Hormone-receptor-positive Breast CancerPhase 2CLARANCT07676331
Clinical Study of Local and Systemic Biological Impact of GLP1/GIP-Receptor Agonists in Patients With Breast Cancer: The CLARA Trial
A Phase 2 study testing Tirzepatide and Letrozole (Aromatase Inhibitors) in people with Hormone-receptor-positive Breast Cancer and Early Breast Cancer, run by Universitaire Ziekenhuizen KU Leuven.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Hormone-receptor-positive Breast Cancer, Early Breast Cancer
- What is being tested?
- Tirzepatide and Letrozole (Aromatase Inhibitors)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 168 participants
- Where
- No sites listed yet
- Study dates
- 1 Aug 2026to 1 May 2028
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
- 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
- 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.
Show all 15Show fewer
- 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
- All histological subtypes are eligible, including but not limited to invasive breast cancer of no special type (IBC-NST) , invasive lobular carcinoma (ILC) etc.
- Have a BMI of
- ≥30 kg/m2 or
- ≥27 kg/m2 and previously diagnosed with at least 1 of the following weight-related comorbidities:
- 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
- Patient should be able to read/understand Dutch, French or English
- Willing to commit to the study program and comply with all related protocol procedures
- 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.
Who cannot join
- 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)
- Have a history of BC exceptions are made for:
- Contralateral in situ BC without systemic treatment
- Ipsilateral in situ BC without systemic treatment or radiation therapy
- 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
Show all 26Show fewer
- 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
- 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
- Family or personal history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN-2)
- Have a self-reported change in body weight >5 kg within 3 months prior to screening
- Have a prior surgical treatment for obesity, excluding liposuction or abdominoplasty
- Have endoscopic and/or device-based therapy for obesity or have had device removal within the last 6 months prior to screening
- Have renal impairment measured as eGFR <30L/min/1.73m2
- 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
- Have a history of chronic or acute pancreatitis
- Is treated with insulin or other hypoglycaemic drugs
- Participation in another interventional Trial with an investigational medicinal product (IMP) or device in the neoadjuvant setting
- Have obesity induced by other endocrinologic disorders, for example, Cushing syndrome, or diagnosed monogenetic or syndromic forms of obesity
- 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:
- Alanine aminotransferase (ALT) level >3.0x ULN for the reference range
- Alkaline phosphatase (ALP) level >2.0x ULN for the reference range, or
- 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
- Has used systemic hormonal substitution therapy within 2 months before screening
- Has used a GLP1/(GIP)/(GC) Receptor Agonist within 2 months of screening
- Has used medications (prescribed or over-the-counter) within 2 months prior to screening that promote weight loss.
Trial locations and contacts
No sites are listed yet. Contact the study team or a site near you to ask about taking part.
About this study
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.
Read the detailed description
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
- Being tested
- Tirzepatide, Letrozole (Aromatase Inhibitors)
- Keywords
- GLP-1/GIP receptor agonist, tirzepatide, letrozole, Window-of-opportunity trial, Weight-loss drugs
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TirzepatideDrug
Tirzepatide 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)Drug
Letrozole is an nonsteroidal aromatase inhibitor (NSAI). It is an adjuvant endocrine treatment indicated for HR+ breast cancer.
| Study group | Role | What they receive |
|---|---|---|
| Arm A (Control): Immediate surgery | No intervention | Patient undergoes immediate surgery without intervention |
| Arm B: letrozole | Active comparator | 3 weeks of neoadjuvant letrozole 2.5 mg/d Receives: Drug: Letrozole (Aromatase Inhibitors) |
| Arm C: tirzepatide | Active comparator | 3 weeks of neoadjuvant tirzepatide. Cycle 1: 2.5 mg/w Cycle 2: 5 mg/w Cycle 3: 5 mg/w Receives: Drug: Tirzepatide |
| Arm D: letrozole + tirzepatide | Active comparator | 3 weeks of neoadjuvant letrozole 2.5mg/d and tirzepatide:
* Cycle 1: 2.5mg/w
* Cycle 2: 5mg/w
* Cycle 3: 5mg/w Receives: Drug: Tirzepatide; Drug: Letrozole (Aromatase Inhibitors) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: From enrollment till time of surgery (4-5 weeks)
Secondary outcomes (5)
Adherence
Adherence to letrozole and/or tirzepatide assessed as relative dose intensity (RDI)
Measured: From enrollment till time of surgery
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,
Measured: From enrollment till 3 weeks postoperative
Perioperative complications
Perioperative complications graded using the Clavien Dindo Classification [1]
Measured: From time of surgery up till 3 weeks postoperative
ctDNA presence
To evaluate the presence of circulating tumour DNA (ctDNA) at baseline, during treatment and at surgery in plasma samples
Measured: From enrollment till 3 weeks postoperative
ctDNA changes
To evaluate changes between baseline, during treatment and at surgery in plasma samples
Measured: From enrollment till 3 weeks postoperative
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jun 2026
- Study start1 Aug 2026 (estimated)
- Primary completion1 Mar 2028 (estimated)
- Study completion1 May 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hormone-receptor-positive Breast CancerStudies of the same condition, open and under way.
- More trials run by Universitaire Ziekenhuizen KU LeuvenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Window-of-Opportunity trial
- Masking
- None (open label)
- Enrolment
- 168 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Universitaire Ziekenhuizen KU Leuven
- Sponsor type
- University, hospital or other
- Collaborators
- King Baudouin Foundation, KU Leuven
- Responsible party
- Sponsor
- Investigators
- Patrick Neven, MD, PhD, Principal investigator, Universitaire Ziekenhuizen KU Leuven
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07676331
- Sponsor's protocol ID
- S71736
- Other IDs
- 2026-525820-76
- Acronym
- CLARA
- Status last verified
- Jun 2026
- First submitted
- 16 Jun 2026
- Last updated
- 7 Jul 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
1. Dindo et al, 2004, Ann Surg