Comparative Study of Neoadjuvant Chemotherapy With and Without Zometa for Management of Locally Advanced Breast Cancers (NEOZOL)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hospices Civils de Lyon
ClinicalTrials.gov Identifier:
NCT01367288
First received: September 17, 2010
Last updated: May 28, 2014
Last verified: May 2014
  Purpose

Breast cancer is the leading female cancer by a very wide margin in France. Despite widespread breast cancer screening, many cases of breast cancer are discovered at a locally advanced stage. The tumoral consequences of a cancer size greater than 3 cm are: increased risk of metastasis and death and, most often, impossibility of performing breast-conserving surgery (a mastectomy is usually advisable in case of a first surgical procedure). It is increasingly recommended to treat locally advanced breast cancers with neoadjuvant chemotherapy. Very numerous studies have shown that by proceeding that way, the oncologic prognosis was not harmed and, on the contrary, it was possible to obtain sufficient tumor response to allow breast-conserving treatment in more than 60% of cases.

The use of zoledronic acid (Zometa) has an established place in the management of malignancies with a predilection for skeletal involvement (in particular metastasis). Although the main target of biphosphonates is the osteoclast, there is also preclinical data indicating that biphosphonates can have effects on cells other than osteoclasts, including tumor cells. Anti-tumor activity including inhibition of tumor cell growth and induction of tumor cell apoptosis, inhibition of tumor cell adhesion and invasion, and anti-angiogenic effects have been demonstrated. In addition several in vitro studies have shown that Zometa causes synergistic induction of breast cancer cell apoptosis when combined with clinically relevant concentrations of chemotherapy drugs such as paclitaxel and doxorubicin. Therefore testing of combinations of biphosphonates with these agents in breast cancer is of significant interest.

In the context of locally advanced breast cancers, the combination of a bisphosphonate with neoadjuvant chemotherapy appears to have an important potential: preventing possible bone metastases, but also possibly amplifying the efficacy of the chemotherapy's tumoricidal activity, both on the primary tumor and on potential metastatic localizations.

So it appears that, the use of bisphosphonates in a neoadjuvant situation presents a potentially favorable benefit-risk ratio. That is why we are proposing to perform a prospective randomized multicenter comparative study to evaluate 2 systemic neoadjuvant treatments, one with Zometa and the other without Zometa, in patients with locally advanced breast cancer. Zometa will be administered according to the usual administration procedure: one infusion every 3 weeks.

The therapeutic response will be evaluated by studying the different biological markers (circulating blood and bone marrow tumor cells, serum cell apoptosis and neoangiogenesis markers, bone resorption markers, etc.), but also by analyzing clinical, radiologic, and histologic response and by breast conservation rates. The impact of other factors that may affect therapeutic response will be taken into account: aggressivity of the tumor, presence or absence of tumor receptors, tumor stage, etc.

The purpose of the study is to show a marked benefit of treatment with Zometa in managing locally advanced breast cancers with synergistic action of the neoadjuvant chemotherapy and improvement in the laboratory parameters of tumor aggressivity. These markers will be used as surrogate markers of long term outcome.


Condition Intervention Phase
Locally Advanced Breast Cancer
Ductal Histologic Type
Without Her2 Overexpression.
Drug: Zometa + Neoadjuvant therapy
Drug: Neoadjuvant therapy
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Comparative Study of Neoadjuvant Chemotherapy With and Without Zometa for Management of Locally Advanced Breast Cancers

Resource links provided by NLM:


Further study details as provided by Hospices Civils de Lyon:

Primary Outcome Measures:
  • Decrease in serum VEGF concentration treatment [ Time Frame: 8 months ] [ Designated as safety issue: No ]
    To assess the improvement obtained by adding Zometa treatment to neoadjuvant chemotherapy in patients with locally advanced breast cancer on concentrations of serum VEGF (neoangiogenesis marker and prognostic factor) before treatment and during surgery after neoadjuvant treatment (i.e., at about 8 months)


Secondary Outcome Measures:
  • Change in CTC [ Time Frame: 8 months ] [ Designated as safety issue: No ]
    To assess the impact of each of the treatment arms on circulating tumor cells (CTC) present in the blood

  • Change in serum markers of apoptosis [ Time Frame: every 3 weeks during 8 months ] [ Designated as safety issue: No ]
    To assess the impact of each of the treatment arms on serum markers of apoptosis,

  • Change in serum tumor markers [ Time Frame: every 3 weeks during 8 monthes ] [ Designated as safety issue: No ]
    assessment of the change in serum tumor markers by CEA, V-EGF and CA 15-3 assay

  • Change in tumor markers of apoptosis and proliferation [ Time Frame: before treatment, at 90-105 days and at surgical excision ] [ Designated as safety issue: No ]
  • Change in circulating gamma-delta T-cell activation [ Time Frame: every 3 weeks during 8 monthes ] [ Designated as safety issue: No ]
  • Therapeutic complications [ Time Frame: at each of the chemotherapy sessions and during the final surgery ] [ Designated as safety issue: Yes ]
    Assessment of renal failure and osteonecrosis of the jaw

  • Assessment of tumor response [ Time Frame: at the start of treatment, at day 90-105, after 4 neoadjuvant treatment sessions, after all 8 neoadjuvant chemotherapy sessions ] [ Designated as safety issue: No ]
    To assess the impact of each of the strategies treatment arms on clinical, and radiological tumour response (maximum tumour diameter)

  • Assessment of histological tumor response [ Time Frame: during the final surgery ] [ Designated as safety issue: No ]
  • Breast conservation rate [ Time Frame: during the final surgery ] [ Designated as safety issue: No ]
    To assess the breast conservation rate for each of the strategies

  • Assessment of the intermediate tumor response [ Time Frame: at day 90-105 ] [ Designated as safety issue: No ]
    To assess the changes in tissue biomarkers at day 90-105 (intermediate biopsy) in each of the strategies.

