Phase III Randomized Trial of Gemtuzumab Ozogamicin with Induction Chemotherapy in Pediatric Acute Myeloid Leukemia, High-Risk Myelodysplastic Syndrome, and Myeloid Sarcoma
- Trial ID
- 2024-516112-21-00
- Protocol
- RG_14-088
- Sponsor
- The University Of Birmingham
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy and safety of various treatment regimens in children with newly diagnosed **acute myeloid leukaemia** (AML), high-risk myelodysplastic syndrome (MDS), and isolated myeloid sarcoma. This includes establishing the optimum tolerated number of 3 mg/m² doses of **gemtuzumab ozogamicin** that can be safely administered in combination with **cytarabine** plus **mitoxantrone** or **liposomal daunorubicin** during induction therapy. Additionally, the study aims to compare the efficacy of mitoxantrone and cytarabine with liposomal daunorubicin and cytarabine as induction therapies, as well as to assess the impact of a single dose versus the optimum tolerated number of doses of gemtuzumab ozogamicin when combined with induction chemotherapy. Furthermore, the study will compare two consolidation regimens: high-dose cytarabine (HD Ara-C) and fludarabine & cytarabine (FLA) in standard-risk patients, and evaluate the toxicity and efficacy of two haemopoietic stem cell transplant (HSCT) conditioning regimens of different intensity: conventional myeloablative conditioning (MAC) with busulfan/cyclophosphamide and reduced intensity conditioning (RIC) with fludarabine/busulfan.
Secondary objectives include:
- Comparing the predictive value of flow and molecular minimal residual disease (MRD) monitoring for relapse risk.
- Evaluating a number of prognostic factors to define a Risk Score for children and adolescents with AML.
Participants
The clinical trial involves a total of **437 participants** diagnosed with newly diagnosed acute myeloid leukaemia (AML), high-risk myelodysplastic syndrome (MDS), or isolated myeloid sarcoma, either de novo or secondary. The study population includes both **male and female subjects** and is characterized by a vulnerable population, as it involves individuals under the age of 18. Participants were selected based on specific inclusion criteria, including a diagnosis of AML, high-risk MDS with more than 10% blasts in the bone marrow, or isolated myeloid sarcoma. The trial does not specify particular lifestyle considerations such as diet or physical activity. Participants are required to have normal renal and hepatic function, and those of reproductive potential must agree to use effective contraception during the therapy period. The trial aims to evaluate the safety and efficacy of various chemotherapy regimens and conditioning regimens for haemopoietic stem cell transplant in this pediatric population.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of various chemotherapeutic regimens in children with newly diagnosed **acute myeloid leukaemia** (AML), high-risk myelodysplastic syndrome (MDS), and isolated myeloid sarcoma. The trial incorporates an embedded dose-finding study for **gemtuzumab ozogamicin** in combination with induction chemotherapy. The trial is expected to commence recruitment on January 31, 2025, and is estimated to conclude by June 30, 2033.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age under 18 years, normal renal and hepatic function, and no prior chemotherapy for AML or high-risk MDS. Following the screening, participants will be randomized into different treatment arms. The trial includes multiple follow-up visits to monitor the incidence of dose-limiting toxicities, event-free survival, and relapse-free survival, among other endpoints. The end-of-study visit will assess the long-term outcomes, including overall survival and any late-onset adverse effects.
The expected length of participant involvement varies depending on the treatment arm and response to therapy, with the maximum treatment period extending up to 28 days for certain regimens. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial aims to provide comprehensive data on the comparative efficacy and safety of the chemotherapeutic regimens, contributing to optimized treatment strategies for pediatric patients with these hematological malignancies.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Cyclophosphamide** is provided as a powder for solution for injection/infusion. It is administered intravenously with a maximum daily dose of 50 mg/kg and a total dose not exceeding 200 mg/kg over a treatment period of up to 4 days. This medication is of chemical origin and is not a paediatric formulation.
**Cytarabine** is utilized in the form of a solution for injection/infusion. It is administered intravenously with a maximum daily dose of 6 gm/m² and a total dose of 39.6 gm/m² over a period of up to 28 days. This chemical-origin medication is also not formulated for paediatric use.
**Fludarabine Phosphate** is available as both a concentrate and a powder for solution for injection/infusion. It is administered intravenously with a maximum daily dose of 30 mg/m² and a total dose of 480 mg/m² over a treatment period of up to 16 days. This medication is of chemical origin and is not a paediatric formulation.
**Busulfan** is provided as a concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 100 mg and a total dose of 100 mg over a period of up to 4 days. This medication is of chemical origin and has an orphan drug designation.
