Breast CancerPhase 2NCT02347163
Pre-operative Zoledronate in Triple Negative Breast Cancer
A Phase 2 study testing Zoledronate in people with Breast Cancer, run by Mario Negri Institute for Pharmacological Research at 4 sites in Italy.
Trial summary
Recent evidences suggest that zoledronate (zol), one of the most used bisphosphonates (BPs) in the clinical setting for the prevention and treatment of bone metastasis in cancer patients, may have antitumor activity in early breast cancer in terms of improved disease free survival, overall survival and better response… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Breast Cancer
- What is being tested?
- Zoledronate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 4 sitesItaly
- Study dates
- 3 Feb 2015to 8 Jun 2018
- 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
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed diagnosis of non-metastatic operable primary invasive TN breast cancer subjected to diagnostic core biopsy
- TNBC defined as HER2/ER/PgR negative receptors
- Ki67 and p53 expression determined by IHC
- Tumour tissue availability at time of diagnosis for IHC evaluation of p53/PIN1, YAP/TAZ and Ki67 protein expression and for RT-PCR molecular testing of critical genes: p53/PIN1, YAP/TAZ
- Age ≥ 18 years old
- ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1
- Patients with reproductive potential. Female patients must have a negative serum pregnancy test within 7 days prior to start of trial. Patients must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months (female patients) and 6 months (male patients) after discontinuation of treatment
- Written informed consent signed prior to enrolment according to ICH/GCP.
Who cannot join
- Presence of metastatic disease
- Clinical indication of debulking neo-adjuvant treatment
- Previous investigational treatment for any condition within 4 weeks from study registration
- Treatment with bisphosphonates, denosumab or other drug that, in the Investigator's judgment, affects bone metabolism
- Treatment with statins or other drugs that, in the Investigator's judgment, potentially affect the mevalonate pathway
- Any previous treatment for the currently diagnosed breast cancer, including radiation therapy, chemotherapy, biotherapy and/or hormonal therapy
Show all 17Show fewer
- Inadequate bone marrow, hepatic or renal function including the following
- Hb< 9.0 g/dL, absolute neutrophil count < 1.5 x 109/L, platelets <100 x 109/L
- Total bilirubin > 1.5 x ULN, excluding cases where elevated bilirubin can be attributed to Gilberts Syndrome
- AST (SGOT), ALT (SGPT) > 2.5 x ULN Creatinine > 1.2 x ULN, calcium <8.6mg/dL
- Co-existing active infection or serious concurrent illness that, at the judgment of the investigator, contra-indicate the inclusion of the patient in the study
- Co-existing dental diseases that form a contraindication to the use of zol or need for immediate dental work
- Any medical or other condition that in the investigator's opinion renders the patient unsuitable for this study due to unacceptable risk
- Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study assessment and procedures
- Anticipation of need for major surgical procedure during the course of the trial
- Known hypersensitivity to any excipients of zoledronate
- Pregnant or breast feeding women.
Trial locations and contacts
4 sites in 1 country.
