Pre-operative Zoledronate in Triple Negative Breast Cancer

NCT02347163 | Terminated Phase 2

• 1 other identifier: IRFMN-BRC-6591
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 4

Brief 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 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).

Conditions

Breast Cancer

Keywords

triple neg; breast cancer; zoledronate; mevalonate pathway

Outcome Measures

Primary Outcomes (1)

• 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

  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)

  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)

  participants will be followed for AE occurrence from the informed consent signature to 2 months after study drug administration

Study Arms (1)

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

Drug: Zoledronate

Interventions

Zoledronate DRUG

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 .

Also known as: Zometa

Zoledronate

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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 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

Sponsors & Collaborators

• Mario Negri Institute for Pharmacological Research: lead
• Associazione Italiana per la Ricerca sul Cancro: collaborator

Study Sites (4)

Azienda Ospedaliera Spedali Civili di Brescia

Brescia, BS, 25123, Italy

Location

Azienda Ospedaliera Papa Giovanni XXIII

Bergamo, 24127, Italy

Location

Oncologia 2 Istituto Oncologico Veneto IRCCS

Padua, 35128, Italy

Location

Fondazione Salvatore Maugeri - IRCCS

Pavia, 27100, Italy

Location

Related Publications (16)

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• Freed-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.

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• Wang 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.

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MeSH Terms

Conditions

Breast Neoplasms

Interventions

Zoledronic Acid

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Alberto Zambelli, MD

  Azienda Ospedaliera Papa Giovanni XXIII, Bergamo

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: January 15, 2015
• First Posted: January 27, 2015
• Study Start: February 3, 2015
• Primary Completion: June 8, 2018
• Study Completion: June 8, 2018
• Last Updated: November 6, 2018

Record last verified: 2018-11

Data Sharing

• IPD Sharing: Will not share

Locations

IT (4)