GEMTUZUMAB OZOGAMICIN for Acute myeloid leukaemia (AML) | Myelodysplastic syndrome (high-risk) | Myeloid sarcoma

Inclusion criteria

• {"criterion_text":"- 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)\n- Gemtuzumab ozogamicin not as part of DFS or R2: Normal renal function, defined as calculated creatinine clearance ≥90 ml/min/1.73m2\n- 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\n- Trial Entry & R1: Age <18 years at trial entry\n- Gemtuzumab ozogamicin not as part of DFS or R2: ALT or AST ≤10 x ULN for age\n- Gemtuzumab ozogamicin not as part of DFS or R2: Written informed consent from the patient and/or parent/legal guardian\n- R2: Patient meets the inclusion criteria for Trial Entry & R1\n- R2: Patient age: ≥12 months OR ≥12 weeks (once R2 open in patients aged ≥12 weeks and <12 months)\n- R2: Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2\n- 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\n- R2: ALT or AST ≤10 x ULN for age\n- Dose Finding Study: Patient meets the inclusion criteria for Trial Entry & R1\n- R2: Written informed consent from the patient and/or parent/legal guardian\n- R3: Patient meets the inclusion criteria for Trial Entry & R1\n- R3: Induction treatment as per MyeChild 01 protocol or treated with 2 courses of mitoxantrone & cytarabine off trial\n- Trial Entry & R1: No prior chemotherapy or biological therapy for AML/high risk MDS/isolated MS other than that permitted in the protocol\n- 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\n- R3: Written informed consent from the patient and/or parent/legal guardian\n- R4: Patient meets the inclusion criteria for Trial Entry & R1\n- 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\n- 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\n- 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\n- Dose Finding Study: Age: ≥12 months for the major dose finding study OR ≥ 12 weeks and <12 months for the minor dose finding study\n- 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\n- R4: Written informed consent from the patient and/or parent/legal guardian\n- Trial Entry & R1: Normal cardiac function defined as fractional shortening ≥28% or ejection fraction ≥55%\n- Trial Entry & R1: Fit for protocol chemotherapy\n- Trial Entry & R1: Documented negative pregnancy test for female patients of childbearing potential\n- Trial Entry & R1: Written informed consent from the patient and/or parent/legal guardian\n- 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.\n- Dose Finding Study: Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2\n- 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\n- Dose Finding Study: ALT or AST ≤10 x ULN for age\n- Dose Finding Study: Written informed consent from the patient and/or parent/legal guardian\n- Gemtuzumab ozogamicin not as part of DFS or R2: Patient meets the inclusion criteria for Trial Entry & R1\n- 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)"}

Exclusion criteria

• {"criterion_text":"- Acute Promyelocytic Leukaemia\n- Down Syndrome\n- Blast crisis of chronic myeloid leukaemia\n- Relapsed or refractory AML\n- Bone marrow failure syndromes\n- Prior anthracycline exposure which would inhibit the delivery of study anthracyclines\n- Concurrent treatment or administration of any other experimental drug or with any other biological therapy for AML/high risk MDS/isolated MS\n- Pregnant or lactating females"}

Primary endpoints

• {"endpoint_text":"- Dose Finding Study: The incidence of dose limiting toxicities (DLTs)","definition_or_measurement_approach":""}
• {"endpoint_text":"- R1: Event-free survival (EFS) from date of randomisation 1 (R1)","definition_or_measurement_approach":"Event-free survival defined as time from randomisation to the relevant question to the first of failure to achieve CR (recorded as an event on day 1), relapse, secondary malignancy or death from any cause."}
• {"endpoint_text":"- R2: Event-free survival (EFS) from date of randomisation 2 (R2)","definition_or_measurement_approach":"Event-free survival defined as time from randomisation to the relevant question to the first of failure to achieve CR (recorded as an event on day 1), relapse, secondary malignancy or death from any cause."}
• {"endpoint_text":"- R3: Relapse-free survival (RFS) from date of randomisation 3 (R3)","definition_or_measurement_approach":""}
• {"endpoint_text":"- R4: Early treatment related adverse reactions defined as the incidence by day 100 post-transplant of grade 3-5 toxicity for specific toxicities in the following systems using the National Cancer Institute (NCI) Common Terminology Criteria v4: Cardiac; Respiratory, thoracic and mediastinal; Gastrointestinal; Investigations; Renal and Urinary; Nervous system","definition_or_measurement_approach":"Incidence measured by occurrence of grade 3-5 toxicities in specified systems by day 100 post-transplant using NCI CTCAE v4."}
• {"endpoint_text":"- R4: Relapse-free survival (RFS) from date of randomisation 4 (R4)","definition_or_measurement_approach":""}

