Locally Advanced Breast CancerPhase 2NEOZOLNCT01367288
Comparative Study of Neoadjuvant Chemotherapy With and Without Zometa for Management of Locally Advanced Breast Cancers
A Phase 2 study testing Zometa + Neoadjuvant therapy and Neoadjuvant therapy in people with Locally Advanced Breast Cancer and Ductal Histologic Type, run by Hospices Civils de Lyon at 1 site in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Locally Advanced Breast Cancer, Ductal Histologic Type, Without Her 2 Overexpression
- What is being tested?
- Zometa + Neoadjuvant therapy and Neoadjuvant therapy
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 53 participants
- Where
- 1 siteFrance
- Study dates
- Apr 2010to Apr 2014
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 13Show fewer
- 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).
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read more
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.
- Being tested
- Zometa + Neoadjuvant therapy, Neoadjuvant therapy
- 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
- Medical subject headings
- Breast Neoplasms, Neovascularization, Pathologic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Zometa + Neoadjuvant therapyDrug
4 mg (in a 15 min. infusion) every 3 weeks for a total of 8 injections
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)
| Study group | Role | What they receive |
|---|---|---|
| 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) Receives: 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) Receives: Drug: Neoadjuvant therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
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)
Measured: 8 months
Secondary outcomes (11)
Change in CTC
To assess the impact of each of the treatment arms on circulating tumor cells (CTC) present in the blood
Measured: 8 months
Change in serum markers of apoptosis
To assess the impact of each of the treatment arms on serum markers of apoptosis,
Measured: every 3 weeks during 8 months
Change in serum tumor markers
assessment of the change in serum tumor markers by CEA, V-EGF and CA 15-3 assay
Measured: every 3 weeks during 8 monthes
Change in tumor markers of apoptosis and proliferation
Measured: before treatment, at 90-105 days and at surgical excision
Change in circulating gamma-delta T-cell activation
Measured: every 3 weeks during 8 monthes
Therapeutic complications
Assessment of renal failure and osteonecrosis of the jaw
Measured: at each of the chemotherapy sessions and during the final surgery
Assessment of tumor response
To assess the impact of each of the strategies treatment arms on clinical, and radiological tumour response (maximum tumour diameter)
Measured: at the start of treatment, at day 90-105, after 4 neoadjuvant treatment sessions, after all 8 neoadjuvant chemotherapy sessions
Assessment of histological tumor response
Measured: during the final surgery
Breast conservation rate
To assess the breast conservation rate for each of the strategies
Measured: during the final surgery
Assessment of the intermediate tumor response
To assess the changes in tissue biomarkers at day 90-105 (intermediate biopsy) in each of the strategies.
Measured: at day 90-105
Assessment of the markers studied in the complementary study
- 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
Measured: at the end of the treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jun 2011 (estimated)
- Study startApr 2010
- Primary completionApr 2014
- Study completionApr 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Locally Advanced Breast CancerStudies of the same condition, open and under way.
- More trials run by Hospices Civils de LyonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 53 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hospices Civils de Lyon
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Patrice Mathevet, Professor, Principal investigator, Hospices Civils de Lyon
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01367288
- Sponsor's protocol ID
- 2009.568
- Acronym
- NEOZOL
- Status last verified
- May 2014
- First submitted
- 17 Sep 2010
- Last updated
- 28 May 2019
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 30098917Adams 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.
PubMed 38979716
Study at a glance
From the registry record, last updated by the sponsor on 28 May 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparative Study of Neoadjuvant Chemotherapy With and Without Zometa for Management of Locally Advanced Breast Cancers
- ClinicalTrials.gov ID
- NCT01367288
- Acronym / sponsor ID
- NEOZOL / 2009.568
- Keywords
- locally advanced breast cancer, neoadjuvant chemotherapy, HER2-negative breast cancer, stage IIb breast cancer, stage IIIa breast cancer, Zoledronic acid, bisphosphonate, zometa
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 53 participants (actual)
- Lead sponsor
- Hospices Civils de LyonUniversity, hospital or other
- Study start
- Apr 2010
- Primary completion
- Apr 2014 (actual)
- Study completion
- Apr 2014 (actual)
- First posted
- 7 Jun 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| A (Neoadjuvant therapy + Zometa) | Experimental | Drug: Zometa + Neoadjuvant therapy, Drug: Neoadjuvant therapyPatients 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) |
| B (Neoadjuvant therapy) | Active comparator | Drug: Neoadjuvant therapyPatients 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) |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (13 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Zometa + Neoadjuvant therapy4 mg (in a 15 min. infusion) every 3 weeks for a total of 8 injections | Drug | A (Neoadjuvant therapy + Zometa) |
| Neoadjuvant therapy4 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) | Drug | A (Neoadjuvant therapy + Zometa), B (Neoadjuvant therapy) |
Primary outcome
Decrease in serum VEGF concentration treatment
Time frame: 8 months
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)
11 secondary outcomes
Change in CTC
Time frame: 8 months
Change in serum markers of apoptosis
Time frame: every 3 weeks during 8 months
Change in serum tumor markers
Time frame: every 3 weeks during 8 monthes
Change in tumor markers of apoptosis and proliferation
Time frame: before treatment, at 90-105 days and at surgical excision
Change in circulating gamma-delta T-cell activation
Time frame: every 3 weeks during 8 monthes
Therapeutic complications
Time frame: at each of the chemotherapy sessions and during the final surgery
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
Assessment of histological tumor response
Time frame: during the final surgery
Breast conservation rate
Time frame: during the final surgery
Assessment of the intermediate tumor response
Time frame: at day 90-105
Assessment of the markers studied in the complementary study
Time frame: at the end of the treatment
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 May 2019.
- Results publication: PubMed 30098917Lelievre 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.
- Derived from this study: PubMed 38979716Adams 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Patrice Mathevet, Professor principal investigator
Hospices Civils de Lyon
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Zometa + Neoadjuvant therapy and Neoadjuvant therapy in people with Locally Advanced Breast Cancer and Ductal Histologic Type, run by Hospices Civils de Lyon at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 May 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Decrease in serum VEGF concentration treatment (time frame: 8 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01367288, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 May 2019.