Italy4 sites
Azienda Ospedaliera Papa Giovanni XXIII
Bergamo, 24127
Azienda Ospedaliera Spedali Civili di Brescia
Brescia, BS, 25123
Oncologia 2 Istituto Oncologico Veneto IRCCS
Padova, 35128
Fondazione Salvatore Maugeri - IRCCS
Pavia, 27100
About this study
Official title: A Multicenter, Single-arm, Phase II Study to Evaluate the Activity of Pre-operative Zoledronate in Triple Negative Breast Cancer Patients, According to p53 Level
Recent evidences suggest that zoledronate (zol), one of the most used bisphosphonates (BPs) in the clinical setting for the prevention and treatment of bone metastasis in cancer patients, may have antitumor activity in early breast cancer in terms of improved disease free survival, overall survival and better response in BPs treated patients. BPs are mevalonate pathway inhibitors and one of the most intriguing hypothesis supporting their anticancer activity relies on the modulation of the mevalonate downstream metabolism. Biologically active mevalonate metabolites are involved in tumour cell proliferation and invasion and selected cancer subtypes may present a more pronounced mevalonate activity, able of maintaining an aggressive phenotype. The mevalonate pathway has deep impact on the function of YAP/TAZ, transcriptional regulators of tumour growth, and preclinical evidences suggest that BPs are able to interfere with YAP/TAZ expression, via mevalonate pathway. This study addresses the clinical role of BPs in triple negative breast cancer (TNBC) patients selected by the level of mevalonate pathway regulation, namely the p53 expression. This study is a multicenter single-arm, phase II study primarily aimed at assessing the anti-tumor activity of pre-operative zol measured through its effect on the Ki67 proliferative biomarker, in TNBC patients classified according to the p53 expression (high vs low p53 expression). Patients with newly diagnosed, untreated, operable TNBC, intended to definitive breast surgery and suitable for pre-operative therapy with zoledronate will receive a pre-operative, single administration of zol (4mg i.v.), 7 days before definitive breast surgery. Ki67 levels will be assessed in tumor samples collected at the time of diagnosis and after zoledronate treatment at the time of definitive surgery. The secondary objective of the study is to investigate the effect of zoledronate on critical genes/proteins related to p53 and mevalonate pathways, p53/PIN1 and YAP/TAZ, analyzed in the tumor tissue collected at the time of diagnosis and at definitive surgery. Zol safety profile will be evaluated by the NCI-CTCAE scale, version 4.0, and by the occurrence of serious adverse reactions. The total number of patients required is forty. The overall duration of the project is 32 months (30 months for accrual, followed by 2 months of follow-up after the recruitment of the last patient).
Read the detailed description
Recent evidences suggest that zoledronate, one of the most used bisphosphonates (BPs) in the clinical setting for the prevention and treatment of bone metastasis in cancer patients, may have antitumor activity in early breast cancer. Notwithstanding some conflicting data, the majority of the clinical trials have shown some positive effects of BPs on patients outcome, reporting improved Disease Free Survival (DFS) and Overall Survival in mostly chemotherapy-naive premenopausal patients after a 3-year treatment with zoledronate and better DFS for immediate use of zoledronate in postmenopausal patients receiving adjuvant aromatase inhibitor treatment. Moreover, early breast cancer patients treated with neoadjuvant chemotherapy in combination with zoledronic acid showed better response compared with chemotherapy alone.
Even though different explanations have been proposed over-time, the exact mechanism of action of the anti-tumor activity of BPs is still not well understood. Basically, BPs are mevalonate pathway inhibitors and one of the most intriguing hypothesis supporting their anticancer activity relies on the modulation of the mevalonate downstream metabolism. Biologically active mevalonate metabolites are involved in tumour cell proliferation, survival, invasion and metastasis. Moreover, there is evidence that selected cancer subtypes may present a more pronounced mevalonate activity, able of maintaining an aggressive phenotype. Indeed, the mevalonate pathway has deep impact on the function of YAP/TAZ, transcriptional regulators of tumour growth. Preclinical evidences, suggest that BPs are able to interfere with YAP/TAZ expression, via mevalonate pathway. This study addresses the clinical role of BPs in triple negative breast cancer (TNBC) patients selected by the level of mevalonate pathway regulation, namely the p53 expression.
