly into the tumor may stimulate the immune system and stop tumor cells from growing. Radiation therapy uses high-energy x-rays to kill tumor cells. Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving combination chemotherapy together with autologous dendritic cells before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving radiation therapy and hormone therapy after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This phase II trial is studying the side effects and how well giving paclitaxel together with cyclophosphamide and doxorubicin followed by autologous dendritic cells and surgery with or without radiation therapy and/or hormone therapy works in treating women with stage II or stage III breast cancer.

Full description

OBJECTIVES:

Assess the safety of intratumoral (IT) autologous dendritic cell (DC) injection in women with stage II or III breast cancer receiving neoadjuvant paclitaxel, cyclophosphamide, and doxorubicin hydrochloride followed by surgery with or without adjuvant radiotherapy and/or hormone therapy.
Determine the clinical and pathologic response in patients treated with this regimen.
Determine the immune response, in terms of tumor cell apoptosis and the presence and characterization of tumor infiltrating white blood cells in resected breast cancer, in patients treated with this regimen.
Determine if IT DC injections administered during neoadjuvant chemotherapy-induced tumor cell apoptosis can induce T-cell responses to tumor antigens in these patients.

OUTLINE: This is an open-label study.

Leukapheresis: Patients undergo leukapheresis at baseline to collect peripheral blood mononuclear cells for dendritic cell (DC) culture.
Neoadjuvant, dose-dense chemotherapy: Patients receive paclitaxel IV over at least 3 hours on day 1 and filgrastim (G-CSF) subcutaneously (SC) on days 4-14 or pegfilgrastim SC on day 2. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Beginning 2 weeks after completion of paclitaxel chemotherapy, patients receive cyclophosphamide IV and doxorubicin hydrochloride IV on day 1 and G-CSF SC on days 4-14 or pegfilgrastim SC on day 2. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Intratumoral injection of autologous DCs: Intratumoral autologous DCs are injected into the primary breast mass or palpable axillary node on day 7 of the 1st, 2nd, and 3rd courses of paclitaxel chemotherapy. If no tumor can be localized by ultrasound after a course of chemotherapy, the DCs are then injected into the site of the tumor bed previously localized by clip or marker. In the event that the previously injected primary tumor cannot be localized by ultrasound, a palpable lymph node, if still present, should be injected rather than the tissue next to the primary tumor clip or marker.
Definitive breast surgery: Within 2-4 weeks after completion of neoadjuvant chemotherapy, patients undergo modified radical mastectomy or lumpectomy with or without standard axillary node dissection.* NOTE: *Standard axillary node dissection is only required if no node assessment was done prior to chemotherapy or if the pre-chemotherapy sentinel node was positive.
Radiotherapy: Patients undergoing lumpectomy or those with residual disease requiring chest wall radiotherapy after mastectomy (e.g., T3 or T4 breast lesions or 4 or more axillary lymph nodes) undergo radiotherapy 2-4 weeks after surgery.
Hormone therapy: Patients with estrogen and/or progesterone receptor-positive tumors receive adjuvant hormone therapy for ≥ 5 years. Premenopausal patients receive tamoxifen citrate and post- or perimenopausal patients receive either tamoxifen citrate or an aromatase inhibitor (AI), or both of these drugs in sequence, as determined by the treating oncologist.

Peripheral blood samples are obtained during each DC injection, at staging/biopsy, and then periodically for up to 2 years. Blood samples are analyzed by ELISPOT and ELISA assays for evaluation of immune response.

Tumor tissue is obtained by core biopsy of the breast primary and/or palpable axillary lymph node at baseline and again after completion of paclitaxel chemotherapy. Tumor tissue is analyzed by IHC and RT-PCR for COX-2 and VEGF-A and -C expression levels, as well as T-cell and DC infiltration of the tumor. T-cell and DC infiltration is evaluated for correlation with clinical outcomes at diagnosis, at the midpoint biopsy following paclitaxel chemotherapy, and at definitive surgery.

After completion of study therapy, patients are followed periodically for up to 2 years.

Enrollment

17 patients

Sex

Female

Ages

19 to 120 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Histologically confirmed invasive breast cancer meeting the following criteria:
- Primary tumor ≥ 3 cm by mammography, ultrasound, or palpation AND/OR palpable axillary lymph nodes > 1 cm
- Survivin- and/or carcinoembryonic antigen-positive by IHC
- Tumor must be localized by exam or ultrasound to allow tumor injection
- No stage IV or metastatic disease
HER2/neu-negative tumor by IHC

o If 2+ or in the indeterminate range, further testing of HER2/neu overexpression by fluorescent in situ hybridization (FISH) is required
Hormone receptor status known
Female
Pre-, peri-, or postmenopausal
ECOG performance status 0-1
Fertile patients must use effective contraception during and for up to 6 months following completion of study therapy
ANC ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Alkaline phosphatase ≤ 1.5 times upper limit of normal (ULN)
Total bilirubin ≤ 1.5 times ULN
AST and ALT ≤ 1.5 times ULN
Creatinine < 1.5 times ULN

Exclusion criteria

No prior chemotherapy or radiotherapy
No active serious infections
No prior malignancy except adequately treated basal cell or squamous cell skin cancer, noninvasive carcinoma, or other cancer from which the patient has been disease free for 5 years
No comorbidity or condition that would interfere with study assessments and procedures or preclude study participation
Not pregnant or nursing/negative pregnancy test

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

17 participants in 1 patient group

Vaccine

Experimental group

Description:

Patients with HER-2/neu negative tumors will receive IT DCs one week after the first three of four cycles of dose dense T therapy and then four cycles of dose dense AC therapy will be given (i.e. T-AC).

Treatment: