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Gedatolisib plus drug combination for HR‑positive, HER2‑negative advanced breast cancer patients whose disease progressed after CDK4/6 inhibitor therapy

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 trial focuses on HR‑positive, HER2‑negative advanced breast cancer, a form of breast cancer that grows because of hormone signals and does not have excess HER2 protein. All participants have already received a CDK4/6 inhibitor together with a non‑steroidal aromatase inhibitor (AI) therapy, but their disease has continued to grow. The study evaluates a new drug called gedatolisib, given together with the oral medicine palbociclib and the injection fulvestrant. For patients whose tumors have a change in the PIK3CA gene, the standard comparison drug is alpelisib combined with fulvestrant. The trial includes two groups based on whether the tumor is PIK3CA wild type (no mutation) or PIK3CA‑mutated (has the mutation).

The purpose of the study is to see if the new combination can keep the cancer from getting worse for a longer time than the standard treatments. Participants are randomly assigned to receive either the new three‑drug regimen or the standard therapy, and they take the medicines in repeated cycles while visiting the clinic for regular check‑ups and imaging scans. The main result being measured is progression‑free survival (PFS), which means the time until the cancer grows or the patient dies, and it is evaluated using standard imaging rules called RECIST and analyzed with the Kaplan‑Meier statistical method. Safety and side‑effects are recorded and graded according to the CTCAE system.

The research process

The trial runs in 6 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Randomization and arm assignment

    After enrollment, a computer assigns the patient to one of the study arms based on the trial design.

    The assigned arm determines which medicines will be received during the trial.

  2. Step 2

    Baseline assessments

    Clinical evaluation, laboratory tests, and imaging are performed to document disease status before treatment.

    Questionnaires about health‑related quality of life are completed.

  3. Step 3

    Initiation of study medication

    According to the assigned arm, the following medicines are taken or administered:

    gedatolisib 180 mg as a powder for intravenous infusion.

    palbociclib 125 mg film‑coated tablet taken orally.

    fulvestrant 500 mg solution for intramuscular injection.

    alpelisib 300 mg film‑coated tablet taken orally.

    The exact schedule for each medication is defined by the study protocol.

  4. Step 4

    Regular clinic visits

    At each visit, safety labs and physical examinations are performed.

    Imaging studies are done periodically to assess disease progression.

    The patient completes quality‑of‑life questionnaires.

  5. Step 5

    Continuation of treatment

    Medications are continued as long as the disease does not progress and side effects are manageable.

    The study team may adjust dose or pause treatment according to safety guidelines.

  6. Step 6

    End‑of‑treatment assessment

    When disease progression, unacceptable toxicity, or study completion occurs, a final evaluation is performed.

    Final imaging, laboratory tests, and questionnaires are collected.

    Overall survival and progression‑free survival data are recorded for analysis.

Who can join the trial?

25 criteria

  • Be 18 years of age or older.
  • Women must be postmenopausal (no periods for at least 12 months) or have medically‑induced menopause using specific hormone‑blocking medicines; men must use an effective birth‑control method during the study and for one year after the last dose.
  • Have breast cancer that has gotten worse while taking a CDK4/6 inhibitor together with a non‑steroidal aromatase inhibitor (a type of hormone therapy).
  • All side effects from previous cancer treatments or surgeries must have improved to mild or none (grade 1 or lower) except hair loss.
  • Heart function must be adequate, shown by a left ventricular ejection fraction of 50 % or higher on an initial heart test.
  • At least 2 weeks must have passed since the last targeted or hormonal therapy or major surgery, and at least 3 weeks since any immunotherapy or radiation, with any side effects now mild (grade 1 or lower) except hair loss.
  • Blood and organ tests must be within normal limits or only slightly abnormal:
    • White blood cell count (neutrophils) at least 1.5 × 10⁹ per liter.
    • Hemoglobin (a measure of red blood cells) at least 9.0 g/dL.
    • Platelet count at least 100 × 10⁹ per liter.
    • Kidney function (creatinine clearance) greater than 50 mL/min.
    • Liver enzymes (AST and ALT) no more than 2.5 times the normal upper limit (or up to 5 times if liver metastases are present).
    • Total bilirubin no more than 1.5 times the normal upper limit.
    • Blood clotting time (PT/INR) within normal range if not on blood thinners.
    • Electrolytes (potassium, calcium, magnesium) within normal range.
    • Pancreatic enzymes (amylase and lipase) no more than 1.5 times the normal upper limit unless there are no signs of pancreatitis.
    • Be willing and able to follow the study schedule for visits, treatments, lab tests, and other procedures.
    • Understand that the treatment is experimental and be able to sign an informed consent form.
    • Women who could become pregnant must have a negative pregnancy test and use effective birth‑control from screening until one year (or two years for fulvestrant) after the last dose.
    • Have a confirmed diagnosis of metastatic or locally advanced breast cancer based on tissue examination.
    • The cancer must be positive for estrogen and/or progesterone receptors (hormone‑driven) as determined by standard lab testing.
    • The cancer must be negative for HER2 (a protein that can drive cancer growth) according to standard testing; if the test result is unclear, an additional test is required.
    • Enough tumor tissue must be available to test for the PIK3CA gene status (whether it is mutated or not) using a specific PCR test.
    • There must be documented progression of disease on imaging scans after the most recent treatment, and the disease must be measurable according to standard criteria (RECIST v1.1). For bone‑only disease, at least one bone lesion must have a soft‑tissue component that can be measured.
    • Have an ECOG performance status of 0 or 1, meaning you are fully active or restricted in physically strenuous activity but able to carry out light work.
    • Have an expected life expectancy of at least 3 months.

