Neoadjuvant Zoledronate and Atorvastatin in Triple Negative Breast Cancer

NCT03358017 | Completed Phase 2

• 2 other identifiers: IRFMN-BRC-71032016-005112-17
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 9

Brief Summary

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. The ABCSG-12 clinical trial have reported improved Disease Free Survival (DFS) and Overall Survival (OS) in mostly chemotherapy naive premenopausal patients after a 3-years of treatment with zoledronate (zol) and ovarian-suppression therapy. The ZO-FAST study showed better DFS for immediate use of zol in postmenopausal patients receiving adjuvant hormonal treatment. Preliminary evidences support the role of zoledronate also in neoadjuvant setting reporting better responses in cases of treatment with zol and chemotherapy (cht) compared with cht alone. The anticancer mechanism of action of BPs still remains not well understood. Basically, BPs are mevalonate (MVA) pathway inhibitors and one of the most intriguing hypothesis supporting their anticancer activity relies on the modulation of the mevalonate downstream metabolism. Selected cancer subtypes may present a more pronounced mevalonate activity able to confer an aggressive phenotype. It has been shown that a mutant p53 acts as promoter of MVA upregulation. One of the most important biological implications of MVA pathway upregulation in cancer cells is the aberrant activation of the Hippo pathway, a molecular axis with a central role in carcinogenesis. Two Hippo pathway related transcriptional coactivators, YAP and TAZ, promote tissue proliferation and the self-renewal of normal and cancer stem cells, and incite metastasis. Due to the strong interplay between the MVA and Hippo pathways, the modulation of MVA axis has deep impact on the function of YAP/TAZ as transcriptional regulators of tumour growth. These findings implicate the mevalonate pathway as a therapeutic target for selected tumors with up-regulation of these pathways. Preclinical and clinical evidences suggest that BPs are able to interfere with YAP/TAZ expression, via MVA pathway. This kind of activity may be part of the mechanism of action of BPs as antitumor drugs. Others medications are able to modulate the MVA pathway. Statins, a first-class of lipid-lowering medications that inhibit the enzyme HMG-CoA reductase, inhibit the sterol biosynthesis via the mevalonate pathway. A possible anti-tumor effect of statins can be predicted with the same mechanism of action described for BPs, through the interference with the MVA axis. Actually, the anti-tumor activity of statins have been investigated in different retrospective analyses. In breast cancer a more robust signal has been retrospectively reported and prospective studies have enquired the exquisite antitumor activity of statins in pre-operative breast cancer setting. From above, the clinical trial herein proposed aims to investigate the antitumoral clinical activity of zoledronate (zol) and statins (atorvastatin) combination, in patients receiving neoadjuvant chemotherapy for triple-negative breast cancer (TNBC). The primary objective of the study is to address in patients with TNBC the antitumor activity of pre-operative standard chemotherapy associated or not with zoledronate (zol) and atorvastatin measured through its effect on YAP and TAZ immunochemistry (IHC) expressions, which are considered co-primary objectives. The primary clinical objective is to assess the anti-tumor activity of the combination of neoadjuvant standard cht associated with zol and atorvastatin, measured by the proportion of pCR obtained after neoadjuvant treatment in patients with TNBC. Secondary objectives are: 1) to evaluate the anti-tumor activity of pre-operative standard chemotherapy associated or not with zol and atorvastatin according to high/low p53 levels 2) to address the efficacy of neoadjuvant cht associated or not with zol/atorvastatin combo in terms of disease free survival and overall survival); 3) to study the safety profile of study treatments; 4) to investigate the treatment modulation of YAP and TAZ gene expression (RNA-Seq) in tumor tissues collected at the time of core-biopsy and definitive surgery; 5) to address the modulation of Ki67expression by IHC in the FFPE diagnostic core biopsy tumor block and in the tumor tissue collected at surgery. Patients fulfilling the eligibility criteria will be randomized to receive standard anthracyclines/taxanes based neoadjuvant cht (ARM A) or the combination of zol and atorvastatin associated with the above mentioned neoadjuvant cht (ARM B).

Conditions

Triple Negative Breast Cancer

Keywords

Triple negative breast cancer; Neoadjuvant chemotherapy; p53; Zoledronate; Atorvastatin; Mevalonate pathway inhibitors; Hippo pathway

Outcome Measures

Primary Outcomes (2)

• Proof of concept primary activity endpoint - Efficacy endpoint

  Relative reductions of YAP and TAZ IHC-expression at surgery with respect to core-biopsy analysis.