This study is a multicenter single-arm, phase II study primarily aimed at assessing the anti-tumor activity of pre-operative zoledronate measured through its effect on the Ki67 proliferative surrogate biomarker, in patients with TNBC classified according to the p53 expression (high vs low p53 expression). An high level of p53 is defined by IHC expression ≥30%, while a low level is defined by IHC expression <30%, as previously described. Patients with newly diagnosed, untreated, operable TNBC, intended to definitive breast surgery and suitable for pre-operative therapy will be registered using a centralized system and will receive a pre-operative, single administration of zoledronate (4mg i.v.), 7 days before definitive breast surgery . Ki67 levels will be assessed in core biopsy tumor samples collected at the time of diagnosis and after zoledronate treatment at the time of definitive surgery. Primary endpoint of the study is the proportion of responder patients, defined as those with at least 30% reduction in Ki67 at surgery with respect to core-biopsy analysis. The secondary objective of the study is to investigate the effect of zoledronate on critical genes/proteins related to p53 and mevalonate pathways, p53/PIN1 and YAP/TAZ, analyzed in the tumor tissue at the time of diagnosis (core biopsy) and at definitive surgery. The safety profile of zoledronate will be evaluated by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale, version 4.0 and by the occurrence of serious adverse reactions. The total number of patients required is forty. The overall duration of the project is expected to be 32 months, divided as follows: 30 months for accrual, followed by 2 months of follow-up after the recruitment of the last patient, aimed to collect data on zoledronate safety and tolerability. The primary analysis will be conducted on the PP population which will include all patients registered, who received the dose of study treatment and underwent definitive breast surgery, with no major violations of the eligibility criteria or during study conduction. Proportion of responder patients, defined as those with at least 30% reduction in Ki67 at surgery with respect to core-biopsy analysis, will be presented as point estimate and 95% confidence intervals (95% CIs) for each group. Logistic regression techniques will be used to compare groups in univariate and multivariate model adjusted for ECOG-PS, sex and pre- and postmenopausal status. The results of this project may eventually contribute to unveil novel anticancer mechanism of action of BPs and new therapeutic options for triple negative breast cancer.
- Conditions
- Breast Cancer
- Being tested
- Zoledronate
- Keywords
- triple neg, breast cancer, zoledronate, mevalonate pathway
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ZoledronateDrug
Also called Zometa
Patients fulfilling the eligibility criteria will be registered using a centralized system and will receive a pre-operative, single administration of zol (4mg i.v.), 7 days before definitive breast surgery .
| Study group | Role | What they receive |
|---|---|---|
| Zoledronate | Experimental | Patients fulfilling the eligibility criteria will receive a pre-operative, single administration of zoledronate (4mg i.v.), 7 days before definitive breast surgery Receives: Drug: Zoledronate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Assessment of zoledronate effect on Ki67 proliferative surrogate biomarker expression, according to p53 expression
The study is primarily aimed at assessing the anti-tumor activity of pre-operative zoledronate, measured through its effect on the Ki67 proliferative surrogate biomarker, in patients with TNBC selected according to the p53 expression (high vs low p53 expression). Primary endpoint of the study is the proportion of responder patients, defined as those with at least 30% reduction in Ki67 at surgery with respect to core-biopsy analysis. Prior to enrolment, the FFPE diagnostic core biopsy specimens will be analyzed by the study pathologist to determine the presence of invasive TNBC and the Ki67/p53 values. The Ki67/p53 evaluation will be then repeated after treatment at the time of definitive surgery
Measured: 18 months
Secondary outcomes (2)
Effect of zoledronate on critical genes/proteins related to p53 and mevalonate pathways, p53/PIN1 and YAP/TAZ (FFPE core biopsy will be tested for critical genes/proteins expression (by RT-PCR and IHC), including p53/PIN1 and YAP/TAZ)
The secondary endpoint of the study is aimed to investigate the effect of zoledronate on critical genes/proteins related to p53 and mevalonate pathways, p53/PIN1 and YAP/TAZ, analyzed at the time of diagnosis (core biopsy) and at definitive surgery (breast cancer resection). After enrolment, the FFPE core biopsy will be tested for critical genes/proteins expression (by RT-PCR and IHC), including p53/PIN1 and YAP/TAZ. The same evaluations will be performed after treatment, at the time of definitive surgery
Measured: 18 months
Assessment of zoledronate safety (valuated by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale, version 4.0 and by the occurrence of serious adverse reactions)
The safety profile of zoledronate will be evaluated by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale, version 4.0 and by the occurrence of serious adverse reactions
Measured: participants will be followed for AE occurrence from the informed consent signature to 2 months after study drug administration
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jan 2015 (estimated)
- Study start3 Feb 2015
- Primary completion8 Jun 2018
- Study completion8 Jun 2018
Why it stopped: The study stopped prematurely due to the low accrual rate
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (16)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by Mario Negri Institute for Pharmacological ResearchThe 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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- Associazione Italiana per la Ricerca sul Cancro
- Responsible party
- Sponsor
- Investigators
- Alberto Zambelli, MD, Principal investigator, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02347163
- Sponsor's protocol ID
- IRFMN-BRC-6591
- Status last verified
- Nov 2018
- First submitted
- 15 Jan 2015
- Last updated
- 6 Nov 2018
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No: The final clinical study report will be sent to the participating researchers
Publications
Reis-Filho JS, Tutt AN. Triple negative tumours: a critical review. Histopathology. 2008 Jan;52(1):108-18. doi: 10.1111/j.1365-2559.2007.02889.x.
