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Phase Ib/II Study of Zongertinib Combined with Ribociclib and Trastuzumab in Patients with Metastatic ER‑positive/HER2‑positive Breast Cancer

Verified siteRegistered drugNo placebo
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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 people with advanced metastatic breast cancer that has spread to other parts of the body. The cancer cells have two specific features: they have receptors for estrogen (ER) and for a protein called HER2 (ER-positive/HER2-positive). The treatment being tested combines three medicines taken by mouth (zongertinib and ribociclib) with an IV medicine (trastuzumab) and hormone‑blocking therapy (endocrine therapy).

The aim is to find a safe dose of the pill combination and to see whether the whole regimen can keep the cancer from growing for a meaningful period of time. Participants will take the oral tablets each day, receive the IV infusion on a regular schedule, and continue hormone therapy, while doctors check for side effects and for any change in tumor size during regular clinic visits.

Throughout the study, participants will have routine blood tests, heart scans, and imaging scans (such as CT or MRI) to watch for safety signals like reduced heart function or lung inflammation, and to see if the cancer shrinks, stays stable, or grows. The study lasts several months, with visits typically every few weeks, and ends when the treatment is stopped because of disease progression, side effects, or after a predefined period.

The research process

The trial runs in 9 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Baseline Assessment

    Baseline assessment is performed on the first day of treatment. You will undergo physical examinations, blood tests, heart function tests (ECG and LVEF), and imaging studies to document the extent of your disease. These results serve as the reference point for all future evaluations.

  2. Step 2

    Start of First Treatment Cycle

    On Cycle 1 Day 1 (C1D1) you begin the study medication regimen. You will receive an intravenous infusion of trastuzumab and start oral tablets of zongertinib and ribociclib. The oral tablets are taken according to the schedule defined in the study protocol.

  3. Step 3

    Daily Oral Medication

    Each day you will swallow the prescribed tablets of zongertinib and ribociclib. The exact dose and timing are provided by the study team and must be followed consistently throughout the cycle.

  4. Step 4

    Weekly Safety Monitoring

    During the first 28‑day cycle you will visit the clinic once a week for safety checks. These visits include blood work to monitor organ function, an ECG to assess heart rhythm, and an LVEF measurement to evaluate heart pumping ability.

  5. Step 5

    Evaluation of Dose‑Limiting Toxicities

    At the end of the first 28‑day cycle the investigators review all safety data to determine whether any dose‑limiting toxicities (serious side effects that prevent further dose escalation) have occurred. This assessment establishes the maximum tolerated dose for future cycles.

  6. Step 6

    Continuation of Treatment Cycles

    If the first cycle is tolerated, you will continue with additional 28‑day cycles. Each new cycle repeats the same oral medications and intravenous trastuzumab. Imaging studies are performed approximately every eight weeks to evaluate tumor response.

  7. Step 7

    Management of Side Effects

    If side effects become significant, the study protocol allows dose reductions or temporary interruptions of the oral tablets. The study team will guide you on any needed adjustments.

  8. Step 8

    End of Treatment

    Treatment stops when disease progression is documented, unacceptable toxicity occurs, or the study reaches its planned end. The decision is made by the investigator based on clinical and imaging findings.

  9. Step 9

    Post‑Treatment Follow‑Up

    After stopping the study drugs you will have regular follow‑up visits to monitor your health status and to record overall survival and any late side effects.

Who can join the trial?

13 criteria

  • Be 18 years of age or older at the time of signing the consent form.
  • Have metastatic ER‑positive/HER2‑positive breast cancer and have already received at least one HER2‑targeted therapy for advanced disease, including prior treatment with Trastuzumab deruxtecan (T‑DXd).
  • Have a baseline LVEF (left ventricular ejection fraction) of 50% or higher, measured by an echocardiogram (ultrasound of the heart) or a MUGA scan (a special nuclear heart test).
  • If you have a history of treated brain (CNS) metastases, you must have measurable disease outside the brain, no new brain tumor growth after brain‑directed therapy, and you must not have had stereotactic radiation within the past 7 days or whole‑brain radiation within the past 14 days before starting the study.
  • If you are female, you must be postmenopausal, or if still having periods, your estradiol hormone level must be in the postmenopausal range.
  • Have an ECOG performance status of 0 or 1 (fully active or able to carry out light work).
  • Have advanced breast cancer that cannot be cured, confirmed by pathology as ER‑positive (≥10% of cells show estrogen receptor) and HER2‑positive (either IHC 3+ or ISH positive).
  • Be able to provide a new tumor tissue sample preserved as FFPE (formalin‑fixed, paraffin‑embedded) or the most recent stored sample from a metastatic site.
  • Have already received prior treatment with T‑DXd; patients whose cancer returned within 12 months after finishing adjuvant T‑DXd are also eligible.
  • Previous use of CDK4/6 inhibitors, tyrosine‑kinase inhibitors (TKI), and endocrine therapy in any setting is allowed.
  • Have adequate function of major organs (blood, liver, kidneys, etc.).
  • Have disease that can be measured or evaluated with imaging scans.
  • Have a QTcF interval (a heart rhythm measurement corrected by Fridericia’s correction) less than 470 ms for females or less than 450 ms for males.

