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Efficacy and Safety of Letrozole SIE Compared with Oral Letrozole, Both with Ribociclib, in Postmenopausal Women with HR‑Positive, HER2‑Negative Metastatic Breast Cancer

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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study looks at postmenopausal women with HR-positive, HER2-negative, inoperable locally advanced or metastatic breast cancer. This type of breast cancer grows because of hormones and cannot be removed by surgery. The treatment being tested combines an injectable form of letrozole (a hormone‑blocking medicine) with a pill containing ribociclib, which belongs to a class called CDK4/6 inhibitor. For comparison, another group receives the standard oral tablet called Femara together with the same ribociclib pill. Some participants will receive a harmless substance that looks like the study medicines (placebo) to keep the study blind.

The main goal of the study is to see if the injectable letrozole works better than the oral Femara when both are given with ribociclib. Participants will be randomly assigned to one of the two treatment groups and will take the study medicines for several months, with regular check‑ups to monitor how the cancer is responding and to watch for side effects. The study does not involve any surgical procedures; all medicines are taken by mouth or by a simple injection into the muscle.

After the first dose, participants will return for clinic visits every few weeks during the first few months, then roughly every two to three months for the rest of the study. At each visit doctors will ask about symptoms, perform basic physical exams, and may order imaging tests such as scans to see if the cancer has grown or shrunk. The study continues until the cancer progresses, unacceptable side effects occur, or the participant chooses to stop.

The research process

The trial runs in 7 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Randomization

    After signing the consent form, you are assigned by the study team to one of two treatment groups. the assignment is done by a computer program and you will not know which group you are in.

    The two possible groups are: letrozole SIE injection plus ribociclib, or femara tablet plus ribociclib.

  2. Step 2

    Starting the study medication

    If you are assigned to the femara group, you will take one film‑coated tablet that contains 2.5 mg of letrozole every day by mouth.

    If you are assigned to the letrozole SIE group, you will receive an intramuscular injection of letrozole suspension. the exact amount of letrozole in the injection is not specified in the protocol.

    Regardless of the group, you will also take ribociclib tablets that contain 600 mg of the drug. the tablets are taken by mouth, following the schedule described in the study medication guide.

  3. Step 3

    Baseline assessments

    Before the first dose, the study site will perform a series of tests that may include blood work, imaging scans, and questionnaires about your quality of life. these assessments create a reference point for later comparisons.

  4. Step 4

    Regular treatment visits

    You will return to the clinic at regular intervals that are defined by the study protocol. during each visit you may receive the next letrozole SIE injection if you are in that group, pick up new supplies of oral tablets, and have blood drawn to check safety.

    The study team will also perform imaging studies (for example, CT or MRI scans) to evaluate whether the cancer is stable, shrinking, or growing. these scans are interpreted using standard criteria called RECIST v1.1.

  5. Step 5

    Monitoring for side effects

    At each visit, you will be asked about any new symptoms such as joint pain, muscle pain, or injection‑site reactions. the study staff will record the type, severity, and seriousness of any adverse events.

    If side effects become severe, the study doctor may adjust the dose of the medication or temporarily stop treatment, following the protocol rules.

  6. Step 6

    Continuation criteria

    You will continue taking the assigned oral tablets daily and receiving the injection (if applicable) until one of the following occurs: disease progression as shown by imaging, an adverse event that requires stopping the medication, or the end of the study period.

  7. Step 7

    End of treatment and final assessments

    When treatment stops, the study team will perform a final set of assessments similar to the baseline tests. these include imaging, blood tests, and quality‑of‑life questionnaires to document the overall outcome.

Who can join the trial?