  • Assessment of the markers studied in the complementary study [ Time Frame: at the end of the treatment ] [ Designated as safety issue: No ]
    • measurement of IPP and ApppI (PBMCs), FPPS mRNA (PBMCs)
    • FACS analysis of gamma-delta T cell subsets, measurement of IFNg, TNFa
    • Measurement of gamma-delta T cells cytotoxic activity
    • Injection of expanded gamma-delta T cells in NOD/SCID mice bearing patients' tumors and follow-up of animals (tumor size measurement, survival, IHC). Correlation with clinicopathological factors and clinical outcome of patients.
    • RNA extraction of primary tumour biopsies before treatment and at the time of surgery for DNA microarray hybridization studies


Enrollment: 53
Study Start Date: April 2010
Study Completion Date: April 2014
Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A (Neoadjuvant therapy + Zometa)
Patients will be treated every 3 weeks (+/- 2 days ) for 8 cycles in total. The 4 first cycles : Zometa 4 mg (in a 15 min. infusion) + doxorubicin (60 mg/m²) + cyclophosphamide (600 mg/m²). The 4 last cycles with Zometa 4 mg (in a 15 min. infusion) + docetaxel (100 mg/m²)
Drug: Zometa + Neoadjuvant therapy
4 mg (in a 15 min. infusion) every 3 weeks for a total of 8 injections
Drug: Neoadjuvant therapy
4 injections of doxorubicin (60 mg/m²) combined with cyclophosphamide (600 mg/m²) every 3 weeks (+/- 2 days), followed by 4 injections of docetaxel (100 mg/m²) every 3 weeks (+/- 2 days)
Active Comparator: B (Neoadjuvant therapy)
Patients will be treated every 3 weeks (+/- 2 days) for 8 cycles in total. The 4 first cycles : doxorubicin (60 mg/m²) combined with cyclophosphamide (600 mg/m²). The 4 last cycles with docetaxel (100 mg/m²)
Drug: Neoadjuvant therapy
4 injections of doxorubicin (60 mg/m²) combined with cyclophosphamide (600 mg/m²) every 3 weeks (+/- 2 days), followed by 4 injections of docetaxel (100 mg/m²) every 3 weeks (+/- 2 days)

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Women 18 years of age or older
  • Absence of contraindication to treatment with Zometa: creatinine clearance greater than 30 mL/min (with Cockroft or MDRD method).
  • Breast cancer (TNM IIa, IIb, IIIa) larger than 2cm in maximal diameter able to benefit from neoadjuvant chemotherapy
  • Ductal or lobular histological type of the breast tumor
  • WHO performance status 0-2
  • Patient who understands the french language
  • Covered by, or having the right to Social Security
  • Signed informed consent

Exclusion Criteria:

  • Breast cancers of rare histological type (other than ductal and lobular)
  • Noninvasive cancer
  • Multifocal tumor (more than 2 tumoral lesions or 2 tumoral lesions distant more than 2cm each other)
  • T4 breast tumor
  • Presence of organ, bone, or skin metastases (in the initial staging workup)
  • Patient with a history of breast cancer
  • Other cancer currently in treatment (except carcinoma in situ).
  • Severe systemic disease potentially interfering with follow-up.
  • Contraindication to injected products: known allergy to bisphosphonates, zoledronic acid or excipients, severe renal failure (creatinine clearance < 30 mL/min with Cockroft or MDRD method).
  • Women who are pregnant (positive pregnancy test) or breast-feeding, or absence of contraception in a woman who is able to become pregnant.
  • Patient with evolutionary dental problems, including dental infection or infection of the jaw,intrabuccal exposure of jawbone, and history or current diagnosis of osteonecrosis of the jaw,requiring a fast chirurgical care.
  • Prior treatment with bisphosphonates (either IV or oral).
  • History of severe bone disease (severe osteoporosis with multiple skeletal-related events).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01367288

Locations
France
Hopital Femme Mère Enfant, Service de Gynécologie
BRON Cedex, France, 69677
Sponsors and Collaborators
Hospices Civils de Lyon
Investigators
Principal Investigator: Patrice Mathevet, Professor Hospices Civils de Lyon
  More Information

No publications provided

Responsible Party: Hospices Civils de Lyon
ClinicalTrials.gov Identifier: NCT01367288     History of Changes
Other Study ID Numbers: 2009.568
Study First Received: September 17, 2010
Last Updated: May 28, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Hospices Civils de Lyon:
locally advanced breast cancer
neoadjuvant chemotherapy
HER2-negative breast cancer
stage IIb breast cancer
stage IIIa breast cancer
Zoledronic acid
bisphosphonate
zometa
therapeutic response
VEGF serum
tumors markers
neoangiogenesis
apoptosis
proliferation
disseminated tumors cells
gamma-delta T cells activation

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Cyclophosphamide
Zoledronic acid
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Bone Density Conservation Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014