PubMed 18171422Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011 Jul;121(7):2750-67. doi: 10.1172/JCI45014.
PubMed 21633166Gnant M, Mlineritsch B, Luschin-Ebengreuth G, Kainberger F, Kassmann H, Piswanger-Solkner JC, Seifert M, Ploner F, Menzel C, Dubsky P, Fitzal F, Bjelic-Radisic V, Steger G, Greil R, Marth C, Kubista E, Samonigg H, Wohlmuth P, Mittlbock M, Jakesz R; Austrian Breast and Colorectal Cancer Study Group (ABCSG). Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncol. 2008 Sep;9(9):840-9. doi: 10.1016/S1470-2045(08)70204-3. Epub 2008 Aug 19.
PubMed 18718815Bundred NJ, Campbell ID, Davidson N, DeBoer RH, Eidtmann H, Monnier A, Neven P, von Minckwitz G, Miller JC, Schenk NL, Coleman RE. Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST Study results. Cancer. 2008 Mar 1;112(5):1001-10. doi: 10.1002/cncr.23259.
PubMed 18205185Coleman RE, Winter MC, Cameron D, Bell R, Dodwell D, Keane MM, Gil M, Ritchie D, Passos-Coelho JL, Wheatley D, Burkinshaw R, Marshall SJ, Thorpe H; AZURE (BIG01/04) Investigators. The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer. 2010 Mar 30;102(7):1099-105. doi: 10.1038/sj.bjc.6605604. Epub 2010 Mar 16.
PubMed 20234364Paterson AH, Anderson SJ, Lembersky BC, Fehrenbacher L, Falkson CI, King KM, Weir LM, Brufsky AM, Dakhil S, Lad T, Baez-Diaz L, Gralow JR, Robidoux A, Perez EA, Zheng P, Geyer CE Jr, Swain SM, Costantino JP, Mamounas EP, Wolmark N. Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial. Lancet Oncol. 2012 Jul;13(7):734-42. doi: 10.1016/S1470-2045(12)70226-7. Epub 2012 Jun 14.
PubMed 22704583Ben-Aharon I, Vidal L, Rizel S, Yerushalmi R, Shpilberg O, Sulkes A, Stemmer SM. Bisphosphonates in the adjuvant setting of breast cancer therapy--effect on survival: a systematic review and meta-analysis. PLoS One. 2013 Aug 26;8(8):e70044. doi: 10.1371/journal.pone.0070044. eCollection 2013.
PubMed 23990894Holen I, Coleman RE. Anti-tumour activity of bisphosphonates in preclinical models of breast cancer. Breast Cancer Res. 2010;12(6):214. doi: 10.1186/bcr2769. Epub 2010 Dec 16.
PubMed 21176176Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990 Feb 1;343(6257):425-30. doi: 10.1038/343425a0.
PubMed 1967820Freed-Pastor WA, Mizuno H, Zhao X, Langerod A, Moon SH, Rodriguez-Barrueco R, Barsotti A, Chicas A, Li W, Polotskaia A, Bissell MJ, Osborne TF, Tian B, Lowe SW, Silva JM, Borresen-Dale AL, Levine AJ, Bargonetti J, Prives C. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell. 2012 Jan 20;148(1-2):244-58. doi: 10.1016/j.cell.2011.12.017.
