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.

CLARA is a randomized, controlled, phase IIb window-of-opportunity trial designed to evaluate the biological effects and safety of tirzepatide, alone or in combination with letrozole, in postmenopausal women with hormone receptor-positive (HR+), HER2-negative, treatment-naïve breast cancer scheduled for primary surgery, who meet the EMA-approved obesity criteria for tirzepatide prescription (BMI ≥30 kg/m² or BMI ≥27 kg/m² with weight-related comorbidities).

168 participants will be randomized equally into four arms: Arm A (Control): Immediate surgery Arm B: 3 weeks of neoadjuvant letrozole alone Arm C: 3 weeks of neoadjuvant tirzepatide alone Arm D: 3 weeks of neoadjuvant tirzepatide combined with letrozole

Primary objective is to compare anti-proliferative tumor response in patients receiving immediate surgery, GLP1/GIP RA, letrozole and combined treatment.

Secondary objectives are:

• To compare adherence to the GLP1/GIP RA, letrozole and combined treatment.
• To compare safety
• To compare perioperative complications
• To explore the feasibility and utility of circulating tumour DNA (ctDNA) in plasma samples collected throughout the study.

Exploratory objectives are:

• To compare fatigue
• To compare body composition changes
• To compare changes in genomic risk score
• To compare postoperative nausea and vomiting
• To compare gastric emptying delays prior to surgery
• To compare anti-proliferative tumor response as complete cell cycle arrest (CCCA)
• To compare endocrine response
• To compare concentrations of letrozole
• To compare impact of stress on tumor biology and on clinical and biological effects of treatment

Inclusion Criteria:

1. Voluntary written informed consent of the participant has been obtained prior to any screening procedures

2. Patient is >18 years of age

3. Patient is postmenopausal, as defined per local practice

4. Tumour size of ≥1 cm

5. The patient has a biopsy-confirmed diagnosis of GII-III ER+, HER2 - early stage breast cancer scheduled for primary surgery as per standard-of-care

   1. To fulfil the requirement for HR+ disease by local testing on primary disease specimen, tumour must be ER positive defined by immunohistochemistry (IHC) according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for hormone receptor testing.
   2. To fulfil the requirement of HER2- disease by local testing on primary disease specimen, tumour must be HER2- according to ASCO/CAP guidelines for HER2 testing
   3. All histological subtypes are eligible, including but not limited to invasive breast cancer of no special type (IBC-NST) , invasive lobular carcinoma (ILC) etc.

6. Have a BMI of

   1. ≥30 kg/m2 or
   2. ≥27 kg/m2 and previously diagnosed with at least 1 of the following weight-related comorbidities:

   i. Hypertension: treated or with systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg ii. Dyslipidaemia: treated or with LDL ≥160 mg/dL (4.1 mmol/L) or triglycerides ≥150 mg/dL (1.7 mmol/L), or HDL iii. Obstructive sleep apnoea iv. Cardiovascular disease, for example, ischemic cardiovascular disease, New York Heart Association Functional Classification Class I-III heart failure

7. Patient should be able to read/understand Dutch, French or English

8. Willing to commit to the study program and comply with all related protocol procedures

9. Willing to undergo a new biopsy of the breast lesion in case no formalin-fixed paraffin-embedded (FFPE) block can be made available for the trial.

Exclusion Criteria:

1. Have Type 1 or 2 diabetes mellitus, history of ketoacidosis, or hyperosmolar state or coma.

2. 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)

3. Have a history of BC exceptions are made for:

   1. Contralateral in situ BC without systemic treatment
   2. Ipsilateral in situ BC without systemic treatment or radiation therapy

4. Have a history of an additional invasive malignancy that is progressing or that has required active treatment in the 3 years prior to breast cancer diagnosis. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer

5. Are receiving or has received within 3 months prior to screening systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, intra-articular, or inhaled preparations) or have evidence of a significant, active autoimmune that has required (within the last 3 months) or is likely to require, in the opinion of the investigator, concurrent treatment with systemic treatment (such as glucocorticoids (excluding topical, intraocular, intranasal, intra-articular, or inhaled preparations)) during the course of the study.

   Note: Replacement therapy with thyroxine is not a contraindication for inclusion if patient is already on same dose for 3 months

6. Have a history of any other condition, such as known drug or alcohol abuse, diagnosed eating disorder, or other psychiatric disorder, that, in the opinion of the investigator, may preclude the participant from following and completing the protocol

7. Family or personal history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN-2)

8. Have a self-reported change in body weight >5 kg within 3 months prior to screening

9. Have a prior surgical treatment for obesity, excluding liposuction or abdominoplasty

10. Have endoscopic and/or device-based therapy for obesity or have had device removal within the last 6 months prior to screening

11. Have renal impairment measured as eGFR <30L/min/1.73m2

12. Have a known clinically significant gastric emptying abnormality (for example, severe gastroparesis or gastric outlet obstruction) or chronically take drugs that directly affect GI motility

13. Have a history of chronic or acute pancreatitis

14. Is treated with insulin or other hypoglycaemic drugs

15. Participation in another interventional Trial with an investigational medicinal product (IMP) or device in the neoadjuvant setting

16. Have obesity induced by other endocrinologic disorders, for example, Cushing syndrome, or diagnosed monogenetic or syndromic forms of obesity

17. Has acute or chronic hepatitis, signs and symptoms of any other liver disease other than NAFLD, or any of the following, as determined by the central laboratory during screening:

    1. Alanine aminotransferase (ALT) level >3.0x ULN for the reference range
    2. Alkaline phosphatase (ALP) level >2.0x ULN for the reference range, or
    3. Total bilirubin level >1.5x ULN for the reference range (except for cases of known Gilbert's Syndrome) Note: Participants with non-alcoholic fatty liver disease (NAFLD) are eligible to participate in this trial if their ALT level is ≤3.0x ULN for the reference range

18. Has used systemic hormonal substitution therapy within 2 months before screening

19. Has used a GLP1/(GIP)/(GC) Receptor Agonist within 2 months of screening

20. Has used medications (prescribed or over-the-counter) within 2 months prior to screening that promote weight loss.