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

NCT01367288 | Completed Phase 2 DMC

• 1 other identifier: 2009.568
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Locally Advanced Breast Cancer; Ductal Histologic Type; Without Her 2 Overexpression

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Decrease in serum VEGF concentration treatment

  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)

  8 months

Secondary Outcomes (11)

• Change in CTC

  8 months

• Change in serum markers of apoptosis

  every 3 weeks during 8 months

• Change in serum tumor markers

  every 3 weeks during 8 monthes

• Change in tumor markers of apoptosis and proliferation

  before treatment, at 90-105 days and at surgical excision

• Change in circulating gamma-delta T-cell activation

  every 3 weeks during 8 monthes

Study Arms (2)

A (Neoadjuvant therapy + Zometa)

EXPERIMENTAL

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; Drug: Neoadjuvant therapy

B (Neoadjuvant therapy)

ACTIVE COMPARATOR

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

Interventions

Zometa + Neoadjuvant therapy DRUG

4 mg (in a 15 min. infusion) every 3 weeks for a total of 8 injections

A (Neoadjuvant therapy + Zometa)

Neoadjuvant therapy DRUG

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)

A (Neoadjuvant therapy + Zometa); B (Neoadjuvant therapy)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (1)

Hopital Femme Mère Enfant, Service de Gynécologie

Bron, 69677, France

Location

Related Publications (2)

• Lelievre L, Clezardin P, Magaud L, Roche L, Tubiana-Mathieu N, Tigaud JD, Topart D, Raban N, Mouret-Reynier MA, Mathevet P. Comparative Study of Neoadjuvant Chemotherapy With and Without Zometa for Management of Locally Advanced Breast Cancer With Serum VEGF as Primary Endpoint: The NEOZOL Study. Clin Breast Cancer. 2018 Dec;18(6):e1311-e1321. doi: 10.1016/j.clbc.2018.07.005. Epub 2018 Jul 10.

  PMID: 30098917 RESULT

• Adams A, Jakob T, Huth A, Monsef I, Ernst M, Kopp M, Caro-Valenzuela J, Wockel A, Skoetz N. Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis. Cochrane Database Syst Rev. 2024 Jul 9;7(7):CD013451. doi: 10.1002/14651858.CD013451.pub2.

  PMID: 38979716 DERIVED

MeSH Terms

Conditions

Breast Neoplasms; Neovascularization, Pathologic

Interventions

Zoledronic Acid; Neoadjuvant Therapy

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Metaplasia; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Combined Modality Therapy; Therapeutics

Study Officials

• Patrice Mathevet, Professor

  Hospices Civils de Lyon

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 17, 2010
• First Posted: June 7, 2011
• Study Start: April 1, 2010
• Primary Completion: April 1, 2014
• Study Completion: April 1, 2014
• Last Updated: May 28, 2019

Record last verified: 2014-05

Locations

FR (1)