  At surgery, after 6 months of study treatment

• The proportion of responded patients

  The clinical primary activity endpoint of the second phase of study is the proportion of responder patients, defined as those obtaining a pCR, defined as ypT0ypN0 or as the absence of any residual tumor burden at surgery.

  After 6 months of study treatment

Secondary Outcomes (9)

• In relation to high/low p53 levels, relative reductions of YAP and TAZ IHC-expression at surgery with respect to core-biopsy analysis. Efficacy endpoint

  At surgery, after 6 months of study treatment

• Proportion of responder patients according to high/low p53 levels - Efficacy endpoint

  After 6 months of study treatment

• Disease Free Survival (DFS) - Efficacy endpoint

  Date of first recurrence or relapse, second cancer, or death, whichever came first, assessed up to 36 months

• Overall survival - Efficacy endpoint

  Date of death from any cause, assessed up to 36 months

• Regulation of YAP and TAZ gene expression by RNA-Seq in tumor tissue - Efficacy endpoint

  At surgery, after 6 months of study treatment

Study Arms (2)

ARM A - standard NACT

ACTIVE COMPARATOR

Standard anthracyclines/taxanes based neoadjuvant chemotherapy chosen by the investigator and administered according to clinical practice, for 6 months, or 4.5 months in case of dose dense schedule (unless disease progression, unacceptable toxicity, patient's refusal or investigator's decision)

Drug: Standard neoadjuvant cht

ARM B - standard NACT + Zol + atorvastatin

EXPERIMENTAL

Standard anthracyclines/taxanes based neoadjuvant CT chosen by the investigator and administered according to clinical practice + Zoledronate 4 mg i.v. every 3-4 weeks and Atorvastatin 80 mg/die administered for 6 months, or 4.5 months in case of dose dense schedule (unless disease progression, unacceptable toxicity, patient's refusal or investigator's decision)

Drug: Zoledronate; Drug: Atorvastatin 80mg; Drug: Standard neoadjuvant cht

Interventions

Zoledronate DRUG

4 mg i.v. every 3/4 weeks for 6 months

Also known as: zoledronic acid

ARM B - standard NACT + Zol + atorvastatin

Atorvastatin 80mg DRUG

80mg /die os for 6 months

ARM B - standard NACT + Zol + atorvastatin

Standard neoadjuvant cht DRUG

Standard neoadjuvant cht chosen by the investigator and administered according to clinical practice

ARM A - standard NACT; ARM B - standard NACT + Zol + atorvastatin

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed diagnosis of non-metastatic operable TNBC subjected to diagnostic core biopsy
• TNBC defined as HER2/ER/PgR negative receptors
• Female, aged ≥ 18 years
• ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1
• Clinical indication for a neoadjuvant approach according to the investigator's judgment. The standard chemotherapy will consist of a complete pre-operative treatment with anthracyclines and taxanes (in sequence or combination), including platinum derivatives and dose-dense schedules, according to the best physician choice (BPC)
• Availability of paraffin-embedded tumor block (FFPE) taken at diagnostic biopsy for IHC and RNA-Seq molecular determinations
• Patients with reproductive potential must have a negative serum pregnancy test within 7 days prior to study entry. They must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months after discontinuation of treatment
• Written informed consent signed prior to enrolment according to ICH/GCP.

You may not qualify if:

• Presence of metastatic disease
• Previous investigational treatment for any condition within four weeks prior to 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 \< 8.6 mg/dL
• Active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal
• Co-existing dental diseases that form a contraindication to the use of zol
• 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
• Known hypersensitivity to the active substance, to other bisphosphonates or to any excipients of zoledronate

Sponsors & Collaborators

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

Study Sites (9)

Azienda Socio Sanitaria Territoriale ASST Lariana - Presidio Ospedaliero Ospedale S. Anna

San Fermo della Battaglia, Como, 22020, Italy

Location

Azienda Socio Sanitaria Territoriale - ASST Papa Giovanni XXIII

Bergamo, 24127, Italy

Location

Azienda Ospedaliero Universitaria di Bologna Policlinico S.Orsola - Malpighi

Bologna, 40138, Italy

Location

Azienda Socio Sanitaria Territoriale - ASST di Cremona

Cremona, 26100, Italy

Location

Azienda Socio Sanitaria Territoriale - ASST di Lodi

Lodi, 26900, Italy

Location

Azienda Socio Sanitaria Territoriale Fatebenefratelli Sacco Sede Ospedale Fatebenefratelli

Milan, 20121, Italy

Location

Azienda Socio Sanitaria Territoriale ASST Monza - Ospedale S. Gerardo

Monza, 20900, Italy

Location

Istituti Clinici Scientifici Maugeri

Pavia, 27100, Italy

Location

IFO - Istituto Nazionale dei Tumori Regina Elena

Roma, 00144, Italy

Location

Related Publications (15)

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• Lehmann 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.

