Clinical Trials /

Pre-operative Zoledronate in Triple Negative Breast Cancer

NCT02347163

Description:

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).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pre-operative Zoledronate in Triple Negative Breast Cancer
  • 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

Clinical Trial IDs

  • ORG STUDY ID: IRFMN-BRC-6591
  • NCT ID: NCT02347163

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
ZoledronateZometaZoledronate

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
ZoledronateExperimentalPatients fulfilling the eligibility criteria will receive a pre-operative, single administration of zoledronate (4mg i.v.), 7 days before definitive breast surgery
  • Zoledronate

Eligibility Criteria

        Inclusion Criteria:

          -  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.

        Exclusion Criteria:

          -  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

               1. Hb< 9.0 g/dL, absolute neutrophil count < 1.5 x 109/L, platelets <100 x 109/L

               2. Total bilirubin > 1.5 x ULN, excluding cases where elevated bilirubin can be
                  attributed to Gilberts Syndrome

               3. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Assessment of zoledronate effect on Ki67 proliferative surrogate biomarker expression, according to p53 expression
Time Frame:18 months
Safety Issue:
Description: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

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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
Measure: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
Safety Issue:
Description: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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mario Negri Institute for Pharmacological Research

Trial Keywords

  • triple neg
  • breast cancer
  • zoledronate
  • mevalonate pathway

Last Updated

November 23, 2017