PubMed 22265415Wang Z, Wu Y, Wang H, Zhang Y, Mei L, Fang X, Zhang X, Zhang F, Chen H, Liu Y, Jiang Y, Sun S, Zheng Y, Li N, Huang L. Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):E89-98. doi: 10.1073/pnas.1319190110. Epub 2013 Dec 23.
PubMed 24367099Sorrentino G, Ruggeri N, Specchia V, Cordenonsi M, Mano M, Dupont S, Manfrin A, Ingallina E, Sommaggio R, Piazza S, Rosato A, Piccolo S, Del Sal G. Metabolic control of YAP and TAZ by the mevalonate pathway. Nat Cell Biol. 2014 Apr;16(4):357-66. doi: 10.1038/ncb2936. Epub 2014 Mar 23.
PubMed 24658687Piccolo S. LIF-ting Hippo averts metastasis. Nat Med. 2012 Oct;18(10):1463-5. doi: 10.1038/nm.2955. No abstract available.
PubMed 23042347Havrilesky L, Darcy kM, Hamdan H, Priore RL, Leon J, Bell J, Berchuck A; Gynecologic Oncology Group Study. Prognostic significance of p53 mutation and p53 overexpression in advanced epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2003 Oct 15;21(20):3814-25. doi: 10.1200/JCO.2003.11.052.
PubMed 14551300Wiltschke C, Kindas-Muegge I, Steininger A, Reiner A, Reiner G, Preis PN. Coexpression of HER-2/neu and p53 is associated with a shorter disease-free survival in node-positive breast cancer patients. J Cancer Res Clin Oncol. 1994;120(12):737-42. doi: 10.1007/BF01194273.
PubMed 7798300
Study at a glance
From the registry record, last updated by the sponsor on 6 Nov 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicenter, Single-arm, Phase II Study to Evaluate the Activity of Pre-operative Zoledronate in Triple Negative Breast Cancer Patients, According to p53 Level
- ClinicalTrials.gov ID
- NCT02347163
- Acronym / sponsor ID
- IRFMN-BRC-6591
- Conditions
- Breast Cancer
- Keywords
- triple neg, breast cancer, zoledronate, mevalonate pathway
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The study stopped prematurely due to the low accrual rate
- Enrolment
- 22 participants (actual)
- Lead sponsor
- Mario Negri Institute for Pharmacological ResearchUniversity, hospital or other
- Collaborators
- Associazione Italiana per la Ricerca sul Cancro
- Study start
- 3 Feb 2015 (actual)
- Primary completion
- 8 Jun 2018 (actual)
- Study completion
- 8 Jun 2018 (actual)
- First posted
- 27 Jan 2015 (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.
Recent evidences suggest that zoledronate (zol), one of the most used bisphosphonates (BPs) in the clinical setting for the prevention and treatment of bone metastasis in cancer patients, may have antitumor activity in early breast cancer in terms of improved disease free survival, overall survival and better response in BPs treated patients. BPs are mevalonate pathway inhibitors and one of the most intriguing hypothesis supporting their anticancer activity relies on the modulation of the mevalonate downstream metabolism. Biologically active mevalonate metabolites are involved in tumour cell proliferation and invasion and selected cancer subtypes may present a more pronounced mevalonate activity, able of maintaining an aggressive phenotype. The mevalonate pathway has deep impact on the function of YAP/TAZ, transcriptional regulators of tumour growth, and preclinical evidences suggest that BPs are able to interfere with YAP/TAZ expression, via mevalonate pathway. This study addresses the clinical role of BPs in triple negative breast cancer (TNBC) patients selected by the level of mevalonate pathway regulation, namely the p53 expression. This study is a multicenter single-arm, phase II study primarily aimed at assessing the anti-tumor activity of pre-operative zol measured through its effect on the Ki67 proliferative biomarker, in TNBC patients classified according to the p53 expression (high vs low p53 expression). Patients with newly diagnosed, untreated, operable TNBC, intended to definitive breast surgery and suitable for pre-operative therapy with zoledronate will receive a pre-operative, single administration of zol (4mg i.v.), 7 days before definitive breast surgery. Ki67 levels will be assessed in tumor samples collected at the time of diagnosis and after zoledronate treatment at the time of definitive surgery. The secondary objective of the study is to investigate the effect of zoledronate on critical genes/proteins related to p53 and mevalonate pathways, p53/PIN1 and YAP/TAZ, analyzed in the tumor tissue collected at the time of diagnosis and at definitive surgery. Zol safety profile will be evaluated by the NCI-CTCAE scale, version 4.0, and by the occurrence of serious adverse reactions. The total number of patients required is forty. The overall duration of the project is 32 months (30 months for accrual, followed by 2 months of follow-up after the recruitment of the last patient).
