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Gedatolisib with drug combination versus standard therapy as first‑line treatment for patients with advanced HR‑positive HER2‑negative 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 focuses on patients with advanced breast cancer that is HR-positive and HER2-negative. Two patterns of disease behavior are considered: cancer that no longer responds to hormone therapy (endocrine-resistant) and cancer that still responds (endocrine-sensitive). The experimental regimen uses the investigational drug gedatolisib, given by intravenous infusion, together with the oral medicines palbociclib and fulvestrant (or with letrozole in the hormone‑responsive group). The comparison regimen uses the standard oral drug ribociclib combined with fulvestrant or letrozole, with fulvestrant administered as an intramuscular injection and the other medicines taken by mouth as oral tablets.

The purpose of the study is to compare how well the new combination controls the disease versus the standard combination. Participants are randomly assigned to one of the two treatment groups and receive their assigned medicines in repeated cycles for several months. Regular clinic visits are scheduled for safety checks, blood tests, and imaging scans to monitor the cancer.

Doctors will use scans to see if the cancer grows. The main outcome measured is the length of time the cancer does not get worse, called progression free survival, and overall survival, which is the time from start of treatment until death from any cause. These measures help determine whether the new treatment offers a benefit over existing therapy.

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

    Randomization and Assignment to Treatment Group

    After joining the study, you are randomly placed into one of four possible treatment groups. The groups are defined by the combination of medicines you will receive: either gedatolisib with palbociclib and fulvestrant, gedatolisib with palbociclib and letrozole, ribociclib with fulvestrant, or ribociclib with letrozole. The random assignment ensures that the comparison between groups is unbiased.

  2. Step 2

    Baseline Screening and Assessments

    Before any medication is started, you undergo a series of baseline examinations. These include a physical examination, blood tests to check organ function, and imaging studies such as scans to document the current extent of the cancer. The results establish a reference point for later comparisons.

    All baseline procedures are performed according to the study protocol and are required to confirm eligibility for continued participation.

  3. Step 3

    Initiation of Study Medications

    On the first day after randomization, you begin taking the study medicines assigned to your group. Oral medicines (palbociclib, ribociclib, letrozole) are taken by mouth in tablet form at the doses listed in the protocol: palbociclib 125 mg, ribociclib 600 mg, and letrozole 2.5 mg each day.

    If your group includes fulvestrant, you receive a 500 mg intramuscular injection, which is administered into a muscle by a healthcare professional.

    If your group includes gedatolisib, you receive a 180 mg intravenous infusion, which is delivered through a vein over a short period under medical supervision.

  4. Step 4

    Ongoing Medication Administration Schedule

    Oral tablets are taken daily as directed, usually at the same time each day, unless the protocol specifies a treatment cycle (for example, three weeks on treatment followed by one week off).

    The fulvestrant injection is repeated at intervals defined by the protocol, commonly every four weeks after the initial loading doses.

    The gedatolisib infusion is given on the same schedule as the oral tablets, typically every three weeks, but the exact timing follows the study’s detailed schedule.

  5. Step 5

    Regular Clinic Visits for Safety Monitoring

    You attend clinic visits at regular intervals, usually every three weeks, to allow the study team to assess your health. During each visit, vital signs are measured, and blood samples are taken to monitor organ function and detect any side effects.

    You are asked to report any symptoms you experience, such as nausea, fatigue, or mouth irritation. If necessary, a dexamethasone mouthwash containing 4 mg may be prescribed to help reduce oral side effects.

  6. Step 6

    Imaging Assessments to Evaluate Disease Status

    Imaging studies, such as CT or MRI scans, are performed at scheduled intervals (often every eight weeks) to determine whether the cancer is stable, responding, or progressing.

    The evaluation follows the RECIST (Response Evaluation Criteria in Solid Tumors) guidelines, which provide standardized criteria for measuring tumor changes.

  7. Step 7

    Management of Side Effects and Supportive Care

    If laboratory results or clinical observations indicate toxicity, the study team may adjust the dose of the oral tablets, delay the next dose, or temporarily stop treatment until the issue resolves.

    Supportive medications, such as anti‑nausea drugs or the dexamethasone mouthwash, may be provided to alleviate side effects.

  8. Step 8

    Continuation Criteria and Possible Discontinuation

    You continue receiving the assigned medicines until one of the following occurs: documented disease progression on imaging, unacceptable toxicity despite dose adjustments, withdrawal of consent, or completion of the study period.

    The decision to stop treatment is made by the study physician based on the predefined criteria in the protocol.

  9. Step 9

    End‑of‑Study Procedures

    When treatment ends, you undergo a final set of assessments similar to the baseline examinations, including blood tests and imaging, to document the final disease status.

    The study team will discuss the results with you and provide information on further medical care options outside the trial.

Who can join the trial?

