Multicenter, Randomized, Phase II Study of Neoadjuvant Chemotherapy Associated or Not With Zoledronate and Atorvastatin in Triple Negative Breast Cancers - YAPPETIZER Study

IRFMN-BRC-7103

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).

2018-03-05

2021-06-17

2023-07-25

Completed

Early phase I

54

Inclusion Criteria: 1. Histologically confirmed diagnosis of non-metastatic operable TNBC subjected to diagnostic core biopsy 2. TNBC defined as HER2/ER/PgR negative receptors 3. Female, aged ≥ 18 years 4. ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1 5. 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) 6. Availability of paraffin-embedded tumor block (FFPE) taken at diagnostic biopsy for IHC and RNA-Seq molecular determinations 7. 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 8. Written informed consent signed prior to enrolment according to ICH/GCP. Exclusion Criteria: 1. Presence of metastatic disease 2. Previous investigational treatment for any condition within four weeks prior to study registration 3. Treatment with bisphosphonates, denosumab or other drug that, in the investigator's judgment, affects bone metabolism 4. Treatment with statins or other drugs that, in the investigator's judgment, potentially affect the mevalonate pathway 5. Any previous treatment for the currently diagnosed breast cancer, including radiation therapy, chemotherapy, biotherapy and/or hormonal therapy 6. 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 4. Creatinine \> 1.2 x ULN, calcium \< 8.6 mg/dL 7. Co-existing active infection or concurrent illness that, at the judgment of the investigator, contra-indicate the inclusion of the patient in the study 8. Active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal 9. Co-existing dental diseases that form a contraindication to the use of zol 10. Any medical or other condition that in the Investigator's opinion renders the patient unsuitable for this study due to unacceptable risk 11. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study assessment and procedures 12. Known hypersensitivity to the active substance, to other bisphosphonates or to any excipients of zoledronate 13. 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 14. Anticipation of need for major surgical procedure during the course of the trial 15. Pregnant or breast feeding women.

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE2'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'PARALLEL', 'interventionModelDescription': '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).\n\nRandomization 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).\n\nRandomization and e-CFR will be handled by HeavyBase , an Open Source push based "peer to peer" electronic data management system.', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'NONE'}}, 'enrollmentInfo': {'count': 54, 'type': 'ACTUAL'}}

2023-10-19