24 criteria

  • Female and at least 18 years old at the time you sign the study consent form.
  • You must have healthy enough blood and organ function, which means:
    • White blood cell count (called ANC) of 1,500 or higher per microliter.
    • Platelet count of 100,000 or higher per microliter.
    • Hemoglobin level (a measure of red blood cells) of 10 g/dL or more.
    • Kidney function measured by eGFR of 60 mL/min/1.73 m² or higher.
    • Liver function tests within normal limits: bilirubin no more than 1.5 times the upper normal range, and the enzymes AST and ALT no more than three times the upper normal range (or five times if you have liver metastases).
    • Blood levels of potassium, calcium, magnesium and phosphorus must be normal for your laboratory.
    • Blood clotting test (INR) must be 1.5 or lower.
    • Any side effects from previous cancer treatments or surgeries must have healed to a mild level (grade 1 or less), except for hair loss or other issues the doctor decides are not a safety risk.
    • Your body‑mass index (BMI) must be between 19 and 39 kg/m².
    • You must be able to understand the study, agree to take part, sign the informed consent, and follow all study procedures.
    • You need a confirmed diagnosis of breast cancer that has returned or spread and cannot be removed or cured with radiation, and for which chemotherapy is not currently recommended.
    • You must be postmenopausal, which can be shown by any one of the following:
      • Both ovaries have been surgically removed and you have had no periods for at least 6 weeks, with a doctor’s note or ultrasound confirming the surgery.
      • Age 60 years or older with no periods for at least 12 months.
      • Under age 60 with no periods for at least 12 months and no recent chemotherapy, tamoxifen, toremifene, or ovarian‑suppressing drugs.
      • Under age 60 with chemotherapy‑induced loss of periods for at least 12 months and blood tests (FSH and estradiol) in the postmenopausal range.
      • Under age 60 while taking tamoxifen with blood tests (FSH and estradiol) in the postmenopausal range.
      • Blood tests for follicle‑stimulating hormone (FSH) and estradiol (17β‑E2) must show levels that match postmenopausal values according to your local lab.
      • Your tumor must be confirmed as estrogen‑receptor (ER) positive and/or progesterone‑receptor (PR) positive, and **HER2** negative.
      • You must be eligible to receive the study medicines letrozole and ribociclib for advanced breast cancer, either because the disease was advanced at first diagnosis or because it returned after earlier hormone therapy.
      • You cannot have received any systemic (whole‑body) cancer therapy for the current advanced disease; you may have had chemotherapy in the past for early‑stage disease, but your cancer must have progressed before joining the study.
      • You need to have disease that can be measured according to the RECIST v1.1 criteria, which means:
        • At least one tumor that can be measured on scans, or
        • At least one bone lesion that can be evaluated (lytic or mixed), but not lesions that are only sclerotic (hard).
        • Your overall health and ability to carry out daily activities must be rated as ECOG performance status 0, 1, or 2 (able to care for yourself and perform most normal activities).

Who cannot join the trial?

23 criteria

  • Advanced cancer that is spreading to vital organs and could cause life‑threatening problems soon (including large fluid build‑up around the lungs, heart, or abdomen, and a condition called pulmonary lymphangitis).
  • History of interstitial lung disease or pneumonitis (lung inflammation or scarring).
  • Any other serious acute or chronic medical or mental health condition, including recent suicidal thoughts, abnormal lab tests or heart tests (ECG) that could raise risk or affect study results.
  • Having an active viral infection such as hepatitis B, hepatitis C, or HIV.
  • History of drug or alcohol dependence.
  • Major surgery, chemotherapy, radiation therapy, any experimental cancer drug, or other cancer treatment within the past 14 days; also, if radiation was given to more than 25 % of bone marrow at any time.
  • Use of bisphosphonates or RANKL inhibitors (medicines that affect bone) that were started or had a dose change within 14 days before randomization; the dose must have been stable for at least 14 days.
  • Use of hormonal medicines or products that change hormone levels (estrogen, progesterone, LH, FSH) within the past 3 months, such as hormone replacement therapy, birth‑control pills, and many supplements for hot flashes.
  • Use of certain medicines or supplements within the past 3 days (or for a period equal to five times the drug’s half‑life, whichever is longer) that strongly affect liver enzymes CYP3A or CYP2A6, including St. John’s wort, strong CYP3A inducers, grapefruit or grapefruit juice (CYP3A inhibitors), and similar agents.
  • Use of any drug that can lengthen the heart’s QT interval or cause a dangerous rhythm called Torsades de Pointes.
  • Taking any other cancer treatment at the same time.
  • Having uncontrolled or symptomatic cancer spread to the brain or spinal cord, or related conditions such as carcinomatous meningitis, spinal cord compression, or leptomeningeal disease, unless previously treated and stable for at least 4 weeks.
  • Participation in another experimental drug study within 30 days (or five drug half‑lives) before randomization.
  • Currently taking part in any other clinical study.
  • Known allergy to letrozole, ribociclib, their ingredients, peanuts, or soy.
  • Difficulty accessing veins for blood draws (venipuncture).
  • Having inflammatory breast cancer.
  • Having another cancer (or a cancer diagnosed within the past 3 years) except for certain skin cancers or fully treated cervical cancer.
  • Active heart disease or a documented history of heart problems such as chest pain (angina), inflammation of the heart lining (pericarditis), heart attack within the past year, Long QT syndrome, severe heart failure (New York Heart Association class III‑IV), cardiomyopathy, severe narrowing of the aortic valve (aortic stenosis), or serious irregular heartbeats within the past year.
  • At screening, any of the following heart measurements abnormal: resting heart rate below 50 beats per minute (bradycardia) or above 90 beats per minute (tachycardia), PR interval over 220 milliseconds, QRS interval over 109 milliseconds, or corrected QT interval (QTcF) 450 milliseconds or higher.
  • Uncontrolled high blood pressure, defined as diastolic pressure ≥ 100 mmHg or systolic pressure ≥ 160 mmHg.
  • History of a painful fracture of the spine, hip, pelvis, wrist, or other major bone that occurred without a fall from standing height (fragility fracture).
  • Bone‑weakening conditions, including genetic bone diseases (osteogenesis imperfecta, Paget’s disease, osteomalacia/rickets), connective‑tissue disorders (Marfan’s syndrome, Ehlers‑Danlos syndrome), very low vitamin D (<10 ng/mL), diseases that affect nutrient absorption (inflammatory bowel disease, gastric bypass surgery), or use of medicines that lower bone density (depo‑medroxyprogesterone acetate, raloxifene, certain seizure medicines) within 14 days before randomization.
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Investigated drugs