Secondary endpoints

• {"endpoint_text":"- Dose Finding Study: The nature, incidence and severity of AEs evaluated until day 45 post course 1 and course 2","definition_or_measurement_approach":"Adverse events evaluated up to day 45 after course 1 and course 2; nature, incidence and severity recorded."}
• {"endpoint_text":"- Dose Finding Study: Response measured by bone marrow morphology and MRD assessment post course 1 and 2","definition_or_measurement_approach":"Response assessed by bone marrow morphology and MRD assessment after course 1 and 2."}
• {"endpoint_text":"- Complete Remission (CR) defined as CR or CRi and evaluated post course 1 and 2 of treatment (R1 and R2 only)","definition_or_measurement_approach":"CR defined as CR or CRi and evaluated after courses 1 and 2 for R1 and R2 entrants."}
• {"endpoint_text":"- Reasons for failure to achieve CR evaluated pose course 1 and 2 of treatment and classified as resistant disease, induction death or not evaluable (R1 and R2 only)","definition_or_measurement_approach":"Reasons classified as resistant disease, induction death or not evaluable for failures to achieve CR after courses 1 and 2 (R1/R2)."}
• {"endpoint_text":"- Cumulative incidence of relapse (CIR) defined as time from first CR or CRi for patients entering at induction or from randomisation to the relevant question for patients entering at R3 or R4, to relapse","definition_or_measurement_approach":"CIR defined as time from first CR/CRi (or from relevant randomisation) to relapse."}
• {"endpoint_text":"- Death in CR (DCR) defined as time from first CR or CRi for patients entering at induction or from randomisation to the relevant question for patients entering at R3 or R4, to date of death from any cause.","definition_or_measurement_approach":"DCR defined as time from first CR/CRi (or relevant randomisation) to death from any cause."}
• {"endpoint_text":"- Event-free survival defined as time from randomisation to the relevant question to the first of failure to achieve CR (recorded as an event on day 1), relapse, secondary malignancy or death from any cause.","definition_or_measurement_approach":"EFS definition: time from randomisation to first of failure to achieve CR (event day 1), relapse, secondary malignancy or death."}
• {"endpoint_text":"- Overall Survival (OS) defined as time from randomisation to the relevant question to death from any cause or date last seen for patients who are alive at the end of the trial","definition_or_measurement_approach":"OS defined as time from randomisation to death from any cause or last seen date for survivors."}
• {"endpoint_text":"- Incidence of cardiotoxicity experienced within 10 years of randomisation and defined as a fall in fractional shortening to <28% or ejection fraction <55% (R1, R2 and R4 only)","definition_or_measurement_approach":"Cardiotoxicity defined as fall in fractional shortening to <28% or ejection fraction <55% within 10 years of randomisation."}
• {"endpoint_text":"- Incidence of bilirubin of grade 3 or higher experienced within 30 days of end of trial treatment (R2 and R4 only)","definition_or_measurement_approach":"Incidence of grade ≥3 bilirubin within 30 days of end of trial treatment (R2 and R4)."}
• {"endpoint_text":"- Incidence of veno-occlusive disease experienced within 30 days of end of trial treatment (R2 and R4 only)","definition_or_measurement_approach":"Incidence of veno-occlusive disease within 30 days of end of trial treatment (R2 and R4)."}
• {"endpoint_text":"- MRD negativity post course 1, course 2 and at the end of treatment (R1 and R2 only)","definition_or_measurement_approach":"MRD negativity assessed after course 1, course 2 and at end of treatment for R1/R2 patients."}
• {"endpoint_text":"- Time to haematological recovery defined as time from start of course to date of neutrophil recovery to 1.0 x 10^9/L and platelet recovery to 80 x 10^9/L for DFS patients; and neutrophil recover to 0.75 x 10^9/L and platelet recovery to 75 x 10^9/L for all other patients","definition_or_measurement_approach":"Time from start of course to neutrophil and platelet recovery thresholds (1.0 x10^9/L & 80 x10^9/L for DFS; 0.75 x10^9/L & 75 x10^9/L for others)."}
• {"endpoint_text":"- Days in hospital per course of treatment","definition_or_measurement_approach":"Number of days in hospital per treatment course."}
• {"endpoint_text":"- Incidence of mixed chimerism at day 100 post-transplant (R4 only)","definition_or_measurement_approach":"Incidence of mixed chimerism measured at day 100 post-transplant."}
• {"endpoint_text":"- Treatment Related Mortality (TRM) defined as the time bwtween randomisation to R4 and death which is unrelated to the underlying disease and considered related to the transplant procedure (R4 only)","definition_or_measurement_approach":"TRM defined as time from randomisation to R4 to death unrelated to underlying disease and considered related to transplant."}
• {"endpoint_text":"- Gonadal function at 1 year post-transplant and end of study follow up, assessed by Tanner stage, gonadotrophins and serum AMH (females)/inhibin B (males) (R4 only)","definition_or_measurement_approach":"Gonadal function assessed by Tanner stage, gonadotrophins and serum AMH (females)/inhibin B (males) at 1 year post-transplant and end of study follow-up."}

France

Earliest CTIS Part Ii Submission Date

30-10-2024

Latest Decision Or Authorization Date

02-12-2024

Processing Time Days

33

Number Of Sites

28

Number Of Participants

261

Ireland

Earliest CTIS Part Ii Submission Date

30-10-2024

Latest Decision Or Authorization Date

02-12-2024

Processing Time Days

33

Number Of Sites

1

Number Of Participants

28

Primary sponsor

Full Name

The University Of Birmingham

Organisation Type

Educational Institution

Country Of Registered Address

United Kingdom

Third parties

• {"country":"Ireland","full_name":"Almac Clinical Services (Ireland) Limited","duties_or_roles":"Sponsor duties codes: 14","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Southmead Hospital","duties_or_roles":"Sponsor duties codes: 4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United Kingdom","full_name":"Guy's And St Thomas' NHS Foundation Trust","duties_or_roles":"Sponsor duties codes: 4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Switzerland","full_name":"Geneva University Hospital","duties_or_roles":"Sub-Study Lead","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"Sponsor duties codes: 14","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"University Of Oxford","duties_or_roles":"Sponsor duties codes: 4","organisation_type":"Educational Institution"}
• {"country":"United Kingdom","full_name":"Newcastle University","duties_or_roles":"Sponsor duties codes: 4","organisation_type":"Educational Institution"}