Multicenter, Randomized, Phase II Study of Neoadjuvant Chemotherapy Associated or Not With Zoledronate and Atorvastatin in Triple Negative Breast Cancers - YAPPETIZER Study
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Enrollment
- 54
- Locations
- 9
- Primary Endpoint
- Proof of concept primary activity endpoint - Efficacy endpoint
Study Overview
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).
Detailed Description
Triple-negative breast cancer (TNBC) is a heterogeneous disease defined by the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Roughly, it represents 15% of all breast cancers. Patients with TNBC are generally younger than the overall population of breast cancer patients and they are more frequently affected by larger and aggressive tumors (i.e. high nuclear-grading), associated with a poor prognosis and with a significant risk of relapse in the first three years after diagnosis. Since the negative expression of HER2 and hormone-receptors, patients affected by TNBC are not candidate for hormonal therapy or anti-HER2 agents, leaving cytotoxic chemotherapy as the only option for systemic therapy.
Despite these common features, TNBCs are characterized by a notable diversity within the group. Histologic variability provides one example of such diversity, with invasive ductal, metaplastic and medullary breast cancers (two very different subtypes of breast cancer) coexisting in this patient population. Furthermore, the TNBC subtype does not directly correspond to a single molecular breast cancer subgroup. Though most fit into the category of basal-like cancers, these groups are overlapping rather than synonymous, with certain populations of ER-positive and HER2-positive tumors also known to express basal-like markers. Indeed, molecular evaluation has identified additional subgroups within the TNBC, confirming the true heterogeneity and complexity of such subtype of breast cancer.
Due to this complex picture of histological and molecular characterization, TNBC still represents a therapeutic challenge for oncologist with several unmet clinical needs. Clearly, there is a need for a better understanding about the biology of TNBC and much more there is an urgent need for therapeutic options in TNBC, ideally in the form of targeted agents. Up to now, the heterogeneity of TNBC has made the achieving of these goals particularly complex. However, the identification of biomarkers able to predict response to systemic therapies is of crucial importance, as it will not only allow for better outcomes in responsive subgroups of TNBC, but also prevent unnecessary exposure of unresponsive patients to ineffective therapy. In this way, predictive biomarkers will facilitate the development of personalized medicine for TNBC.
At present, there is not a clear, proven effective single agent that targets a driving vulnerability in TNBC. However, there are a number of potential therapies currently under investigation that may eventually improve outcomes in these patients. Deep understanding of molecular pathways involved in TNBC carcinogenesis is of paramount importance for identify novel therapeutic options, including the optimal repositioning of drugs already available for clinical intent and potentially active in TNBC, such as the case of platinum salts, PARP-inhibitors (in BRCA mutation) and potentially bisphosphonates and statins, that represent the focus of this study.
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. Clinical trials have shown some positive effects of BPs on patients outcome, reporting an improved Disease Free Survival (DFS) and Overall Survival (OS) in mostly premenopausal early breast cancer patients after a 3-years of treatment with zoledronate and ovarian suppression therapy and a better DFS for immediate use of zoledronate in postmenopausal patients receiving adjuvant hormonal treatment. Moreover, preliminary evidences support the role of zoledronate also in neoadjuvant setting with reported better responses in cases of treatment with zoledronate and chemotherapy compared with chemotherapy alone, suggesting a direct antitumor effect of zol in combination with cht.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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.
Exclusion Criteria
- •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
- •Co-existing active infection or concurrent illness that, at the judgment of the investigator, contra-indicate the inclusion of the patient in the study
- •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
- •Known hypersensitivity to the active substance or to any excipients of atorvastatin. Conditions of rare hereditary problems of galactose intolerance, Lapp lactose deficiency or glucose-galactose malabsorption
- •Anticipation of need for major surgical procedure during the course of the trial
- •Pregnant or breast feeding women.
Arms & Interventions
ARM A - standard NACT
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)
Intervention: Standard neoadjuvant cht (Drug)
ARM B - standard NACT + Zol + atorvastatin
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)
Intervention: Zoledronate (Drug)
ARM B - standard NACT + Zol + atorvastatin
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)
Intervention: Atorvastatin 80mg (Drug)
ARM B - standard NACT + Zol + atorvastatin
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)
Intervention: Standard neoadjuvant cht (Drug)
Outcomes
Primary Outcomes
Proof of concept primary activity endpoint - Efficacy endpoint
Time Frame: At surgery, after 6 months of study treatment
Relative reductions of YAP and TAZ IHC-expression at surgery with respect to core-biopsy analysis.
The proportion of responded patients
Time Frame: After 6 months of study treatment
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.
Secondary Outcomes
- Regulation of YAP and TAZ gene expression by RNA-Seq in tumor tissue - Efficacy endpoint(At surgery, after 6 months of study treatment)
- Study treatment safety - Safety endpoint - AE(From the date of randomization/registration to the end of study, up to 36 months)
- Study treatment safety - Safety endpoint - Maximum grade(From the date of randomization/registration to the end of study, up to 36 months)
- 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)
- Study treatment safety - Safety endpoint - Percentage(From the date of randomization/registration to the end of study, up to 36 months)
- 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)
- Relative reduction of Ki67 in tumor samples - Efficacy endpoint(At surgery, after 6 months of study treatment)