Evaluating Idasanutlin in Combination Therapy for Young Patients with Leukemia or Solid Tumors

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    What is this study about?

    This clinical trial is an important study that aims to find out how safe and effective a new treatment called Idasanutlin is when used alone or in combination with either chemotherapy or a medication named Venetoclax. This study is specifically for children and young adults who have certain types of cancer that have not responded to previous treatments. These cancers include Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Neuroblastoma, and other solid tumors.

    The study is organized into three parts. The first part will focus on finding the highest dose of Idasanutlin that can be given safely to patients with solid tumors. After that, the study will look at how well Idasanutlin works in combination with chemotherapy or Venetoclax in patients with neuroblastoma, AML, and ALL. The goal is to determine the best dose of Idasanutlin to use in these combinations. In the second part of the study, new patients will be treated with these combinations to further evaluate their safety and how effective they are. There might be a third part to the study, which would allow even more patients to receive these treatments, providing more information on their safety and effectiveness.

    Idasanutlin will be taken orally once a day for the first 5 days of a 28-day cycle. Venetoclax’s dose will depend on the type of cancer being treated and will also be taken orally. The chemotherapy drugs used in the study include Cyclophosphamide, Topotecan, Fludarabine, and Cytarabine, which are given through an IV. Additionally, patients with leukemia will receive intrathecal chemotherapy to treat cancer cells in the spinal fluid.

    The main things the study will look at are how many patients experience side effects and how severe those side effects are, how many patients have serious side effects from the treatment, and how well the treatment works against the cancer. This includes looking at how many patients with neuroblastoma respond to the treatment, how many patients with leukemia achieve complete remission, and how many patients with ALL have no detectable cancer cells after treatment.

    This study is a chance for patients who have not had success with other treatments to try a new approach that could potentially be more effective. It’s also an opportunity to contribute to medical research that could help future patients with similar conditions.

    Learn more about this Trial

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      Locations

      Where does the clinical trial take place?

      You can join this study in:

      Study Steps

      How Complex Will My Study Be and What Phases Will I Go Through?

      In this clinical trial, patients will go through a series of steps involving the administration of drugs over specific periods, known as cycles. Each cycle in this study lasts for 28 days. Here’s a simplified overview of the steps a patient might take, based on the drugs mentioned in the trial:

      1. Idasanutlin:
      – Administered as an oral medication once daily on Days 1-5 of a 28-day cycle.

      2. Venetoclax:
      – Administered orally at the adult dose equivalent (adjusted by body weight) of 400 milligrams (mg) for participants with neuroblastoma and 600 mg for participants with leukemia.

      3. Cyclophosphamide:
      – Administered once daily on Days 1-5 of each 28-day cycle at 250 milligrams per meter squared of body surface area (mg/m^2) as an intravenous (IV) infusion.

      4. Topotecan:
      – Administered once daily on Days 1-5 of each 28-day cycle at 0.75 mg/m^2 as an IV infusion.

      5. Fludarabine:
      – Administered once daily on Days 1-5 of each 28-day treatment cycle at 30 mg/m^2 as an IV infusion.

      6. Cytarabine:
      – Administered once daily on Days 1-5 of each 28-day treatment cycle at 2000 mg/m^2 as an IV infusion.

      7. Intrathecal Chemotherapy (for participants with leukemia, irrespective of the arm):
      – Administered on Day 1 of each 28-day treatment cycle. The specific drugs used for intrathecal chemotherapy can include single-agent cytarabine or methotrexate, or a combination of methotrexate, cytarabine, and hydrocortisone, with dosing appropriate to the patient’s age as specified in the protocol.

      It’s important for patients to follow the treatment schedule closely and attend all scheduled appointments for monitoring and assessment. The exact timeline and combination of drugs will depend on the specific arm of the trial the patient is enrolled in and the phase of the trial. The study aims to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of these treatments in pediatric and young adult participants with acute leukemias or solid tumors.


      Diseases Under Investigation

      What Conditions Qualify Me for This Study?