23 criteria

  • Be an adult aged 18 or older (19 or older if you live in the Republic of Korea).
  • Have a life expectancy of more than 6 months, as judged by your doctor.
  • Be able to start the study treatment at least 2 weeks after any major surgery or radiation therapy, and be fully recovered from any side effects of those procedures.
  • Have stopped any previous cancer medicines for at least 2 weeks (or longer if the drug stays in the body longer) and stopped any antibody‑based treatments for at least 4 weeks, and have recovered from any side effects to a mild level (grade ≤ 1), except for hair loss.
  • Have adequate bone marrow (blood‑forming tissue), liver (hepatic), kidney (renal), and blood‑clotting (coagulation) function, as defined by the study protocol.
  • Be willing and able to follow the study schedule, including clinic visits, lab tests, and other required procedures.
  • Understand that the study is experimental and sign an informed consent form (or have a legally authorized representative sign, if allowed by law).
  • Meet one of the following hormone‑status requirements:
    • Be a postmenopausal woman (as defined in the study).
    • Be a pre‑ or perimenopausal woman who has had menopause induced medically with drugs such as goserelin or leuprolide.
    • Be a man who receives a hormone‑suppressing injection (luteinizing hormone‑releasing hormone agonist) and uses contraception for up to 2 years after stopping the study treatment.
    • Have a negative pregnancy test if you could become pregnant, and use birth control as recommended for up to 2 years after stopping the study treatment.
    • Have a confirmed diagnosis of HR+/HER2‑ breast cancer that is advanced (cannot be removed by surgery) or has spread to other parts of the body (metastatic).
    • Show disease progression that fits the study’s definition:
      • For the “endocrine‑resistant” group (Study 1): cancer grew while you were on hormone therapy after surgery (adjuvant endocrine therapy) or within 12 months after finishing that therapy. “Primary resistance” means the cancer came back within the first 2 years of hormone therapy; “secondary resistance” means it came back after 2 years or within 12 months after finishing therapy.
      • For the “endocrine‑sensitive” group (Study 2): cancer came back at least 12 months after finishing at least 2 years of hormone therapy, or you have newly metastatic disease without any prior hormone therapy.
      • May have had certain prior cancer treatments, if allowed:
        • Previous hormone therapy such as an aromatase inhibitor or tamoxifen.
        • Previous fulvestrant (another hormone drug) for less than 6 months.
        • Previous chemotherapy.
        • Previous CDK4/6 inhibitor (a drug that blocks a specific cell‑growth pathway) if your cancer progressed more than 6 months after finishing it (Study 1) or more than 12 months after finishing it (Study 2).
        • Have a confirmed estrogen‑receptor‑positive and/or progesterone‑receptor‑positive tumor, according to standard pathology guidelines.
        • Have a confirmed HER2‑negative tumor by immunohistochemistry; if the test result is borderline (+2), a further genetic test must be done.
        • Have measurable disease on imaging scans according to RECIST v1.1 criteria; if the disease is only in bone, you must have at least one bone lesion that includes a soft‑tissue part that can be measured (purely blastic bone lesions are not allowed).
        • Agree to provide a fresh tumor biopsy, an older tumor tissue sample, or a blood sample for a central test that looks for a PIK3CA gene mutation.
        • Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, meaning you are fully active (0) or capable of self‑care and up‑and‑about for most daily activities (1‑2).

Who cannot join the trial?

18 criteria

  • Having another active cancer at the same time (concurrent malignancies), except for cured non‑melanoma skin cancer or in‑situ cervical cancer.
  • Additional exclusion rule (criterion 10) is described in the study protocol.
  • History of lung inflammation caused by drugs or radiation (interstitial lung disease or pneumonitis) or liver inflammation (hepatitis).
  • Unable to swallow tablets or capsules, or has a condition that prevents proper absorption of nutrients (malabsorption) such as inflammatory bowel disease or a very short intestine.
  • Known allergy (hypersensitivity) to any of the study medicines or their inactive ingredients.
  • The investigator believes the person cannot follow the study treatment or meet study requirements.
  • Current uncontrolled medical, mental health, or social problems that could interfere with participation.
  • Being under legal custody or institutional order, if required by local regulations.
  • Pregnant or breastfeeding females.
  • Participating in another interventional clinical trial at the same time.
  • Previously treated with a PI3K inhibitor, AKT inhibitor, mTOR inhibitor, or any other selective estrogen receptor degrader (SERD) except fulvestrant, in the (neo)adjuvant setting (treatment given before or after surgery).
  • Previously received any systemic anticancer therapy (whole‑body chemotherapy or hormone therapy) for advanced breast cancer.
  • Having type 1 diabetes, or type 2 diabetes that is not controlled and requires daily insulin injections.
  • Active human immunodeficiency virus (HIV) infection; only those with well‑controlled HIV and a CD4+ T‑cell count greater than 350 cells/µL may be allowed.
  • Active hepatitis B or C infection unless it is fully controlled by medication; eligibility depends on specific test results such as negative surface antigen or negative PCR.
  • Untreated or active cancer spread to the brain or the membranes covering the brain (leptomeningeal metastases); previously treated brain metastases are allowed only if no steroids are needed, no recent seizures, and no worsening neurological function in the past 28 days.
  • Advanced, symptom‑causing spread of cancer to internal organs that could cause life‑threatening problems soon, such as uncontrolled fluid buildup (effusions) in the chest (pleural), heart lining (pericardial), or abdomen (peritoneal) that requires repeated drainage.
  • History of significant heart or blood‑vessel problems (cardiovascular abnormalities) as defined in the study protocol.
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Investigated drugs