Detailed description
Recent evidences suggest that zoledronate, one of the most used bisphosphonates (BPs) in the clinical setting for the prevention and treatment of bone metastasis in cancer patients, may have antitumor activity in early breast cancer. Notwithstanding some conflicting data, the majority of the clinical trials have shown some positive effects of BPs on patients outcome, reporting improved Disease Free Survival (DFS) and Overall Survival in mostly chemotherapy-naive premenopausal patients after a 3-year treatment with zoledronate and better DFS for immediate use of zoledronate in postmenopausal patients receiving adjuvant aromatase inhibitor treatment. Moreover, early breast cancer patients treated with neoadjuvant chemotherapy in combination with zoledronic acid showed better response compared with chemotherapy alone.
Even though different explanations have been proposed over-time, the exact mechanism of action of the anti-tumor activity of BPs is still not well understood. Basically, BPs are mevalonate pathway inhibitors and one of the most intriguing hypothesis supporting their anticancer activity relies on the modulation of the mevalonate downstream metabolism. Biologically active mevalonate metabolites are involved in tumour cell proliferation, survival, invasion and metastasis. Moreover, there is evidence that selected cancer subtypes may present a more pronounced mevalonate activity, able of maintaining an aggressive phenotype. Indeed, the mevalonate pathway has deep impact on the function of YAP/TAZ, transcriptional regulators of tumour growth. Preclinical evidences, suggest that BPs are able to interfere with YAP/TAZ expression, via mevalonate pathway. This study addresses the clinical role of BPs in triple negative breast cancer (TNBC) patients selected by the level of mevalonate pathway regulation, namely the p53 expression.
This study is a multicenter single-arm, phase II study primarily aimed at assessing the anti-tumor activity of pre-operative zoledronate measured through its effect on the Ki67 proliferative surrogate biomarker, in patients with TNBC classified according to the p53 expression (high vs low p53 expression). An high level of p53 is defined by IHC expression ≥30%, while a low level is defined by IHC expression <30%, as previously described. Patients with newly diagnosed, untreated, operable TNBC, intended to definitive breast surgery and suitable for pre-operative therapy will be registered using a centralized system and will receive a pre-operative, single administration of zoledronate (4mg i.v.), 7 days before definitive breast surgery . Ki67 levels will be assessed in core biopsy tumor samples collected at the time of diagnosis and after zoledronate treatment at the time of definitive surgery. Primary endpoint of the study is the proportion of responder patients, defined as those with at least 30% reduction in Ki67 at surgery with respect to core-biopsy analysis. The secondary objective of the study is to investigate the effect of zoledronate on critical genes/proteins related to p53 and mevalonate pathways, p53/PIN1 and YAP/TAZ, analyzed in the tumor tissue at the time of diagnosis (core biopsy) and at definitive surgery. The safety profile of zoledronate will be evaluated by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale, version 4.0 and by the occurrence of serious adverse reactions. The total number of patients required is forty. The overall duration of the project is expected to be 32 months, divided as follows: 30 months for accrual, followed by 2 months of follow-up after the recruitment of the last patient, aimed to collect data on zoledronate safety and tolerability. The primary analysis will be conducted on the PP population which will include all patients registered, who received the dose of study treatment and underwent definitive breast surgery, with no major violations of the eligibility criteria or during study conduction. Proportion of responder patients, defined as those with at least 30% reduction in Ki67 at surgery with respect to core-biopsy analysis, will be presented as point estimate and 95% confidence intervals (95% CIs) for each group. Logistic regression techniques will be used to compare groups in univariate and multivariate model adjusted for ECOG-PS, sex and pre- and postmenopausal status. The results of this project may eventually contribute to unveil novel anticancer mechanism of action of BPs and new therapeutic options for triple negative breast cancer.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Zoledronate | Experimental | Drug: ZoledronatePatients fulfilling the eligibility criteria will receive a pre-operative, single administration of zoledronate (4mg i.v.), 7 days before definitive breast surgery |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Histologically confirmed diagnosis of non-metastatic operable primary invasive TN breast cancer subjected to diagnostic core biopsy
