Targeting the Hippo Transducer TAZ in Breast Cancer With Statins (TRINACRIA)

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)

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.

Study Overview

• Status: Unknown
• Conditions: Breast Neoplasms
• Intervention / Treatment: Drug: Atorvastatin

• Study Type: Interventional
• Enrollment (Anticipated): 78
• Phase: Phase 2

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Regina Elena Cancer Institute

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Anticipated): December 1, 2016
• Study Completion (Anticipated): December 1, 2016

Study Registration Dates

• First Submitted: April 2, 2015
• First Submitted That Met QC Criteria: April 9, 2015
• First Posted (Estimate): April 15, 2015

Study Record Updates

• Last Update Posted (Estimate): April 15, 2015
• Last Update Submitted That Met QC Criteria: April 9, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: Atorvastatin; ki67; TAZ; Hippo pathway
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: 637/15