**Mitoxantrone** is administered as a concentrate for solution for infusion. It is given intravenously with a maximum daily dose of 12 mg/m² and a total dose of 84 mg/m² over a treatment period of up to 7 days. This medication is of chemical origin and is not a paediatric formulation.
**Gemtuzumab Ozogamicin**, marketed as MYLOTARG, is provided as a powder for concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 3 mg/m² and a total dose of 9 mg/m² over a period of up to 7 days. This medication is of both chemical and biological origin, has an orphan drug designation, and is not a paediatric formulation. The product is affixed with a clinical label for trial purposes.
All medications are administered intravenously, and participant compliance is monitored throughout the trial. The trial also includes non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, as applicable. The dosing schedules and administration routes are designed to optimize therapeutic outcomes while minimizing potential adverse effects.
Efficacy
Efficacy in this clinical trial will be assessed using a range of primary and secondary endpoints. The primary endpoints include the incidence of dose-limiting toxicities (DLTs) in the dose-finding study, event-free survival (EFS) from the date of randomization for different phases (R1 and R2), and relapse-free survival (RFS) from the date of randomization for subsequent phases (R3 and R4). Additionally, early treatment-related adverse reactions will be evaluated by day 100 post-transplant, focusing on specific toxicities in various systems using the National Cancer Institute (NCI) Common Terminology Criteria v4.
Secondary endpoints encompass a variety of measures, such as the nature, incidence, and severity of adverse events (AEs) evaluated until day 45 post-course 1 and course 2, response measured by bone marrow morphology and minimal residual disease (MRD) assessment post-course 1 and 2, and complete remission (CR) defined as CR or CRi evaluated post-course 1 and 2 of treatment. Other secondary endpoints include cumulative incidence of relapse (CIR), death in CR (DCR), overall survival (OS), incidence of cardiotoxicity, and MRD negativity post-treatment courses. The trial will also assess time to hematological recovery, days in hospital per course of treatment, incidence of mixed chimerism at day 100 post-transplant, treatment-related mortality (TRM), and gonadal function at 1 year post-transplant and end of study follow-up.
The efficacy parameters will be measured and collected at specified timepoints throughout the trial, with analyses conducted to evaluate the outcomes. The trial aims to provide comprehensive data on the efficacy of the treatment regimens in children with acute myeloid leukemia (AML) and related conditions.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Trial Entry & R1 : A diagnosis of acute myeloid leukaemia (AML)/high risk myelodysplastic syndrome (MDS)(>10% blasts in the bone marrow)/isolated myeloid sarcoma(MS) (either de novo or secondary)
- Dose Finding Study: Patient meets the inclusion criteria for Trial Entry & R1
- Dose Finding Study: Age: ≥12 months for the major dose finding study OR ≥ 12 weeks and <12 months for the minor dose finding study
- Dose Finding Study: Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2
- Dose Finding Study: Normal hepatic function defined as total bilirubin ≤2.5 upper limit of normal (ULN) for age unless it is caused by leukaemic involvement or Gilbert’s syndrome or similar disorder
- Dose Finding Study: ALT or AST ≤10 x ULN for age
- Dose Finding Study: Written informed consent from the patient and/or parent/legal guardian
- Gemtuzumab ozogamicin not as part of DFS or R2: Patient meets the inclusion criteria for Trial Entry & R1
- Gemtuzumab ozogamicin not as part of DFS or R2: Age: ≥12 months OR ≥ 12 weeks OR ≥28 days and <12 weeks (patients will receive a maximum of one dose of gemtuzumab ozogamicin)
- Gemtuzumab ozogamicin not as part of DFS or R2: Normal renal function, defined as calculated creatinine clearance ≥90 ml/min/1.73m2
- Gemtuzumab ozogamicin not as part of DFS or R2: Normal hepatic function, defined as total bilirubin ≤2.5 upper limit of normal (ULN) for age and not due to leukaemic involvement or Gilbert’s syndrome or similar disorder
- Trial Entry & R1: Age <18 years at trial entry
- Gemtuzumab ozogamicin not as part of DFS or R2: ALT or AST ≤10 x ULN for age
- Gemtuzumab ozogamicin not as part of DFS or R2: Written informed consent from the patient and/or parent/legal guardian
- R2: Patient meets the inclusion criteria for Trial Entry & R1
- R2: Patient age: ≥12 months OR ≥12 weeks (once R2 open in patients aged ≥12 weeks and <12 months)
- R2: Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2