Who cannot join the trial?

7 criteria

  • Previously taken ribociclib, unless it was used for 21 days or less and stopped for reasons other than cancer progression or severe side effects.
  • Having serious, uncontrolled heart disease or heart rhythm problems, including low or high blood minerals (electrolytes), or taking medicines that can lengthen the QT interval (a part of the heart’s electrical cycle) or cause a dangerous rhythm called Torsades de Pointes (TdP), and those medicines cannot be stopped or replaced.
  • Having uncontrolled high blood pressure with a systolic reading above 180 mmHg, or low blood pressure below 90 mmHg.
  • History of a drop in heart pumping ability (LVEF less than 40%) or symptoms of congestive heart failure while previously receiving trastuzumab.
  • Currently using strong or moderate drugs that block or increase the activity of the enzymes cytochrome P450 (CYP)3A4/5, or affect BCRP or CYP2C8, which can change how the study medicines work.
  • History of non‑infectious interstitial lung disease (ILD) or pneumonitis that required steroids, or any current ILD/pneumonitis of any severity.
  • Severe, ongoing nausea or vomiting, problems absorbing nutrients (malabsorption), chronic gastrointestinal disease, inability to swallow the medication, major bowel surgery, or conditions such as Crohn’s disease, ulcerative colitis, or chronic diarrhea that would prevent the study drugs from being absorbed properly.
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Investigated drugs

  • Zongertinib

    is an experimental oral medication that targets a specific protein involved in the growth of certain breast cancer cells. In this trial it is being tested to see if it can help stop the cancer from growing when given together with other treatments.

  • Ribociclib

    is an oral drug that blocks signals that tell cancer cells to divide. It is used in combination with other medicines in this study to try to keep the tumor from growing and to improve treatment effectiveness.

  • Trastuzumab

    is a targeted therapy given by injection that attaches to the HER2 protein on cancer cells. By binding to HER2, it helps the immune system recognize and destroy the cancer cells. In the trial it is combined with the other drugs to attack HER2‑positive breast cancer.

  • Endocrine therapy

    (also called hormone therapy) uses medicines that lower estrogen levels or block estrogen from acting on cancer cells. Since the tumors in this study are estrogen‑receptor positive, endocrine therapy helps to slow or stop their growth and is given together with the other agents.

What is already known about the treatment

  • Zongertinib

    Zongertinib is taken by mouth as a film‑coated tablet and is currently an investigational drug being studied in early‑phase clinical trials. It is designed to block the activity of the HER2 protein, which helps stop the growth signals that cancer cells use to multiply. By inhibiting this protein, Zongertinib belongs to the class of tyrosine‑kinase inhibitors that target growth‑factor receptors. The medication is being tested for use in patients with advanced ER‑positive/HER2‑positive breast cancer.

  • Ribociclib

    Ribociclib is also taken orally as a film‑coated tablet and is an approved medicine for certain types of breast cancer. It works by stopping two enzymes called CDK4 and CDK6, which are needed for cancer cells to move through the cell‑division cycle. This makes ribociclib a cyclin‑dependent kinase 4/6 inhibitor that helps keep tumor cells from growing. It is used together with hormone therapy and other drugs to treat ER‑positive/HER2‑positive metastatic breast cancer.

Investigated diseases

Metastatic ER‑positive HER2‑positive breast cancer - This disease is a form of breast cancer that grows in response to estrogen and also over‑expresses the HER2 protein. It has spread from the original breast tissue to distant parts of the body such as bone, liver, lung, or brain. Cancer cells continue to divide and form new tumor sites in these organs. Over time the disease can involve additional sites and become more extensive. It is considered advanced because it has progressed despite earlier HER2‑targeted therapy. The condition is followed for changes in tumor size and the appearance of new metastatic lesions.
Trial detailsLast updated 17 Oct 2026
Age18+ yearsPhasePhase ITrial ID2026-526704-67-00Protocol codeSOLTI - 2407Estimated enrolment42 patientsSponsorSolti Group

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