  • Letrozole (Femara)

    is an oral tablet taken by mouth. In this study it is used as a standard treatment to lower estrogen levels in postmenopausal women with certain types of breast cancer. Lowering estrogen helps slow the growth of tumors that need this hormone to grow.

  • Letrozole SIE

    is a suspension that is injected into a muscle. It contains the same active ingredient as Femara but is given by injection instead of a tablet. The trial is testing whether this injectable form works as well or better than the oral tablet when both are combined with another cancer drug.

  • Ribociclib (Kisqali)

    is a pill taken by mouth that blocks proteins called CDK4 and CDK6, which cancer cells need to multiply. In the trial every participant receives ribociclib together with either the oral letrozole tablet or the injectable letrozole, to see how the combination affects cancer progression.

What is already known about the treatment

  • Letrozole

    This medication is given either as a 2.5 mg film‑coated tablet taken by mouth or as a suspension that is injected into a muscle. It is an approved drug that has been studied for many years and is listed in the medical literature as a standard treatment for certain breast cancers. It is used mainly for postmenopausal women whose breast cancer is hormone‑receptor positive and HER2‑negative, especially when the disease cannot be removed by surgery. Letrozole works by blocking the enzyme aromatase, which stops the body from making estrogen, and it belongs to the class of non‑steroidal aromatase inhibitors, a type of hormone therapy.

  • Ribociclib

    This drug comes as a film‑coated tablet that is swallowed whole. It is an approved cancer medicine that has been widely reported in clinical studies and is used together with hormone therapies for breast cancer. The main use is for postmenopausal women with hormone‑receptor‑positive, HER2‑negative breast cancer that is advanced or has spread. Ribociclib blocks proteins called CDK4 and CDK6, which are needed for cancer cells to divide, and it is classified as a CDK4/6 inhibitor, a form of targeted cancer therapy.

Investigated diseases

Hormone receptor‑positive, HER2‑negative, inoperable locally advanced or metastatic breast cancer - It is a form of breast cancer that grows in response to hormones such as estrogen or progesterone but lacks excess HER2 protein. The tumor cannot be removed by surgery because it has spread beyond the breast or involves surrounding tissues. It may first appear as a large, non‑resectable mass and later spread to distant sites such as bone, liver, or lungs. As the disease advances, the cancer cells continue to multiply and can cause new symptoms in the affected organs. Ongoing imaging is used to track changes in tumor size and spread.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2025-524846-85-00Protocol codeROV-SIE-2025-02Estimated enrolment300 patientsSponsorLaboratorios Farmaceuticos Rovi S.A.

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