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• Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Heck D, Menzel C, Jakesz R, Seifert M, Hubalek M, Pristauz G, Bauernhofer T, Eidtmann H, Eiermann W, Steger G, Kwasny W, Dubsky P, Hochreiner G, Forsthuber EP, Fesl C, Greil R; Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol. 2011 Jul;12(7):631-41. doi: 10.1016/S1470-2045(11)70122-X. Epub 2011 Jun 5.

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• Bundred 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.

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• Coleman 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.

  PMID: 20234364 BACKGROUND

• Coleman R, Cameron D, Dodwell D, Bell R, Wilson C, Rathbone E, Keane M, Gil M, Burkinshaw R, Grieve R, Barrett-Lee P, Ritchie D, Liversedge V, Hinsley S, Marshall H; AZURE investigators. Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. Lancet Oncol. 2014 Aug;15(9):997-1006. doi: 10.1016/S1470-2045(14)70302-X. Epub 2014 Jul 15.

  PMID: 25035292 BACKGROUND

• Hasegawa Y, Tanino H, Horiguchi J, Miura D, Ishikawa T, Hayashi M, Takao S, Kim SJ, Yamagami K, Miyashita M, Konishi M, Shigeoka Y, Suzuki M, Taguchi T, Kubota T, Akazawa K, Kohno N; JONIE Study Group. Randomized Controlled Trial of Zoledronic Acid plus Chemotherapy versus Chemotherapy Alone as Neoadjuvant Treatment of HER2-Negative Primary Breast Cancer (JONIE Study). PLoS One. 2015 Dec 3;10(12):e0143643. doi: 10.1371/journal.pone.0143643. eCollection 2015.

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• Ben-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.

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• Valachis A, Polyzos NP, Coleman RE, Gnant M, Eidtmann H, Brufsky AM, Aft R, Tevaarwerk AJ, Swenson K, Lind P, Mauri D. Adjuvant therapy with zoledronic acid in patients with breast cancer: a systematic review and meta-analysis. Oncologist. 2013;18(4):353-61. doi: 10.1634/theoncologist.2012-0261. Epub 2013 Feb 12.

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• Feldt M, Bjarnadottir O, Kimbung S, Jirstrom K, Bendahl PO, Veerla S, Grabau D, Hedenfalk I, Borgquist S. Statin-induced anti-proliferative effects via cyclin D1 and p27 in a window-of-opportunity breast cancer trial. J Transl Med. 2015 Apr 29;13:133. doi: 10.1186/s12967-015-0486-0.

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• Gobel A, Thiele S, Browne AJ, Rauner M, Zinna VM, Hofbauer LC, Rachner TD. Combined inhibition of the mevalonate pathway with statins and zoledronic acid potentiates their anti-tumor effects in human breast cancer cells. Cancer Lett. 2016 May 28;375(1):162-171. doi: 10.1016/j.canlet.2016.03.004. Epub 2016 Mar 8.

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  PMID: 38979716 DERIVED

MeSH Terms

Conditions

Triple Negative Breast Neoplasms

Interventions

Zoledronic Acid; Atorvastatin

Condition Hierarchy (Ancestors)

Breast Neoplasms; 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; Pyrroles; Heptanoic Acids; Fatty Acids; Lipids

Study Officials

• Valter Torri, MD

  Mario Negri Institute for Pharmacological Research Milano (Italy)

  STUDY CHAIR

• Alberto Zambelli, MD

  ASST Papa Giovanni XXIII, Bergamo, Italy

  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

Model Details: After providing informed consent for study participation, patients fulfilling the eligibility criteria will be randomized to receive standard anthracyclines/taxanes based neoadjuvant chemotherapy (ARM A) or the combination of zoledronate and atorvastatin associated with the above mentioned neoadjuvant chemotherapy (ARM B). Randomization will use a biased-coin minimization procedure having as stratification factor the type of neoadjuvant chemotherapy chosen by the center and the p53 level in the FFPE diagnostic core biopsy determined by IHC (\<30% vs \>30% vs unknown). Randomization and e-CFR will be handled by HeavyBase , an Open Source push based "peer to peer" electronic data management system.

Study Record Dates

• First Submitted: November 13, 2017
• First Posted: November 30, 2017
• Study Start: March 5, 2018
• Primary Completion: June 17, 2021
• Study Completion: July 25, 2023
• Last Updated: October 19, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

IT (9)