International Randomised Phase III Clinical Trial in Children With Acute Myeloid Leukaemia

NCT02724163 | Recruiting Phase 3 DMC

• 2 other identifiers: RG_14-0882014-005066-30
• Study Type: interventional
• Target: 700
• Locations: 6 countries
• Sites: 68

Brief Summary

The main purpose of this study is :

1. 1.To establish which number of doses of gemtuzumab ozogamicin (up to a maximum of 3 doses) is tolerated and can be safety delivered in combination with cytarabine plus mitoxantrone or liposomal daunorubicin in induction
2. 2.To compare mitoxantrone (anthracenedione) \& cytarabine with liposomal daunorubicin (anthracycline) \& cytarabine as induction therapy. (Randomisation 1 (R1) closed early to recruitment on 8th September 2017, due to liposomal daunorubicin manufacturing issues resulting in unavailability of the drug.)
3. 3.To compare a single dose of gemtuzumab ozogamicin with the optimum tolerated number of doses of gemtuzumab ozogamicin (identified by the dose-finding study) when combined with induction chemotherapy.
4. 4.To compare two consolidation regimens: high dose cytarabine (HD Ara-C) and fludarabine \& cytarabine (FLA) in standard risk patients.
5. 5.To compare the toxicity and effectiveness 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.

Conditions

Acute Myeloid Leukaemia

Keywords

Acute Myeloid Leukaemia; Children; Gemtuzumab ozogamicin; Liposomal daunorubicin; Mitoxantrone; Randomised controlled trial; Risk stratification; Minimal residual disease; Stem cell transplant

Outcome Measures

Primary Outcomes (6)

• Incidence of dose limiting toxicities (DLTs).

  Incidence of DLTs will be evaluated up to day 45 post course 1 and course 2 of induction chemotherapy.

• Event Free Survival (EFS).

  The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. EFS estimates will be presented at 24 months along with 95% confidence intervals.

  Event free survival (EFS) will be evaluated as the time from randomisation one to the first event, up to 16 years.

• Event Free Survival (EFS).

  The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. EFS estimates will be presented at 24 months along with 95% confidence intervals.

  Event free survival (EFS) will be evaluated as the time from randomisation two to the first event, up to 16 years..

• Relapse free survival (RFS).

  The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. RFS estimates will be presented at 24 months along with 95% confidence intervals.

  Relapse free survival (RFS) will be evaluated as the time of randomisation three to the first relapse or death from any cause, up to 16 years.

• Early treatment related adverse reactions.

  Early treatment related adverse reactions defined as the incidence by day 100 post-transplant of grade 3-5 toxicity for the following systems using the National Cancer Institute (NCI) Common Terminology Criteria v4: * Cardiac (pericardial effusion/Left ventricular systolic dysfunction). * Respiratory, thoracic and mediastinal (hypoxia/pneumonitis). * Gastrointestinal (GI) (diarrhoea/typhlitis/upper and lower GI haemorrhage). * Investigations (bilirubin). * Renal and Urinary (acute kidney injury/haematuria). * Nervous system (seizure).

  Early treatment related adverse reactions will be evaluated at day 100 post-transplant.

• Relapse free survival (RFS).

  The primary analysis will be carried out once the last patient has a minimum of 1 year follow up. RFS estimates will be presented at 12 months along with 95% confidence intervals.

  Relapse free survival (RFS) will be evaluated as the time of randomisation four to the first relapse or death from any cause, up to 16 years.

Secondary Outcomes (20)

• The nature, incidence and severity of adverse events (AEs) (gemtuzumab ozogamicin dose finding study).

  Evaluated by day 45 post course 1 and course 2.

• Response measured by bone marrow assessment using morphology and minimal residual disease (MRD) assessment (gemtuzumab ozogamicin dose finding study).

  Evaluated by day 45 post course 1 and course 2.

• Serum pharmacokinetic (PK) parameters of gemtuzumab ozogamicin: Clearance (CL) (gemtuzumab ozogamicin dose finding study)

  Evaluated up to one month after the first dose of gemtuzumab ozogamicin.

• Serum pharmacokinetic (PK) parameters of gemtuzumab ozogamicin: Volume of distribution (Vd) (gemtuzumab ozogamicin dose finding study)

  Evaluated up to one month after the first dose of gemtuzumab ozogamicin.

• Complete remission (CR) (R1 & R2).

