Treatment Study for Children and Adolescents With Acute Promyelocytic Leukemia

April 12, 2024 updated by: Associazione Italiana Ematologia Oncologia Pediatrica
The trial is open to all patients with a diagnosis of acute promyelocytic leukemia (APL) who are PCR-positive for the PML-RARα transcript and less than 18 years of age.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Acute promyelocytic leukemia (APL) in children has become a highly curable disease with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy with an overall remission rates equal to or higher than 98% and cure rates now exceeding 80% 1-9.

Based on data coming from adults indicating that at least standard-risk APL patients may be cured without chemotherapy (i.e., with a treatment combining arsenic trioxide (ATO) and ATRA only) 10-12, this ICC APL 02 study was designed with the aim of validating the efficacy of a treatment combining:

  • ATO and ATRA in newly diagnosed APL standard-risk (SR) children and adolescents and
  • ATO, ATRA and gemtuzumab ozogamicin (GO) in newly diagnosed APL high-risk (HR) children and adolescents.

Following one induction course of treatment combining ATO and ATRA +/- GO depending on risk stratification, patients will receive 4 ATO/ATRA based consolidation blocks. This is the first pediatric trial delivering a non-chemotherapy-based treatment for children with APL, being the whole treatment based on the use of ATRA, ATO (and GO in HR patients). The aim of the study is to demonstrate at least an equivalent efficacy and safety of this treatment not containing cytostatic agents compared to the standard protocols combining ATRA and chemotherapy (i.e. ICC APL Study 01).

The trial is open to all patients with a diagnosis of acute promyelocytic leukemia (APL) who are PCR-positive for the PML-RARα transcript and less than 18 years of age.

This will be an international study, comprising the most important pediatric European groups, expecting to recruit 46 and 43 patients in SR and HR arms, respectively, in 3 years. The duration of study recruitment will be 36 months with a minimum follow-up per patient of 2 years.

The evaluation of morphological CR will be carried out after induction therapy, prior to the first block of consolidation therapy. MRD results after induction will not have an impact on subsequent therapy. By contrast, MRD results after the third consolidation course will influence the subsequent treatment, MRD-positive patients being eligible to rescue treatment, including hematopoietic stem cell transplantation (HSCT). BM aspirates will be repeated after the end of therapy, and 3 months, 6 months, 9 months and 12 months after treatment discontinuation.

This is a collaborative international study in APL in children and adolescents aimed at providing information about procedures for the entry, treatment and follow-up of pediatric patients with APL. It is not intended that this document be used as an aide-memoir or guide for the treatment of other patients. Every care has been taken in its drafting, but corrections and amendments may be necessary. Before entering patients into the study, clinicians must ensure that the study has received clearance from their Local Research Ethics Committee and any other necessary body.

Study Type

Interventional

Enrollment (Estimated)