  • Gedatolisib

    is an experimental drug given through an IV infusion. It belongs to a group of medicines that aim to block signals that help cancer cells grow and survive. In this study it is being tested to see if adding it to other breast‑cancer medicines can improve how long the disease stays under control.

  • Fulvestrant

    is an injectable hormone therapy that works by lowering the amount of estrogen that can stimulate certain breast cancers. It is given as a shot into the muscle and is used in patients whose tumors grow because of estrogen.

  • Palbociclib

    is an oral tablet that blocks proteins called CDK4 and CDK6, which are important for cancer cells to divide. By stopping these proteins, the drug helps slow down the growth of hormone‑sensitive breast cancer.

  • Ribociclib

    is also an oral tablet that inhibits CDK4 and CDK6, working in a similar way to palbociclib. It is used together with hormone therapy to keep the cancer from growing quickly.

  • Letrozole

    is a pill taken by mouth that reduces the body’s production of estrogen. It belongs to a class of drugs called aromatase inhibitors and is used to treat breast cancers that need estrogen to grow.

  • Dexamethasone

    is a steroid that can be given as a mouthwash or a soluble tablet. In this trial it is used as background medication to help manage side effects and reduce inflammation that may occur with the cancer treatments.

What is already known about the treatment

  • Fulvestrant

    Fulvestrant is given as an intramuscular injection in a pre‑filled syringe. It is an approved drug used for hormone‑receptor positive breast cancer that no longer responds to other hormone treatments. It works by binding to estrogen receptors and causing them to break down, which stops the cancer cells from growing. It belongs to the class of selective estrogen receptor degraders (SERDs).

  • Palbociclib

    Palbociclib is taken as an oral film‑coated tablet. It is an approved medication for hormone‑receptor positive, HER2‑negative advanced breast cancer, usually together with hormone therapy. It blocks the activity of proteins called CDK4 and CDK6, which are needed for cancer cells to divide. It is classified as a CDK4/6 inhibitor.

  • Ribociclib

    Ribociclib is also taken as an oral film‑coated tablet. It is approved for the same type of breast cancer as palbociclib and is used together with hormone therapy. Like palbociclib, it stops CDK4 and CDK6 enzymes from helping cancer cells multiply. It belongs to the CDK4/6 inhibitor drug class.

  • Letrozole

    Letrozole comes as an oral film‑coated tablet. It is an approved aromatase inhibitor used for hormone‑receptor positive breast cancer, especially after menopause. It reduces the amount of estrogen made by the body, which slows the growth of estrogen‑dependent tumors. Its pharmacological class is aromatase inhibitor.

  • Dexamethasone

    Dexamethasone is given as a mouthwash or soluble tablet for oral use. It is a widely used corticosteroid that is approved for many conditions, including inflammation and as a supportive drug in cancer therapy. It works by calming the immune system and reducing swelling. It is classified as a glucocorticoid steroid.

  • Gedatolisib

    Gedatolisib is administered by intravenous infusion of a powder that is mixed into a solution. It is an investigational drug currently being studied in clinical trials for advanced breast cancer. It blocks two key pathways, PI3K and mTOR, that many cancer cells use to grow and survive. It is classified as a PI3K/mTOR inhibitor.

Investigated diseases

  • Endocrine‑resistant hormone receptor‑positive, HER2‑negative advanced breast cancer

    This disease is a type of breast cancer that grows in response to hormones such as estrogen or progesterone and does not overexpress the HER2 protein. It has spread beyond the breast to other parts of the body, classifying it as advanced. The cancer cells no longer respond to hormonal therapies that previously slowed their growth, indicating resistance. As the disease progresses, tumors may increase in size or appear in new locations. Imaging studies are used to monitor this growth over time.

  • Endocrine‑sensitive hormone receptor‑positive, HER2‑negative advanced breast cancer

    This disease is a hormone‑driven breast cancer without HER2 overexpression that has spread to distant sites. The cancer cells still respond to hormonal signals, making them sensitive to endocrine therapy. Over time, the tumors can enlarge or form new metastatic lesions if left untreated. The disease course is monitored by regular scans to track changes in tumor burden.

Trial detailsLast updated 29 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2024-518933-28-01Protocol codeCELC-G-302Estimated enrolment935 patientsSponsorCelcuity Inc.

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