  Evaluated and presented at the completion of course 1 and 2 of treatment up to a maximum of 45 days post each course of treatment

Study Arms (7)

Mitoxantrone

ACTIVE COMPARATOR

Course 1 * Mitoxantrone: 12 mg/m2 daily by IV infusion over 1 hour on days 1, 2, 3 and 4 (total 4 doses). * Cytarabine:100 mg/m2 12 hourly by IV bolus on days 1-10 inclusive (total 20 doses). Course 2 * Mitoxantrone: 12 mg/m2 daily by IV infusion over 1 hour on days 1, 2 and 3 (total 3 doses). * Cytarabine: 100 mg/m2 12 hourly by IV bolus on days 1-8 inclusive (total 16 doses).

Drug: Mitoxantrone; Drug: Cytarabine

Liposomal daunorubicin

EXPERIMENTAL

Randomisation 1 (R1)) closed early to recruitment on 8th September 2017, due to liposomal daunorubicin manufacturing issues resulting in unavailability of the drug. Course 1 * Liposomal daunorubicin: 80 mg/m2 daily by 1 hour IV infusion on days 1, 3 and 5 (total 3 doses). * Cytarabine: 100 mg/m2 12 hourly by IV bolus on days 1-10 inclusive (total 20 doses). Course 2 * Liposomal daunorubicin: 60 mg/m2 daily by 1 hour IV infusion on days 1, 3 and 5 (total 3 doses). * Cytarabine: 100 mg/m2 12 hourly by IV bolus on days 1-8 inclusive (total 16 doses).

Drug: Liposomal daunorubicin; Drug: Cytarabine

Gemtuzumab Ozogamicin Dose Finding Study

EXPERIMENTAL

* Cohort 1: 1x3mg/m2 IV infusion over 2hours on day 4. * Cohort 2: 2x3mg/m2 IV infusion over 2hours on day 4 and day 7. * Cohort 3: 3x3mg/m2 IV infusion over 2hours on days 4, 7 and 10.

Drug: Gemtuzumab ozogamicin

High dose cytarabine

ACTIVE COMPARATOR

Two courses of Cytarabine: 3 g/m2 12 hourly by IV infusion over 4 hours on days 1, 3 and 5 (total 6 doses).

Drug: Cytarabine

Fludarabine & cytarabine

EXPERIMENTAL

Two courses of: * Fludarabine: 30 mg/m2 daily by IV infusion over 30 minutes on days 1-5 inclusive (total 5 doses). * Cytarabine: 2 g/m2 daily by IV infusion over 4 hours on days 1-5 inclusive (total 5 doses).The cytarabine infusion should be started 4 hours after the start of the fludarabine infusion

Drug: Fludarabine; Drug: Cytarabine

Myeloablative conditioning

ACTIVE COMPARATOR

* Busulfan Area Under the Curve (AUC) 70-100mg/L x hr by IV infusion over 3 hours, given 12 hourly on days -10 to -7 (8 doses). * Cyclophosphamide 50mg/kg/day by IV infusion over 1 hour, on days -5 to -2 (4 doses).

Drug: Busulfan; Drug: Cyclophosphamide

Reduced intensity conditioning

EXPERIMENTAL

* Busulfan AUC60-65mg/L X hr by IV infusion over 3 hours, given 12 hourly on days -5 to -2 (8 doses). * Fludarabine 30mg/m2/day by IV infusion over 30 minutes on days -8 to -3 (6 doses).

Drug: Fludarabine; Drug: Busulfan

Interventions

Gemtuzumab ozogamicin DRUG

Antibody-conjugated chemotherapy agent.

Also known as: Mylotarg

Gemtuzumab Ozogamicin Dose Finding Study

Liposomal daunorubicin DRUG

Anthracycline (Randomisation 1 (R1)) closed early to recruitment on 8th September 2017, due to liposomal daunorubicin manufacturing issues resulting in unavailability of the drug.

Liposomal daunorubicin

Mitoxantrone DRUG

DNA-reactive agent

Mitoxantrone

Fludarabine DRUG

A water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabine.

Fludarabine & cytarabine; Reduced intensity conditioning

Cytarabine DRUG

Pyrimidine nucleoside analogue, an antineoplastic agent.

