Study on carfilzomib effect on children’s leukemia

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    What is this study about?

    This clinical trial focuses on children who face the difficult situation of acute lymphoblastic leukemia (ALL), a type of blood cancer. When cancer returns or does not respond to standard treatments, doctors call it relapsed or refractory, and it can be difficult to treat. The study is evaluating a drug called carfilzomib, which is being tested alongside common chemotherapy drugs. The drugs used in the clinical trial include carfilzomib, dexamethasone, mitoxantrone, PEG-asparaginase, vincristine, Intrathecal Methotrexate, Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate), 6-mercaptopurine, cyclophosphamide, cytarabine, and daunorubicin. The process has two main goals. First, he wants to find an appropriate dose of carfilzomib that is safe for children. This is significant because finding the right dose means balancing effectiveness with minimizing side effects. Once a safe dose is determined, the second part of the study begins. This part is about seeing how well carfilzomib works when it is part of a treatment regimen. Doctors and researchers will carefully monitor the children’s response to treatment. They will check whether the cancer responds to the new approach and how the children’s bodies cope with it. They will also track any side effects to ensure your treatment is safe.

    Learn more about this Trial

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      Locations

      Where does the clinical trial take place?

      Wien , Austria

      Sofia , Bulgaria

      Brno , Czechia

      Kobenhavn O , Denmark

      Paris , France

      Athens , Greece

      Goudi , Greece

      Goudi , Greece

      Patra , Greece

      Thessaloniki , Greece

      Bari , Italy

      Catania , Italy

      Genova , Italy

      Monza (MB) , Italy

      Napoli , Italy

      Padova , Italy

      Pavia , Italy

      Roma , Italy

      Torino , Italy

      Utrecht , Netherlands

      Oslo , Norway

      Krakow , Poland

      Lodz , Poland

      Lublin , Poland

      Warszawa , Poland

      Wroclaw , Poland

      Zabrze , Poland

      Coimbra , Portugal

      Lisboa , Portugal

      Porto , Portugal

      Bucharest , Romania

      Cluj Napoca , Romania

      Timisoara , Romania

      Esplugues de Llobregat , Spain

      Madrid , Spain

      Madrid , Spain

      Solna , Sweden

      You can join this study in:

      Italy: Bari, Catania, Pavia.

      Czechia: Brno.

      Romania: Bucharest, Cluj-Napoca.

      Portugal: Coimbra, Porto.

      Spain: Esplugues de Llobregat, Madrid.

      Greece: Goudi, Thessaloniki.

      Poland: Łódź, Lublin, Wrocław, Zabrze.

      Norway: Oslo.

      France: Paris.

      Bulgaria: Sofia.

      Sweden: Solna.

      Netherlands: Utrecht.


      Study Steps

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

      The steps patients need to take in this clinical trial depend on the phase they are participating in. Here is a summary of the steps for each phase outlined in the trial document:

      Phase 1b:

      1. In Phase 1b: Dose Escalation 1, subjects will receive carfilzomib in combination with an induction chemotherapy regimen. This includes:
        • A 1-week carfilzomib single agent Lead in Window prior to the Induction Cycle.
        • A 4-week cycle of induction chemotherapy.
        • An optional 4-week cycle of consolidation chemotherapy if stable disease or a better response is achieved at the end of the Induction Cycle.
      2. In Phase 1b: Dose Escalation 2, the process is similar with:
        • A 4-week cycle of carfilzomib and induction chemotherapy.
        • An optional 4-week cycle of consolidation chemotherapy following the same criteria as Dose Escalation 1.

      Phase 2:

      1. For subjects aged ≥ 12 months at screening:
        • They will receive the recommended phase 2 dose (RP2D) of carfilzomib.
        • A 4-week cycle of carfilzomib and induction chemotherapy.
        • An optional 4-week cycle of carfilzomib in combination with consolidation chemotherapy if no disease progression is observed at the end of the Induction Cycle.
      2. For subjects aged < 12 months at screening:
        • They will also receive the RP2D of carfilzomib.
        • A modified 5-week cycle of carfilzomib and induction chemotherapy.
        • An optional 5-week cycle of carfilzomib with consolidation chemotherapy following the same criteria.