Who cannot join the trial?

28 criteria

  • You have had another type of cancer (except certain skin cancers, early‑stage cervical cancer, or other solid tumors that were cured and have been disease‑free for at least 3 years).
  • You have a history of drug‑induced lung inflammation (pneumonitis) or a condition called interstitial lung disease, which affects the tissue of the lungs.
  • The doctor believes you cannot take the study medicines or follow the study rules because of uncontrolled medical, mental, or social problems.
  • You are under a legal order that keeps you in an institution (such as a jail or psychiatric facility) and therefore cannot freely participate.
  • You have previously taken medicines that block the PI3K pathway, Akt proteins, or mTOR (these are specific types of cancer‑targeting drugs).
  • You are pregnant or are breastfeeding.
  • You are already taking part in another clinical trial that tests a new treatment (observational studies are allowed).
  • You have already received chemotherapy or antibody‑drug conjugates (special drugs like Enhertu®) for advanced disease. (Chemotherapy given before cancer spread is allowed, but if the disease came back within 6 months after that treatment, it counts as advanced‑disease chemotherapy.)
  • You have had more than two different hormone‑therapy treatments for metastatic or locally advanced breast cancer.
  • Your cancer is only in the bones and is purely “blastic” (hard, without any soft‑tissue tumor).
  • You have type 1 diabetes or type 2 diabetes that is not well‑controlled.
  • You have an active HIV infection (unless your immune cells called CD4+ T‑cells are above 350 cells/µL and you have not had serious AIDS‑related infections).
  • You have untreated or active cancer spread to the brain or the covering of the brain (leptomeningeal metastases). (If brain metastases were treated and are stable for at least 4 weeks, without need for steroids, seizures, or uncontrolled symptoms, you may be eligible.)
  • You test positive for hepatitis B virus (HBsAg positive) or have evidence of past hepatitis B infection with detectable viral DNA. (If you are negative for HBsAg and have no viral DNA, you can join.)
  • You test positive for hepatitis C antibodies but have a negative PCR test for the virus.
  • You have medical problems that make the study drugs unsafe, such as:
    • Active jaw bone death (osteonecrosis) from previous bone‑strengthening medicines (bisphosphonates or denosumab).
    • History of severe skin reactions like Stevens‑Johnson syndrome.
    • You have advanced, symptomatic disease that has spread to vital organs (viscera) and could cause a life‑threatening problem soon.
    • You have serious heart conditions, including:
      • Heart failure classified as NYHA II or higher within the past 6 months.
      • Heart attack (myocardial infarction) within the past 12 months.
      • Uncontrolled or untreated serious heart rhythm problems (arrhythmias) such as ventricular tachycardia, complete left bundle branch block, high‑grade AV block (including bifascicular block, Mobitz II or third‑degree block), or other significant rhythm issues in the past year.
      • High blood pressure that is not controlled (systolic ≥160 mm Hg or diastolic ≥100 mm Hg), even if medication is being adjusted.
      • Long QT syndrome or risk factors for a dangerous rhythm called Torsades de Pointes, such as low potassium or magnesium, or a very slow heart rate, or an ECG that cannot be read properly or shows QTc >480 ms.
      • You have a gastrointestinal (digestive‑system) disease that prevents you from absorbing pills taken by mouth.
      • You have had a sudden inflammation of the pancreas (acute pancreatitis) within the past 12 months, or you have chronic pancreatitis.
      • You are unable to swallow tablets or capsules.
      • You are allergic (hypersensitive) to any of the study drugs or their ingredients.
      • You have had a blood clot in the lungs (pulmonary embolus) or a deep vein thrombosis (blood clot in a leg vein) within the past 6 months.
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Investigated drugs

  • Alpelisib

    is an oral medicine that blocks a protein called PI3K, which can help cancer cells grow. In this study it is given together with fulvestrant to patients whose breast cancer has a specific mutation (PIK3CA‑mutated). This combination is used as a standard‑of‑care comparison (Arm E) to see how well it works against the new treatment being tested.