Fludarabine & cytarabine; High dose cytarabine; Liposomal daunorubicin; Mitoxantrone

Busulfan DRUG

Alkylsulfonate

Myeloablative conditioning; Reduced intensity conditioning

Cyclophosphamide DRUG

A nitrogen mustard alkylating agent from the oxazaphosphorine group

Myeloablative conditioning

Eligibility Criteria

• Age: Up to 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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).
• Age \<18 years at trial entry.
• No prior chemotherapy or biological therapy for AML/high risk MDS/isolated MS other than that permitted in the protocol.
• Normal cardiac function defined as fractional shortening ≥28% or ejection fraction ≥55%.
• Fit for protocol chemotherapy.
• Documented negative pregnancy test for female patients of childbearing potential.
• Patient agrees to use effective contraception (patients of child bearing potential).
• Written informed consent from the patient and/or parent/legal guardian.
• Centres must be formally activated in order to be take part in the embedded dose escalation study. Please contact the trial office for further information.
• Age:
• ≥12 months for the major dose finding study
• ≥ 12 weeks and \<12 months for the minor dose finding study
• Normal renal function defined as calculated creatinine clearance ≥90ml/min/1.73m2.
• 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.
• Alanine transaminase (ALT) or aspartate transaminase (AST) ≤10 x ULN for age.

You may not qualify if:

• Acute Promyelocytic Leukaemia.
• Myeloid Leukaemia of 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.

Sponsors & Collaborators

• University of Birmingham: lead
• Assistance Publique - Hôpitaux de Paris: collaborator
• Cancer Research UK: collaborator
• National Cancer Institute, France: collaborator
• Pfizer: collaborator

Study Sites (68)

Women and Children's Hospital Adelaide

Adelaide, Australia

RECRUITING

Queensland Children's Hospital

Brisbane, Australia

RECRUITING

Monash Children's Hospital

Melbourne, Australia

RECRUITING

Royal Childrens Hospital

Melbourne, Australia

RECRUITING

John Hunter Children's Hopsital

New Lambton Heights, Australia

RECRUITING

Perth Children's Hospital

Perth, Australia

RECRUITING

Sydney Children's Hospital

Sydney, Australia

RECRUITING

The Childrens Hospital At Westmead

Westmead, Australia

RECRUITING

Centre Hospitalier Universitaire Amiens - Picardie

Amiens, France

RECRUITING

Centre Hospitalier Universitaire D'angers

Angers, France

RECRUITING

Centre Hospitalier Regional Universitaire Besancon - Hopital Jean Minjoz

Besançon, France

RECRUITING

Centre Hospitalier Universitaire De Bordeaux - Hopital Pellegrin

Bordeaux, France

RECRUITING

Centre Hospitalier Regional Universitaire Brest - Hopital Morvan

Brest, France

RECRUITING

Centre Hospitalier Universitaire De Caen

Caen, France

RECRUITING

Centre Hospitalier Universitaire De Clermont-ferrand

Clermont-Ferrand, France

RECRUITING

Centre Hospitalier Universitaire Dijon Bourgogne - Hopital D'enfants

Dijon, France

RECRUITING

Centre Hospitalier Universitaire De Grenoble

Grenoble, France

RECRUITING

Hopital Jeanne Dr Flandre

Lille, France

RECRUITING

Centre Hospitalier Universitaire De Limoges

Limoges, France

RECRUITING

Centre Leon Berard

Lyon, France

RECRUITING

Hopital De La Timone

Marseille, France

RECRUITING

Centre Hospitalier Regional Universitaire Montpellier - Hopital Arnaud-de-villeneuve