      Note: The induction chemotherapy regimen includes a backbone of drugs like dexamethasone, mitoxantrone, PEG asparaginase, vincristine, and for some cases, daunorubicin. The consolidation chemotherapy includes drugs like 6 mercaptopurine, cyclophosphamide, cytarabine, and PEG asparaginase, as well as vincristine. Intrathecal therapy including methotrexate, and intrathecal triple therapy with cytarabine, hydrocortisone, and methotrexate, may also be part of the regimen.

      These steps are quite complex, so patients should discuss the process in detail with their healthcare providers to make sure they understand each phase of the trial.


      Diseases Under Investigation

      What Conditions Qualify Me for This Study?

      To join the study, you need to have a diagnosis of Acute Lymphoblastic Leukemia (ALL). The specific eligibility criteria related to diseases are as follows:

      1. Age 21 years or younger at the time of initial ALL diagnosis and age >1 year at the time of study treatment initiation.
      2. Diagnosed with relapsed or refractory ALL with ≥ 5% blasts in the bone marrow (M2 or M3 disease), with or without extramedullary disease.
      3. Must have had 1 or more prior therapeutic attempts, which include:
        1. Early first relapse (< 36 months from original diagnosis) after achieving a Complete Remission (CR) for B-ALL, or first relapse any time following the original diagnosis after achieving a CR for T-ALL.
        2. First refractory bone marrow relapse occurring any time after original diagnosis after achieving a CR or relapse after achieving a CR following the first or subsequent relapse (i.e., ≥2 relapses).
        3. Failing to achieve a CR from original diagnosis after at least 1 induction attempt.
      4. All previous chemotherapy, immunotherapy, or radiotherapy treatment must be fully recovered from.
      5. The specific eligibility for Phase 2 includes subjects that must be diagnosed with relapsed or refractory relapsed ALL, and must have a documented first remission, less than 5% blasts in the bone marrow (M1 bone marrow) and no evidence of extramedullary disease.

      Terms and conditions

      What Requirements I Have to Meet To Join This Study?

      When Am I Eligible to Join the Study?

      Inclusion Criteria for Phase 1b:

      1. Age must be 21 years or younger at the time of initial ALL diagnosis and older than 1 year at the time of study treatment initiation.
      2. Diagnosis of relapsed or refractory Acute Lymphoblastic Leukemia (ALL) with ≥5% blasts in the bone marrow (M2 or M3 disease), with or without extramedullary disease.
      3. Fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatments before enrollment.
      4. Serum creatinine level ≤1.5× the institutional upper limit of normal (ULN) for age or, if higher, a calculated creatinine clearance or radioisotope Glomerular Filtration Rate (GFR) ≥70 mL/min/1.73 m².
      5. Adequate liver function, with total bilirubin ≤1.5× institutional ULN (unless due to Gilbert Syndrome) and Alanine Aminotransferase (ALT) ≤5× institutional ULN.
      6. Karnofsky or Lansky performance status score ≥50 for subjects >16 years or ≤16 years old, respectively. Note: The Karnofsky and Lansky scales are methods to assess the functional status of a patient and their ability to carry out activities of daily living.

      Karnofsky and Lansky Performance Status:

      • The Karnofsky Performance Status Scale measures cancer patients’ ability to perform ordinary tasks. It assigns scores ranging from 100 (normal, no complaints, no evidence of disease) to 0 (death).
      • The Lansky Play-Performance Scale is similar, used specifically for children, scoring from 100 (fully active, normal) to 0 (unresponsive).

