Targeting the Hippo Transducer TAZ in Breast Cancer With Statins

Study Overview
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Brief Summary
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This pre-surgical, window-of-opportunity study is designed to investigate whether atorvastatin reduces the proliferation marker Ki-67 via modulation of the Hippo transducer TAZ.

Official Title
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A Phase II, Randomized, Non-comparative, Pre-surgical Study of Atorvastatin or Observation in Ki-67 Positive, TAZ-expressing Early Breast Cancer Patients (TRINACRIA Trial)

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Atorvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion: Signed written informed consent Female aged >18 years and <75 years at the time of the enrolment Histologically confirmed Breast Cancer (BC) independently on the intrinsic subtype Stage I-IIa BC patients candidate for elective surgery BC expressing Ki-67 ≥ 15% and TAZ > 10% in diagnostic core biopsies Adequate baseline organ function Negative pregnancy test Exclusion: Previous systemic therapy including chemotherapy, hormone therapy and targeted agents Administration of an investigational drug prior to enrolment History of another malignancy, except for a history of completely resected non-melanoma skin cancer or successfully treated cervical in situ carcinoma Eastern Cooperative Oncology Group (ECOG) performance status ≥2 Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome and asymptomatic gallstones) Serious cardiac illness or medical conditions including but not confined to: history of documented congestive heart failure (CHF) or systolic dysfunction (LVEF <50%); high-risk uncontrolled arrhythmias (ventricular tachycardia, high-grade AV-block, supraventricular arrhythmias which are not adequately controlled); angina pectoris requiring antianginal medication; clinically significant valvular heart disease; evidence of transmural infarction on ECG; poorly controlled hypertension (e.g. systolic >180mm Hg or diastolic >100mm Hg) Have a concurrent disease or condition that may interfere with study participation, or any serious medical disorder that would interfere with the subject's safety (for example, active or uncontrolled infection or any psychiatric condition prohibiting understanding or rendering of informed consent) Current or recent therapy with statins for hypercholesterolemia or other lipid-lowering drugs Current or recent therapy with glucose-lowering drugs for diabetes Current or recent therapy with strong CYP3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, itraconazole) given potential interactions with atorvastatin Current or recent therapy with gemfibrozil or other fibrates given potential interactions with atorvastatin. Patients who are pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Atorvastatin 80 mg/day for 3 weeks | Drug: Atorvastatin<br>* Atorvastatin will be administered at 80 mg/day for 3 weeks in the time window between diagnostic biopsy and curative surgery<br>|
| No Intervention: Arm B<br>Observation | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ki-67 reduction below the 15% (marker response). |  | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • Decreased TAZ expression | Reduced TAZ expression evaluated by IHC when comparing pre- and post-treatment samples. Staining intensity will be graded on a four-grade scale (0: negative, 1: weak, 2: moderate, 3: strong). The final score will be obtained by considering staining intensity, percentage of expressing cells, and localization (nuclear versus cytoplasmic) | 4 weeks | 
| Pathway inhibition | Decreased expression of TAZ targets (AXL and CTGF) and Atorvastatin target (HMGCoAR) evaluated by IHC when comparing pre- and post-treatment samples. Staining intensity for all the molecular endpoints analyzed will be graded on a four-grade scale (0: negative, 1: weak, 2: moderate, 3: strong). | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atorvastatin, TAZ, Hippo pathway, ki67