Clinical trial NCT00499083: Paclitaxel, Cyclophosphamide & Doxorubicin, Autologous Dendritic Cells & Surgery in Stage II/III Breast Cancer (Women)
Official title: Neoadjuvant Intratumoral Injection of Dendritic Cells in Breast Cancer Translation of Biotechnology Into the Clinic
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
Lead sponsor: University of Nebraska
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-07-11
Enrollment: 17
Sex: FEMALE
Minimum age (years): 19
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Patients With Pathological Complete Response
timeFrame: At definitive surgery.
Secondary outcomes:
measure: Inflammatory Cell Infiltration
timeFrame: Post-vaccination peripheral blood (PB) after the last chemotherapy.
measure: Antibody-dependent Cell-mediated Cytotoxicity
timeFrame: Post-vaccination peripheral blood (PB) after the last chemotherapy.
measure: Influence of Tumor COX-2 and VEGF Expression on Dendritic Cell-mediated Tumor-specific Immunity
timeFrame: Post-vaccination peripheral blood (PB) after the last chemotherapy.
Other outcomes:
Locations:
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute, University of South Florida
state: Florida
city: Omaha
country: United States
facility: Eppley Cancer Center, University of Nebraska Medical Center
state: Nebraska
Study officials:
affiliation: University of Nebraska
name: Elizabeth C Reed, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Nebraska
name: Kenneth H Cowan, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hong WX, Sagiv-Barfi I, Czerwinski DK, Sallets A, Levy R. Neoadjuvant Intratumoral Immunotherapy with TLR9 Activation and Anti-OX40 Antibody Eradicates Metastatic Cancer. Cancer Res. 2022 Apr 1;82(7):1396-1408. doi: 10.1158/0008-5472.CAN-21-1382.