      Inclusion Criteria for Phase 2:

      1. Legal representative consent provided for the subject who is legally too young to give informed consent. If applicable, subject’s assent is also required prior to initiating study-specific activities/procedures.
      2. Age from 1 month to less than 21 years at the time of enrollment. If ≥18 years old, original diagnosis must have occurred before 18 years of age.
      3. Documented first remission with less than 5% blasts in the bone marrow (M1 bone marrow) and no signs of disease outside the bone marrow.
      4. Subjects must have a diagnosis of relapsed or refractory T-cell ALL with bone marrow relapse (≥5% leukemia blasts in the bone marrow) or refractory relapse, or relapsed or refractory B-cell ALL (after targeted B-cell immune therapy) with bone marrow relapse or refractory relapse, with or without extramedullary disease.
      5. Adequate liver function: bilirubin ≤1.5× ULN and ALT ≤5× ULN.
      6. Adequate renal function: serum creatinine ≤1.5× ULN or GFR ≥70 mL/min/1.73 m² (or ≥50 mL/min/1.73 m² for children less than 2 years of age).
      7. Adequate cardiac function: shortening fraction ≥30% or ejection fraction ≥50%. Note: The shortening fraction and ejection fraction are measures of how well the heart pumps with each beat. An ejection fraction of 50% or higher is considered normal.
      8. Performance status: Karnofsky or Lansky score ≥50% depending on the age as described above.
      9. Life expectancy of greater than 6 weeks as per investigator´s judgment at the time of screening.

      These are only the inclusion criteria for the study and not the exclusion criteria. Please ensure that you meet these requirements before considering participation in the study.

      What Reasons Could Exclude Me from the Study?

      Here is a list of conditions that would exclude you from participating in the study, along with explanations of the medical terms used:

      Phase 1b Key Exclusion Criteria:

      1. Allergy to Drugs in the Study: Having a known allergy to any drugs being used in the study. This includes a previous allergy to PEG-asparaginase, although Erwinia asparaginase may be an alternative option with the investigator’s approval.
      2. Allergy to Captisol: Having a known allergy to Captisol, which is a substance used to help dissolve carfilzomib, one of the study drugs.
      3. Cardiac Function: A measure of the heart’s ability to contract that’s lower than required (Left ventricular fractional shortening < 30%).
      4. Pancreatitis: Having a history of Grade 2 or higher pancreatitis, which is an inflammation of the pancreas.
      5. Graft vs. Host Disease: An active condition following a transplant where the donated bone marrow or peripheral blood stem cells view the recipient’s body as foreign and attack it, requiring systemic treatment.
      6. Infection: A positive culture or clinical evidence of bacterial or fungal infection within 14 days prior to starting the study treatment.
      7. Down Syndrome: A genetic disorder associated with a third copy of chromosome 21.
      8. Prior Therapy Restrictions: Requirements regarding completion of previous therapies, including certain growth factors, immunotherapies, biologic agents, and time since last dose of monoclonal antibodies.
      9. Hepatitis B Infection: Having an infection with positive hepatitis B DNA.

      Phase 2 Exclusion Criteria:

      1. Prior Treatment with Carfilzomib: Having previously received treatment with carfilzomib, one of the study drugs.
      2. Intolerance to Chemotherapy: Being intolerant or hypersensitive to any components of the VXLD chemotherapy regimen, except in certain scenarios relating to allergies to asparaginase products.
      3. Stem Cell Transplant: Having had an autologous (from the patient) or allogeneic (from a donor) hematopoietic stem cell transplant within a certain period before starting the study treatment.
      4. Active GVHD: Having active graft-versus-host disease that requires systemic immune suppression.
      5. Extramedullary Relapse: An isolated relapse occurring outside of the bone marrow.
      6. Infection Restrictions: Positive infection within 14 days of enrollment, with specific conditions for line infections.
      7. Monoclonal Antibody Restrictions: Specific time frames required after the last dose of certain monoclonal antibodies before starting the study drug.
      8. Cell-based Immunotherapy: Having received cell-based immunotherapy within a certain period prior to the first dose of the investigational product.
      9. Active Cancer: Presence of another active cancer apart from the one being studied.

