The CLARA trial is a phase II window-of-opportunity trial evaluating how a commonly used weight-loss medication (tirzepatide, a GLP-1/GIP receptor agonist) affects breast cancer biology, alone and in combination with standard hormone therapy (letrozole).
The main goal is to determine whether tirzepatide, alone or combined with letrozole, reduces tumor cell growth.
Voluntary written informed consent of the participant has been obtained prior to any screening procedures
Patient is >18 years of age
Patient is postmenopausal, as defined per local practice
Tumour size of ≥1 cm
Have Type 1 or 2 diabetes mellitus, history of ketoacidosis, or hyperosmolar state or coma.
Have at least 1 laboratory value suggestive of diabetes during screening : HbA1c ≥6.5% (≥48 mmol/mol) or fasting glucose ≥126 mg/dL (≥7.0 mmol/L)
Contralateral in situ BC without systemic treatment
Ipsilateral in situ BC without systemic treatment or radiation therapy
Parallel
Tirzepatide
DrugTirzepatide is a GIP and GLP-1R agonist. It is approved by FDA and EMA as a weight-loss drug for patients with BMI ≥30 kg/m2 or ≥27 kg/m2 and previously diagnosed with at least 1 weight-related comorbidity.
Letrozole (Aromatase Inhibitors)
DrugLetrozole is an nonsteroidal aromatase inhibitor (NSAI). It is an adjuvant endocrine treatment indicated for HR+ breast cancer.
Ki67 proliferation marker
The primary endpoint is the mean change in log-transformed KI67 expression values between baseline and time of surgery in the different arms
Adherence
Adherence to letrozole and/or tirzepatide assessed as relative dose intensity (RDI)
Adverse Event profile
The type, incidence, severity (as graded by the National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] v6.0), seriousness, time till onset and duration of Adverse Events (AEs)/SAEs and any laboratory abnormalities. This will be assessed by clinical history, blood tests and clinical examination at each cycle. Following surgery, patients will be followed for 14 days for AEs. Except surgical complications will be logged till 30 days after surgery. All surgical complications will be classified using CTCAE v6.0 and Clavien dindo,
Perioperative complications
Perioperative complications graded using the Clavien Dindo Classification \[1\]
ctDNA presence
To evaluate the presence of circulating tumour DNA (ctDNA) at baseline, during treatment and at surgery in plasma samples
Fatigue
Change in fatigue assessed using the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue V4.0 questionnaire. The FACIT fatigue V4.0 score ranges from 0 to 52. Higher scores equal lower fatigue levels.
Body composition changes
As evaluated with bioimpedance measurements performed weekly till time of surgery and then repeated once at 3 weeks postoperatively.
Change in genomic risk score
PONV
Postoperative nausea and vomiting (PONV) will be measured using the simplified PONV impact scale
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Universitaire Ziekenhuizen KU Leuven
Lead sponsor
King Baudouin Foundation
Collaborator
KU Leuven
Collaborator
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