Montpellier, France

RECRUITING

Centre Hospitalier Universitaire De Nancy

Nancy, France

RECRUITING

Centre Hospitalier Universitaire De Nantes

Nantes, France

RECRUITING

Centre Hospitalier Universitaire De NICE

Nice, France

RECRUITING

Hopital Armand Trousseau

Paris, France

RECRUITING

Hopital Robert Debre

Paris, France

RECRUITING

Hopital Saint Louis

Paris, France

RECRUITING

Centre Hospitalier Universitaire De Poitiers

Poitiers, France

RECRUITING

Chu De Reims

Reims, France

RECRUITING

Centre Hospitalier Universitaire De Rennes - Hopital Sud

Rennes, France

RECRUITING

Centre Hospitalier Universitaire De Rouen

Rouen, France

RECRUITING

Centre Hospitalier Universitaire Saint-etienne

Saint-Etienne, France

RECRUITING

Strasbourg Hautepierre

Strasbourg, France

RECRUITING

Centre Hospitalier Universitaire De Toulouse - Hopital Des Enfants

Toulouse, France

RECRUITING

Centre Hospitalier Regional Universitaire De Tours - Hopital Clocheville

Tours, France

RECRUITING

Our Lady's Hospital for Sick Children

Dublin, Ireland

RECRUITING

Starship Childrens Hospital

Auckland, New Zealand

RECRUITING

Christchurch Hospital

Christchurch, New Zealand

RECRUITING

Kantonsspital Aarau

Aarau, Switzerland

RECRUITING

Universitäts-Kinderspital beider

Basel, Switzerland

RECRUITING

Ospedale San Giovanni

Bellinzona, Switzerland

RECRUITING

Inselspital Bern

Bern, Switzerland

RECRUITING

Hug Hopitaux Universitaires De Geneve

Geneva, Switzerland

RECRUITING

Centre Hospitalier Universitaire Vaudois Chuv Lausanne

Lausanne, Switzerland

RECRUITING

Luzerner Kantonspital - Kinderspital Luzern

Lucerne, Switzerland

RECRUITING

Ostschweizer Kinderspital

Sankt Gallen, Switzerland

RECRUITING

University Children's Hospital Zurich

Zurich, Switzerland

RECRUITING

Royal Belfast Hospital for Sick Children

Belfast, County Antrim, BT12 6BE, United Kingdom

RECRUITING

Royal Aberdeen Children's Hospital

Aberdeen, AB25 2ZG, United Kingdom

RECRUITING

Aberdeen Royal Infirmary, NHS Grampian

Aberdeen, AB25 2ZN, United Kingdom

RECRUITING

Birmingham Children's Hospital NHS Foundation Trust

Birmingham, B4 6NH, United Kingdom

RECRUITING

University Hospitals Bristol NHS Foundation Trust

Bristol, BS1 3NU, United Kingdom

RECRUITING

Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust

Cambridge, CB2 0QQ, United Kingdom

RECRUITING

Cardiff and Vale University Health Board, Noah's Ark Children's Hospital for Wales

Cardiff, CF14 4XW, United Kingdom

RECRUITING

NHS Lothian, Royal Hospital for Sick Children

Edinburgh, EH9 1LF, United Kingdom

RECRUITING

NHS Greater Glasgow and Clyde, The Royal Hospital for Children

Glasgow, G51 4TF, United Kingdom

RECRUITING

Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust

Leeds, LS9 7TF, United Kingdom

RECRUITING

Alder Hey Children's NHS Foundation Trust

Liverpool, L12 2AP, United Kingdom

RECRUITING

University College London Hospitals NHS Foundation Trust

London, NW1 2PG, United Kingdom

RECRUITING

The Royal Marsden NHS Foundation Trust

London, SW3 6JJ, United Kingdom

RECRUITING

Great Ormond Street Hospital For Children NHS Trust

London, WC1N 3JH, United Kingdom

RECRUITING

Royal Manchester Childrens' Hospital , Central Manchester University Hospitals NHS Foundation Trust

Manchester, M13 9WL, United Kingdom

RECRUITING

The Newcastle Upon Tyne Hospitals NHS Foundation Trust

Newcastle, NE7 7DN, United Kingdom

RECRUITING

Nottingham University Hospitals NHS Trust

Nottingham, NG7 2UH, United Kingdom

RECRUITING

John Radcliffe Hospital, Oxford Radcliffe Hospitals NHS Trust

Oxford, OX3 9DU, United Kingdom

RECRUITING

Sheffield Children's NHS Foundation Trust

Sheffield, S10 2TH, United Kingdom

RECRUITING

Southampton University Hospitals NHS Trust

Southampton, SO16 6YD, United Kingdom

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Neoplasm, Residual

Interventions

Gemtuzumab; Daunorubicin; Mitoxantrone; fludarabine; Cytarabine; Busulfan; Cyclophosphamide

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Calicheamicins; Aminoglycosides; Glycosides; Carbohydrates; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Anthraquinones; Anthrones; Anthracenes; Quinones; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Butylene Glycols; Glycols; Alcohols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds

Study Officials

• Brenda Gibson

  Royal Hospital for Children Glasgow

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Christina Ryan

CONTACT

01214151049; myechild01@trials.bham.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 8, 2016
• First Posted: March 31, 2016
• Study Start: April 1, 2016
• Primary Completion (Estimated): December 1, 2031
• Study Completion (Estimated): December 1, 2032
• Last Updated: October 8, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (28); GB (20); CH (9); IE (1); NZ (2); AU (8)