      These criteria are in place to help ensure the safety of participants and the integrity of the study results. If you have any of these conditions, it will be important to discuss them with the study investigator to determine your eligibility.


      Investigational Medicinal Product

      What Products Are Being Used in This Study?

      The clinical study involves several drugs, which are detailed below along with the active substances:

      1. Carfilzomib (active substance: carfilzomib) – a proteasome inhibitor used in cancer treatment, specifically for multiple myeloma.
      2. Vincristine (active substance: vincristine) – a chemotherapy medication used to treat various types of cancer, including acute lymphoblastic leukemia.
      3. Dexamethasone (active substance: dexamethasone) – a corticosteroid used to reduce inflammation and suppress the immune system, and is used in combination with other drugs to treat cancer.
      4. PEG-asparaginase (active substance: pegaspargase) – an enzyme used in the treatment of acute lymphoblastic leukemia, which deprives the leukemia cells of the amino acid asparagine, necessary for their growth.
      5. Daunorubicin (active substance: daunorubicin) – an anthracycline antibiotic used in chemotherapy to treat various cancers, including acute lymphoblastic leukemia.
      6. Mitoxantrone (active substance: mitoxantrone) – an anthracenedione antineoplastic agent used in the treatment of certain types of cancer.
      7. 6-Mercaptopurine (active substance: mercaptopurine) – a chemotherapy medication used to treat acute lymphoblastic leukemia.
      8. Cyclophosphamide (active substance: cyclophosphamide) – a chemotherapy drug used for treating various types of cancer, including lymphoma and leukemia.
      9. Cytarabine (active substance: cytarabine) – a chemotherapy agent used mainly in the treatment of leukemia.

      These drugs are used alone or in combination as part of induction chemotherapy to assess the safety, tolerability, and activity in children with relapsed or refractory acute lymphoblastic leukemia (ALL).

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

      The clinical trial involves several well-known active substances that are already known to medicine and the medical literature. Below is a list of these substances along with descriptions regarding their known status in medical literature:

      1. Vincristine: Vincristine is a well-known chemotherapy medication used to treat various types of cancer. It works by inhibiting the growth of cancer cells.
      2. Intrathecal (IT) Methotrexate: Methotrexate is commonly used both as a chemotherapeutic agent and in the treatment of certain autoimmune diseases. Intrathecal administration refers to the delivery of the drug into the cerebrospinal fluid to treat or prevent central nervous system disorders.
      3. Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate): This combination is used in the treatment of cancer, particularly in the prophylaxis or treatment of central nervous system leukemia or lymphoma. Each drug in the combination has a specific function – Cytarabine and Methotrexate as chemotherapies and Hydrocortisone as a corticosteroid to relieve inflammation.
      4. 6-Mercaptopurine: 6-Mercaptopurine (6-MP) is an antimetabolite and a purine analog that interferes with nucleic acid metabolism and hinders cell proliferation. It is used in the treatment of leukemia.
      5. Cyclophosphamide: Cyclophosphamide is used in the treatment of various cancers and some autoimmune disorders. It is a chemotherapy and immune system suppressant.
      6. Cytarabine: Cytarabine is a chemotherapy drug used mainly in the treatment of leukemia and lymphomas. It is a cytosine analog that interferes with DNA synthesis.
      7. Daunorubicin: Daunorubicin is an anthracycline chemotherapeutic used to treat certain types of leukemia. It works by intercalating DNA and thus inhibiting the replication of rapidly growing cancerous cells.

      Each of these substances is widely recognized and has been extensively researched and documented in the field of oncology and hematology.


      Study ID

      CT-EU-00041157

      Recruitment status

      Recruting new patients

      Start of the trial

      9 years ago