      The diseases you need to have to join the study are:

      1. Acute Myeloid Leukemia (AML): This is a type of cancer that starts in the cells that are supposed to mature into different types of blood cells. AML affects the white blood cells called myeloblasts, making them grow quickly and crowd out normal cells.
      2. Acute Lymphoblastic Leukemia (ALL): This is a cancer of the blood and bone marrow that affects white blood cells. ALL causes the body to produce too many lymphocytes, a type of white blood cell that’s immature and doesn’t work properly.
      3. Neuroblastoma: This is a cancer that develops from immature nerve cells found in several areas of the body. Neuroblastoma most commonly affects children aged 5 or younger, though it may rarely occur in older children.
      4. Solid Tumors: These are abnormal masses of tissue that form when cells grow and divide more than they should or do not die when they should. Solid tumors can be benign (not cancerous) or malignant (cancerous) and can occur in various parts of the body.

      Terms and conditions

      What Requirements I Have to Meet To Join This Study?

      When Am I Eligible to Join the Study?

      Sure, here’s a simplified list of conditions you must meet to join the study, with explanations for medical terms where necessary:

      1. Age Requirements: Participants must be under 18 years old for part 1a of the study, and under 30 years old for parts 1b, 2, and 3.
      2. Diagnosis: For single-agent therapy dose escalation (Part 1), you must have a histologically confirmed diagnosis of neuroblastoma or another solid tumor that has progressed or recurred despite standard therapy. For the combination safety run-in, initial expansion (Part 2), and additional expansion (Part 3), you must have a histologically confirmed diagnosis of neuroblastoma, Acute Myeloid Leukemia (AML), or precursor-B Acute Lymphoblastic Leukemia (ALL) that has progressed, recurred, or is refractory to standard therapy.
      3. Performance Status:
        • Participants under 16 years of age must have a Lansky performance status of 50% or higher. The Lansky performance scale measures a child’s ability to perform daily activities. A higher score indicates a better ability to carry out daily activities.
        • Participants 16 years of age and older must have a Karnofsky performance status of 50% or higher. The Karnofsky performance scale is used to measure an adult’s ability to perform daily tasks. A higher score means the person is better able to carry out daily activities.
      4. Adequate End-Organ Function: Participants must have adequate end-organ function, as defined in the study protocol. This means that the organs must be working well enough to meet the study’s criteria.
      5. Contraception:
        • Females of childbearing potential must agree to remain abstinent or use contraception and refrain from donating eggs. They must follow these guidelines during the treatment and for a follow-up period as specified in the study or according to national guidelines.
        • Males must agree to remain abstinent or use a condom, and refrain from donating sperm, with a female partner of childbearing potential or a pregnant female partner. These guidelines must be followed during the treatment period and for a follow-up period as specified in the study or according to national guidelines.
      6. Additional Criteria for Participants with Solid Tumors (including Neuroblastoma): Participants must have at least one evaluable or measurable radiological site of disease as defined by standard criteria for the participant’s tumor type, or measurable bone marrow disease by morphology. This means there must be a way to measure the disease to track its progress or response to treatment.
      7. Additional Criteria for Patients with Leukemia: Bone marrow with ≥5% lymphoblasts by morphologic assessment at screening and available bone marrow aspirate or biopsy from screening. This means that a certain percentage of cancer cells must be present in the bone marrow, and a sample must be available for examination.

      What Reasons Could Exclude Me from the Study?

      Sure, here’s a simplified list of conditions that would prevent someone from taking part in the study, with explanations for medical terms where needed:

      1. Primary Central Nervous System (CNS) tumors: This means if the main location of the cancer is in the brain or spinal cord.
      2. Symptomatic CNS metastases: If cancer has spread to the brain or spinal cord and is causing symptoms, and these symptoms require increasing doses of medication to control.
      3. CNS3 leukemia: This is a specific condition where there is a high number of leukemia cells in the cerebrospinal fluid, which surrounds the brain and spinal cord.
      4. Acute promyelocytic leukemia: A type of leukemia where there are too many immature blood-forming cells (promyelocytes) in the blood and bone marrow.
      5. White blood cell count >50 × 10^9 cells/Liter (L): This means having a very high number of white blood cells, which can indicate an active infection or other medical conditions.
      6. Down syndrome, Li-Fraumeni syndrome, history of severe aplastic anemia, or any known bone marrow failure predisposition syndrome: These are genetic conditions that can affect the body’s ability to produce healthy blood cells.
      7. Burkitt-type acute lymphoblastic leukemia: A fast-growing type of leukemia that often requires immediate treatment.
      8. T-cell lymphoblastic leukemia: A type of leukemia that affects a specific type of white blood cell called T lymphocytes.
      9. Prior treatment with a MDM2 antagonist: If you have already been treated with a specific type of cancer drug that blocks the MDM2 protein, which can help cancer cells grow.
      10. Prior treatment with venetoclax (if potential for enrollment in a venetoclax arm): Venetoclax is a drug used to treat certain types of leukemia and lymphoma. If you’ve already been treated with it, you might not be eligible for parts of this study that also use venetoclax.
      11. Infection considered by the investigator to be clinically uncontrolled or of unacceptable risk to the participant: If you have an infection that isn’t under control or could pose a risk to your health during the study.
      12. Any uncontrolled medical condition or other identified abnormality that precludes the patient’s safe participation in and completion of the study: This means any health issue that isn’t well-managed and could make it unsafe for you to be in the study.
      13. Systemic anticancer therapy within 28 days or 5 half-lives, whichever is shorter, prior to initiation of study treatment: If you’ve had cancer treatment recently, you might need to wait before joining this study.
      14. Treatment with monoclonal antibodies, antibody drug conjugates, or cellular therapy for anti-neoplastic intent within 30 days prior to initiation of study treatment: Similar to the above, if you’ve had certain types of cancer treatment recently, there’s a waiting period before you can start this study.
      15. I-131 meta-iodobenzylguanidine (MIBG) therapy within 6 weeks prior to initiation of study treatment: MIBG therapy is a type of radiation therapy used for certain cancers. If you’ve had this treatment, you need to wait a certain amount of time before joining the study.
      16. Myeloablative therapy with autologous or allogeneic hematopoietic stem cell rescue within 100 days of study treatment initiation: This is a type of bone marrow transplant. If you’ve had this procedure, there’s a waiting period before you can participate in the study.
      17. Immunosuppressive therapy for treatment of graft-versus-host disease within 2 weeks of study treatment initiation: If you’re taking medication to prevent or treat graft-versus-host disease (a possible complication of a bone marrow transplant), you need to wait before starting the study.
      18. Radiotherapy within 3 weeks prior to study treatment initiation: If you’ve had radiation therapy for cancer, there’s a waiting period before you can join the study.
      19. Specific restrictions are applicable for patients treated with drugs interacting with CYP2C8, CYP3A4, OATP1B1/B3, and P-gp: These are enzymes and proteins that help the body process drugs. If you’re taking medication that affects these, it might affect your eligibility.
      20. Received anti-coagulant or anti-platelet agent within 7 days or 5 half-lives prior to study treatment initiation: These are medications that prevent blood clots. If you’ve taken them recently, you might need to wait before starting the study.
      21. Underwent major surgical procedure within 21 days of study treatment initiation, or anticipate need for major surgical procedure during the course of the study: If you’ve had or will need major surgery, there’s a waiting period before you can participate.

      Investigational Medicinal Product

      What Products Are Being Used in This Study?

      Sure, here’s a list of the drugs involved in the study along with a brief description of each active substance and their role in the study:

      1. Idasanutlin (RG7388): Idasanutlin is an oral medication designed to inhibit the MDM2-p53 interaction. p53 is a tumor suppressor protein that regulates cell cycle and apoptosis. Many cancers have a dysfunctional p53 pathway, and by inhibiting MDM2, Idasanutlin aims to reactivate p53’s tumor-suppressing functions. In this study, Idasanutlin is being evaluated for its effectiveness and safety when used alone or in combination with other drugs in treating pediatric and young adult participants with relapsed or refractory acute leukemias or solid tumors.
      2. Venetoclax (RG7601, GDC-0199, ABT-199): Venetoclax is an oral medication that selectively inhibits the B-cell lymphoma 2 (BCL-2) protein. BCL-2 is known for its role in preventing apoptosis in cancer cells, particularly in chronic lymphocytic leukemia cells. By inhibiting BCL-2, Venetoclax aims to induce cancer cell death. In this study, Venetoclax is used in combination with Idasanutlin and other drugs to assess its safety and preliminary activity against certain types of leukemia and neuroblastoma.
      3. Cyclophosphamide: Cyclophosphamide is an alkylating agent used in chemotherapy. It works by cross-linking DNA strands, leading to cell death. It is used to treat various types of cancer by slowing or stopping cell growth. In this study, Cyclophosphamide is administered intravenously in combination with Idasanutlin and other drugs to treat neuroblastoma.
      4. Topotecan: Topotecan is a topoisomerase inhibitor used in chemotherapy. It works by interfering with the action of topoisomerase enzymes, which are involved in DNA replication. This interference leads to DNA damage and cell death. In this study, Topotecan is used alongside Idasanutlin and Cyclophosphamide to treat neuroblastoma.
      5. Fludarabine: Fludarabine is a purine analog used in chemotherapy. It inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase, leading to cell death. Fludarabine is used in this study in combination with Idasanutlin, Cytarabine, and Intrathecal Chemotherapy to treat acute myeloid leukemia (AML).
      6. Cytarabine: Cytarabine is a chemotherapy agent that works as an antimetabolite. It interferes with the synthesis of DNA, inhibiting the growth of cancer cells. In this study, Cytarabine is used in combination with Idasanutlin and other drugs to treat AML.
      7. Intrathecal Chemotherapy: This involves the direct administration of chemotherapy drugs into the cerebrospinal fluid, bypassing the blood-brain barrier. It is used to treat or prevent cancer that involves the brain and spinal cord. In this study, Intrathecal Chemotherapy is used in combination with Idasanutlin and other drugs for participants with leukemia, aiming to treat or prevent central nervous system involvement.

      Have the Medicinal Substances Used in the Trial Been Previously Studied in Medicine?

      Yes, the active substances participating in the clinical trial are already known to medicine and the medical literature. Here is a list of the substances along with a brief description:

      1. Idasanutlin: Idasanutlin, also known as RG7388, is an oral medication being studied for its potential to treat various types of cancer. It is known to the medical literature as an MDM2 antagonist, which means it works by blocking the MDM2 protein, thereby helping to reactivate the p53 tumor suppressor protein.
      2. Venetoclax: Venetoclax, with other names such as RG7601, GDC-0199, and ABT-199, is an orally administered drug that targets the B-cell lymphoma 2 (BCL-2) protein and is used in the treatment of certain types of chronic lymphocytic leukemia (CLL) and other hematological malignancies. It is well-documented in medical literature for its role in inducing apoptosis in cancer cells.
      3. Cyclophosphamide: Cyclophosphamide is an alkylating agent used in chemotherapy and is administered intravenously. It has a broad spectrum of activity against various types of cancer and is also used to suppress the immune system for treating certain autoimmune diseases. Its mechanism and use are well-established in medical literature.
      4. Topotecan: Topotecan is a chemotherapy medication used to treat certain types of cancer, including ovarian cancer, lung cancer, and certain types of leukemia. It is a topoisomerase inhibitor, which works by preventing DNA replication in cancer cells. Its pharmacology and clinical applications are well-documented.
      5. Fludarabine: Fludarabine is a chemotherapy medication used primarily for the treatment of hematological malignancies, particularly chronic lymphocytic leukemia. It is an antimetabolite that interferes with DNA synthesis. The drug’s mechanism of action and its clinical use are extensively covered in the medical literature.
      6. Cytarabine: Cytarabine, also known as cytosine arabinoside, is a chemotherapy agent used mainly in the treatment of leukemia. It is an antimetabolite and works by inhibiting the synthesis of DNA. Its use, mechanism of action, and effectiveness are well-documented in oncology.
      7. Intrathecal Chemotherapy: This refers to the method of delivering chemotherapy directly into the cerebrospinal fluid, which is used for treating or preventing central nervous system (CNS) involvement in leukemia. Drugs commonly used for intrathecal chemotherapy include cytarabine and methotrexate, among others, and are well-known in medical practice and literature.

      Study ID

      CT-EU-00114995

      Recruitment status

      ACTIVE_NOT_RECRUITING

      Start of the trial

      4 years ago