- TNBC defined as HER2/ER/PgR negative receptors
- Ki67 and p53 expression determined by IHC
- Tumour tissue availability at time of diagnosis for IHC evaluation of p53/PIN1, YAP/TAZ and Ki67 protein expression and for RT-PCR molecular testing of critical genes: p53/PIN1, YAP/TAZ
- Age ≥ 18 years old
Key exclusion criteria (17 listed)
- Presence of metastatic disease
- Clinical indication of debulking neo-adjuvant treatment
- Previous investigational treatment for any condition within 4 weeks from study registration
- Treatment with bisphosphonates, denosumab or other drug that, in the Investigator's judgment, affects bone metabolism
- Treatment with statins or other drugs that, in the Investigator's judgment, potentially affect the mevalonate pathway
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 |
|---|---|---|
| ZoledronateAlso: ZometaPatients fulfilling the eligibility criteria will be registered using a centralized system and will receive a pre-operative, single administration of zol (4mg i.v.), 7 days before definitive breast surgery . | Drug | Zoledronate |
Primary outcome
Assessment of zoledronate effect on Ki67 proliferative surrogate biomarker expression, according to p53 expression
Time frame: 18 months
The study is primarily aimed at assessing the anti-tumor activity of pre-operative zoledronate, measured through its effect on the Ki67 proliferative surrogate biomarker, in patients with TNBC selected according to the p53 expression (high vs low p53 expression). Primary endpoint of the study is the proportion of responder patients, defined as those with at least 30% reduction in Ki67 at surgery with respect to core-biopsy analysis. Prior to enrolment, the FFPE diagnostic core biopsy specimens will be analyzed by the study pathologist to determine the presence of invasive TNBC and the Ki67/p53 values. The Ki67/p53 evaluation will be then repeated after treatment at the time of definitive surgery
2 secondary outcomes
Effect of zoledronate on critical genes/proteins related to p53 and mevalonate pathways, p53/PIN1 and YAP/TAZ (FFPE core biopsy will be tested for critical genes/proteins expression (by RT-PCR and IHC), including p53/PIN1 and YAP/TAZ)
Time frame: 18 months
Assessment of zoledronate safety (valuated by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale, version 4.0 and by the occurrence of serious adverse reactions)
Time frame: participants will be followed for AE occurrence from the informed consent signature to 2 months after study drug administration
Results and safety
The study was stopped early (reason given: The study stopped prematurely due to the low accrual rate). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Nov 2018.
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- Individual participant dataSharing planned: No. The final clinical study report will be sent to the participating researchers
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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.
Alberto Zambelli, MD principal investigator
Azienda Ospedaliera Papa Giovanni XXIII, Bergamo
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Zoledronate in people with Breast Cancer, run by Mario Negri Institute for Pharmacological Research at 4 sites in Italy.
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 17 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: stopped early, as of the sponsor's last update on 6 Nov 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Italy. 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 was stopped early (reason given: The study stopped prematurely due to the low accrual rate). Results are not available in the source record.
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?
Assessment of zoledronate effect on Ki67 proliferative surrogate biomarker expression, according to p53 expression (time frame: 18 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 NCT02347163, which also lists 16 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 6 Nov 2018; AzTrials last refreshed its copy on 7 Nov 2026.