  • Gedatolisib

    is a drug given by IV infusion that targets two pathways (PI3K and mTOR) that cancer cells use to survive. In the trial it is tested together with palbociclib and fulvestrant. The purpose is to find out if adding gedatolisib improves the time patients live without their cancer getting worse (progression‑free survival) in several study arms.

  • Fulvestrant

    is an injectable hormone therapy that blocks estrogen receptors on breast cancer cells. It is used in many parts of the study: alone as a standard comparison (Arm C) and together with either alpelisib (Arm E) or gedatolisib (Arms A, B, D). Its role is to provide a common backbone treatment so the effect of the other drugs can be measured.

  • Palbociclib

    is an oral medication that stops cancer cells from dividing by inhibiting CDK4/6 enzymes. In this trial it is combined with gedatolisib and fulvestrant in the experimental arms (A and D) to see if adding a CDK4/6 blocker to the new drug improves outcomes compared with other standard treatments.

  • Dexamethasone

    is a steroid that is given as a mouthwash in the study. It is used as background therapy to help control inflammation and other side effects that can occur with the cancer medicines, making patients more comfortable during treatment.

What is already known about the treatment

  • Alpelisib

    This medicine is taken as a film‑coated tablet by mouth. It is an approved drug used for hormone‑receptor‑positive, HER2‑negative advanced breast cancer that has a PIK3CA mutation, and many clinical studies have reported its benefits. It works by blocking the PI3Kα enzyme, which helps stop cancer cells from growing. Alpelisib belongs to the class of PI3Kα‑specific inhibitors.

  • Gedatolisib

    Gedatolisib is given as a powder that is mixed and infused into a vein. It is still an investigational drug being tested in trials for advanced breast cancer and is not yet approved for general medical use. The drug blocks both PI3K and mTOR proteins, which are important signals that cancer cells use to multiply. It is classified as a dual PI3K/mTOR inhibitor.

  • Fulvestrant

    Fulvestrant is administered as an intramuscular injection in a pre‑filled syringe. It is an approved treatment for hormone‑receptor‑positive metastatic breast cancer and is widely described in the medical literature. The drug binds to estrogen receptors and causes them to be broken down, removing the signal that fuels tumor growth. It belongs to the class of estrogen receptor antagonists/down‑regulators.

  • Palbociclib

    Palbociclib comes as a film‑coated tablet taken orally. It is an approved therapy for hormone‑receptor‑positive, HER2‑negative advanced breast cancer and has extensive clinical data supporting its use. The medication blocks CDK4 and CDK6 enzymes, which are needed for cancer cells to progress through the cell‑division cycle. It is classified as a cyclin‑dependent kinase (CDK4/6) inhibitor.

  • Dexamethasone

    Dexamethasone is provided as a mouthwash that is used on the oral mucosa. It is an approved corticosteroid used for many conditions, including reducing inflammation and managing side effects in cancer treatment. The drug works by attaching to glucocorticoid receptors, which then lower inflammatory signals throughout the body. It belongs to the class of glucocorticoids.

Investigated diseases

  • Hormone receptor‑positive, HER2‑negative advanced breast cancer (PIK3CA wild type)

    This disease is a form of breast cancer that grows in response to hormones such as estrogen but does not have excess HER2 protein. “Advanced” indicates that the cancer has spread beyond the breast or cannot be removed surgically. After prior therapy with a CDK4/6 inhibitor and a non‑steroidal aromatase inhibitor, the cancer may continue to enlarge or appear in new locations. Progression is identified by growing tumors or new metastatic sites on imaging studies. The rate of growth can vary from slow to more rapid increase in tumor size.

  • Hormone receptor‑positive, HER2‑negative advanced breast cancer (PIK3CA mutated)

    This disease is a type of breast cancer driven by hormones and lacking HER2 overexpression, with a mutation in the PIK3CA gene. “Advanced” means the cancer has spread beyond the original breast tissue or cannot be fully removed. Following earlier treatment with a CDK4/6 inhibitor and a non‑steroidal aromatase inhibitor, the cancer may still enlarge or develop new metastatic lesions. Progression is seen as an increase in tumor size or the appearance of disease in additional areas on scans. The presence of the PIK3CA mutation can influence how quickly the cancer grows.

Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2022-502145-10-00Protocol codeCELC-G-301Estimated enrolment635 patientsSponsorCelcuity Inc.

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