- R2: Normal hepatic function defined as total bilirubin ≤2.5 upper limit of normal (ULN) for age and not due to leukaemic involvement or Gilbert’s syndrome or similar disorder
- R2: ALT or AST ≤10 x ULN for age
- R2: Written informed consent from the patient and/or parent/legal guardian
- R3: Patient meets the inclusion criteria for Trial Entry & R1
- R3: Induction treatment as per MyeChild 01 protocol or treated with 2 courses of mitoxantrone & cytarabine off trial
- Trial Entry & R1: No prior chemotherapy or biological therapy for AML/high risk MDS/isolated MS other than that permitted in the protocol
- R3: MRD response: Patients with good risk cytogenetics/molecular genetics and a MRD level <0.1% by flow after course 2, or a decrease in transcript levels of >3 logs after course 2 for those with an informative molecular marker, but without an informative marker of sufficient sensitivity for flow MRD monitoring OR Patients with intermediate risk cytogenetics/molecular genetics with a MRD level <0.1% by flow after course 1 and course 2, or a decrease in transcript levels of >3 logs after course 1 and course 2 for those with an informative molecular marker, but without an informative marker of sufficient sensitivity for flow MRD monitoring
- R3: Written informed consent from the patient and/or parent/legal guardian
- R4: Patient meets the inclusion criteria for Trial Entry & R1
- R4: Induction treatment as per MyeChild 01 protocol or treated with 1 or 2 courses of mitoxantrone & cytarabine ± treatment intensification with FLA-Ida off trial
- R4: Patient is in CR or CRi defined as <5% blasts confirmed by flow cytometry/ molecular/FISH in a bone marrow aspirate taken within 6 weeks prior to randomisation to R4
- R4: Patient meets one of the following criteria and is a candidate for HSCT as per the protocol: High risk after course 1 (all patients with poor risk cytogenetics and patients with intermediate risk cytogenetics who fail to achieve CR/CRi) OR Intermediate risk cytogenetics with MRD >0.1% after course 1 and 2 measured by flow. If no flow MRD marker of sufficient sensitivity is identified, a molecular MRD marker with a sensitivity of >0.1% may be used OR Good risk cytogenetics with flow MRD >0.1% or a decrease in molecular MRD of <3 logs or rising transcript levels after course 3 despite treatment intensification (FLA-Ida) and after discussion with the Clinical Co-ordinators
- R4: Availability of a 9-10/10 HLA matched family or unrelated donor or 5-8/8 matched cord blood unit with an adequate cell dose as defined by the protocol section 17.1
- R4: Written informed consent from the patient and/or parent/legal guardian
- Trial Entry & R1: Normal cardiac function defined as fractional shortening ≥28% or ejection fraction ≥55%
- Trial Entry & R1: Fit for protocol chemotherapy
- Trial Entry & R1: Documented negative pregnancy test for female patients of childbearing potential
- Trial Entry & R1: Written informed consent from the patient and/or parent/legal guardian
- Trial Entry & R1: Patients with reproductive potential must agree to use effective contraception during the period of therapy. Both men and women of childbearing potential should be advised to use effective contraception to avoid pregnancy up to 12 months after the last dose of study treatment. Effective contraceptive methods include hormonal and barrier contraception etc.
Exclusion Criteria
- Acute Promyelocytic Leukaemia
- Down Syndrome
- Blast crisis of chronic myeloid leukaemia
- Relapsed or refractory AML
- Bone marrow failure syndromes
- Prior anthracycline exposure which would inhibit the delivery of study anthracyclines
- Concurrent treatment or administration of any other experimental drug or with any other biological therapy for AML/high risk MDS/isolated MS
- Pregnant or lactating females
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 31 Jan 2025 | 261 |
 Ireland | Not Recruiting | 31 Jan 2025 | 28 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CYCLOPHOSPHAMIDE | Comparator | — | INTRAVENOUS USE | 50 | 4 | SUB06859MIG |
CYTARABINE | Comparator | — | INTRAVENOUS USE | 6 | 28 | SUB06880MIG |
CYTARABINE | Comparator | — | INTRAVENOUS USE | 6 | 28 | SUB06880MIG |
FLUDARABINE PHOSPHATE | Test | — | INTRAVENOUS USE | 30 | 16 | SUB13897MIG |
BUSULFAN | Test | — | INTRAVENOUS USE | 100 | 4 | SUB05993MIG |
CYCLOPHOSPHAMIDE | Comparator | — | INTRAVENOUS USE | 50 | 4 | SUB06859MIG |
FLUDARABINE PHOSPHATE | Test | — | INTRAVENOUS USE | 30 | 16 | SUB13897MIG |
CYTARABINE | Comparator | — | INTRAVENOUS USE | 6 | 28 | SUB06880MIG |
MITOXANTRONE | Comparator | — | INTRAVENOUS USE | 12 | 7 | SUB09012MIG |
CYCLOPHOSPHAMIDE | Comparator | — | INTRAVENOUS USE | 50 | 4 | SUB06859MIG |