89

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Belgium
      • Brussels, Belgium, 1020
        • Not yet recruiting
        • Hôpital Universitaire des Enfants Reine Fabiola (HUDERF)
        • Contact:
  • Czechia
      • Praga, Czechia, 15006
        • Not yet recruiting
        • University Hospital Motol
        • Contact:
  • Denmark
      • Aarhus N, Denmark, 8200
        • Not yet recruiting
        • Pediatrics and Adolescent Medicine Aarhus University Hospital
        • Contact:
          • Henrik Hasle, Prof.
  • France
  • Germany
      • Essen, Germany, 45147
        • Not yet recruiting
        • Universitätsklinikum Essen (AöR) Zentrum für Kinder-und Jugendmedizin Klinik für Kinderheilkunde III
        • Contact:
  • Ireland
      • Dublin, Ireland, 12
        • Not yet recruiting
        • Our Lady's Children's Hospital Crumlin
        • Contact:
  • Israel
      • Haifa, Israel
        • Not yet recruiting
        • Rappaport Children'S Hospital, Rambam Health Care Campus
        • Contact:
  • Italy
      • Bari, Italy, 70124
        • Not yet recruiting
        • AOU Policlinico Dipartimento di Pediatria
      • Bergamo, Italy, 24100
        • Not yet recruiting
        • Ospedale Papa Giovanni XXIII - USS Oncoematologia Pediatrica
        • Contact:
          • Massimo Provenzi, Dr
      • Bologna, Italy, 40138
        • Recruiting
        • AOU Policlinico Sant'Orsola-Malpighi - Oncologia ed Ematologia Pediatrica
        • Contact:
          • Andrea Pession, Prof
      • Cagliari, Italy, 09121
        • Recruiting
        • Ospedale Pediatrico Microcitemico "A.Cau", Az.Ospedaliera Brotzu - SC Oncoematologia Ped. e Patologia della coagulazione
        • Contact:
          • Rosamaria Mura, Dr
      • Catania, Italy, 95123
        • Recruiting
        • AOU Policlinico Vittorio Emanuele - UOC Ematologia ed Oncologia Pediatrica con TNO
        • Contact:
          • Luca Lo Nigro, Dr
      • Firenze, Italy, 50139
        • Not yet recruiting
        • A.O. Universitaria Meyer - DAI Oncoematologia Pediatrica
        • Contact:
          • Tommaso Casini, Dr
      • Genova, Italy, 16147
        • Recruiting
        • IRCCS Istituto Gannina Gaslini - Dipartimento di Oncoematologia
        • Contact:
          • Concetta Micalizzi, Dr
      • Monza, Italy, 20900
        • Recruiting
        • Fondazione Monza e Brianza per il Bambino e la sua Mamma (MBBM) - Ospedale San Gerardo
        • Contact:
          • Carmelo Rizzari, Dr
      • Napoli, Italy, 80123
        • Recruiting
        • AORN Santobono-Pausilipon
        • Contact:
          • Giuseppe Menna, Dr
      • Napoli, Italy, 80138
        • Recruiting
        • Univerità degli Studi della Campania- Luigi Vanvitelli - Sevizio di Oncologia Pediatrica
        • Contact:
          • Francesca Rossi, Prof
      • Padova, Italy, 35128
        • Not yet recruiting
        • Azienda Ospedaliera di Padova - Oncoematologia Pediatrica
        • Contact:
          • Alessandra Biffi, Prof
      • Palermo, Italy, 90127
        • Not yet recruiting
        • ARNAS Civico di Cristina e Benfratelli - UOC Oncoematologia Pediatrica
        • Contact:
          • Paolo D'Angelo, Dr
      • Pavia, Italy, 27100
        • Recruiting
        • Fondazione IRCCS Policlinico San Matteo - Oncoematologia Pediatrica
        • Contact:
          • Marco Zecca, Dr
      • Pisa, Italy, 56126
        • Not yet recruiting
        • Ospedale santa Chiara - AOU Pisana, UO Oncoematologia Pediatrica
        • Contact:
          • Gabriella Casazza, Dr
      • Roma, Italy, 00161
        • Not yet recruiting
        • Policlinico Umberto I Università "LA Sapienza" - Dip. Biotecnologie cellulari ed ematologia UOS Ematologia Pediatrica
        • Contact:
          • Anna Maria Testi, Dr
      • Roma, Italy, 00165
        • Recruiting
        • Dipartimento di Onco-Ematologia e Terapia Cellulare e Genica - Ospedale Pediatrico "Bambino Gesù"
        • Contact:
          • Valentina Cirillo, Dr
        • Principal Investigator:
          • Franco Locatelli, Prof
      • Torino, Italy, 10126
        • Recruiting
        • AOU Città della Salute e della Scienza di Torino - Presidio Infantile Regina Margherita
        • Contact:
          • Franca Fagioli, Prof
    • Foggia
      • San Giovanni Rotondo, Foggia, Italy, 71013
        • Recruiting
        • Ospedale "Casa Sollievo della Sofferenza" - UO Oncoematologia Pediatrica
        • Contact:
          • Saverio Ladogana, Dr
  • Netherlands
      • Amsterdam, Netherlands
        • Not yet recruiting
        • VU Medisch Centrum
        • Contact:
          • Gertjan Kasper, Prof. dr.
  • Portugal
      • Coimbra, Portugal, 3000-602
        • Not yet recruiting
        • Centro Hospitalar Universitário de Coimbra - Hospital Pediátrico de Coimbra
        • Contact:
          • Manuel Brito, Dr.
      • Lisbon, Portugal, 1099-023
        • Not yet recruiting
        • Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE
        • Contact:
          • Ximo Duarte, Dr.
      • Porto, Portugal, 4200-072
        • Not yet recruiting
        • Instituto Português de Oncologia do Porto Francisco Gentil, E. P. E.
        • Contact:
          • Vítor Costa, Dr.
  • Spain
      • Valencia, Spain, 46026
        • Not yet recruiting
        • Valencia University Medical School University Hospital La Fe
        • Contact:
  • Sweden
      • Uppsala, Sweden, .O. Box 256, SE-751 05

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 14 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Newly diagnosed APL confirmed by the presence of PML/RARα fusion gene
  • Age <18 years
  • Written informed consent by parents or legal guardians

Exclusion Criteria:

  • Patients with a clinical diagnosis of APL but subsequently found to lack PML/RARα rearrangement should be withdrawn from the study and treated on an alternative protocol
  • Significant liver dysfunction (bilirubin serum levels >3 mg/dL, ALT/AST serum levels greater than 5 times the normal values)
  • Creatinine serum levels >2 times the normal value for age
  • Significant arrhythmias, EKG abnormalities (*see below), other cardiac contraindications (L-FEV <50% or LV-FS <28%)
  • Neuropathy
  • Concurrent active malignancy
  • Uncontrolled life-threatening infections
  • Pregnant or lactating female
  • Patients who had received alternative therapy (APL not initially suspected; ATRA and/or ATO not available

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Standard Risk (SR)
Patient with APL and WBC less than 10x10e9/L at presentation before start treatment
Drug: Arsenic Trioxide
See the protocol
Other Names:
  • ATO
Drug: All-trans retinoic acid
See the protocol
Other Names:
  • ATRA
Experimental: High Risk (HR)
Patient with APL, with the highest pre-treatment WBC count equal to or greater than 10x10e9/L at presentation
Drug: Arsenic Trioxide
See the protocol
Other Names:
  • ATO
Drug: All-trans retinoic acid
See the protocol
Other Names:
  • ATRA
Drug: Mylotarg
See the protocol
Other Names:
  • GO

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Event Free Survival (EFS) probability
Time Frame: 3 years
SR patients: To evaluate the efficacy in terms of event-free survival of a treatment combining arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) in newly diagnosed APL standard-risk children and adolescents HR patients: To evaluate the efficacy in terms of event-free survival of a treatment combining arsenic trioxide (ATO), all-trans retinoic acid (ATRA) and gemtuzumab ozogamicin (GO) in newly diagnosed APL high-risk children and adolescents
3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of hematological CR/CRi after induction
Time Frame: 5 years
To evaluate the rate of hematological Complete Remission (CR) (defined as bone marrow regenerating normal hematopoietic cells and containing < 5% blast cells by morphology, with ANC in peripheral blood > 1.0 x 10^9/L and platelet count > 100 x 10^9/L) and Complete Remission with incomplete hematologic recovery (CRi) (defined as CR except that peripheral blood neutrophils and/or platelets do not meet the criteria as defined above) after induction therapy.
5 years
Rate of molecular CR/CRi after induction
Time Frame: 5 years
To evaluate the rate of molecular CR/CRi (defined as the absence of PML/RARα fusion transcript in bone marrow assessed by RQ-PCR, with an assay sensitivity of at least 10^-4).
5 years
Rate of early death during induction
Time Frame: 5 years
To evaluate the rate of early death during induction (defined as any death occurring within 14 days from diagnosis from any cause).
5 years
Probability of overall survival (OS) at 3 years
Time Frame: 3 years
To evaluate the rate of overall survival
3 years
Cumulative incidence of relapse (CIR) at 3 years
Time Frame: 3 years
To evaluate the cumulative incidence of hematological relapse (defined as reappearance of promyeloblasts/abnormal promyelocytes > 5% in the bone marrow) and molecular relapse (defined as reappearance of PML/RARα fusion transcript in two successive samples taken at least 2 weeks apart in patients previously in molecular remission).
3 years
Incidence of hematological and non-hematological toxicity
Time Frame: 5 years
Incidence of treatment-related hematological and non-hematological toxicity assessed by CTCAE v4.0
5 years
Rate of molecular remission after 3 consolidation cycles
Time Frame: 5 years
To evaluate the rate of molecular remission (defined as the absence of PML/RARα fusion transcript in bone marrow assessed by RQ-PCR, with an assay sensitivity of at least 10^-4) after 3 consolidation cycles.
5 years
Assessment of PML/RARα transcription level reduction during treatment
Time Frame: 5 years
To evaluate the reduction of PML/RARα fusion transcript in bone marrow by means of RQ-PCR during treatment.
5 years
Pediatric Quality of Life assessment
Time Frame: 5 years
Pediatric Quality of life assessed by PedsQoL questionnaire, in the questionnaire there is a list of things that might be a problem for the child. The minimum value is 0 (never a problem) - maximum value 4 (almost always problem)
5 years
Total hospitalization days during therapy
Time Frame: 5 years
Number of total hospitalization days during the treatment.
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Associazione Italiana Ematologia Oncologia Pediatrica

Investigators

  • Principal Investigator: Fanco Locatelli, Prof, Dept. of Pediatric Hematology Oncology - Bambino Gesù Children's Hospital Rome

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 9, 2019

Primary Completion (Estimated)

October 9, 2025

Study Completion (Estimated)

October 10, 2027

Study Registration Dates

First Submitted

November 13, 2019

First Submitted That Met QC Criteria

March 10, 2021

First Posted (Actual)

March 11, 2021

Study Record Updates

Last Update Posted (Estimated)

April 15, 2024

Last Update Submitted That Met QC Criteria

April 12, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ICC APL STUDY 02
  • 2017-002383-40 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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