Treatment Study for Children and Adolescents With Acute Promyelocytic Leukemia

Acute Promyelocytic Leukemia Clinical Trial

Official title:

Treatment Study for Children and Adolescents With Acute Promyelocytic Leukemia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04793919
• Other study ID #: ICC APL STUDY 02
• Secondary ID: 2017-002383-40
• Status: Recruiting
• Phase: Phase 2
• Start date: October 9, 2019
• Est. completion date: October 10, 2027

Study information

• Verified date: April 2024
• Source: Associazione Italiana Ematologia Oncologia Pediatrica
• Contact: AIEOP
• Phone: 0039 051 2144667
• Email: studiclinici[@]aieop.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 89
• Est. completion date: October 10, 2027
• Est. primary completion date: October 9, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

Inclusion Criteria:

• Newly diagnosed APL confirmed by the presence of PML/RARa 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/RARa 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

Related Conditions & MeSH terms

• Acute Promyelocytic Leukemia
• Leukemia
• Leukemia, Promyelocytic, Acute

Intervention

Drug:
• Mylotarg
See the protocol
• Arsenic Trioxide
See the protocol
• All-trans retinoic acid
See the protocol

Locations

Country	Name	City	State
Belgium	Hôpital Universitaire des Enfants Reine Fabiola (Huderf)	Brussels
Czechia	University Hospital Motol	Praga
Denmark	Pediatrics and Adolescent Medicine Aarhus University Hospital	Aarhus N
France	CHU de Bordeaux - Hôpital des Enfants	Bordeaux-Cedex
Germany	Universitätsklinikum Essen (AöR) Zentrum für Kinder-und Jugendmedizin Klinik für Kinderheilkunde III	Essen
Ireland	Our Lady's Children's Hospital Crumlin	Dublin
Israel	Rappaport Children'S Hospital, Rambam Health Care Campus	Haifa
Italy	AOU Policlinico Dipartimento di Pediatria	Bari
Italy	Ospedale Papa Giovanni XXIII - USS Oncoematologia Pediatrica	Bergamo
Italy	AOU Policlinico Sant'Orsola-Malpighi - Oncologia ed Ematologia Pediatrica	Bologna
Italy	Ospedale Pediatrico Microcitemico "A.Cau", Az.Ospedaliera Brotzu - SC Oncoematologia Ped. e Patologia della coagulazione	Cagliari
Italy	AOU Policlinico Vittorio Emanuele - UOC Ematologia ed Oncologia Pediatrica con TNO	Catania
Italy	A.O. Universitaria Meyer - DAI Oncoematologia Pediatrica	Firenze
Italy	IRCCS Istituto Gannina Gaslini - Dipartimento di Oncoematologia	Genova
Italy	Fondazione Monza e Brianza per il Bambino e la sua Mamma (MBBM) - Ospedale San Gerardo	Monza
Italy	AORN Santobono-Pausilipon	Napoli
Italy	Univerità degli Studi della Campania- Luigi Vanvitelli - Sevizio di Oncologia Pediatrica	Napoli
Italy	Azienda Ospedaliera di Padova - Oncoematologia Pediatrica	Padova
Italy	ARNAS Civico di Cristina e Benfratelli - UOC Oncoematologia Pediatrica	Palermo
Italy	Fondazione IRCCS Policlinico San Matteo - Oncoematologia Pediatrica	Pavia
Italy	Ospedale santa Chiara - AOU Pisana, UO Oncoematologia Pediatrica	Pisa
Italy	Dipartimento di Onco-Ematologia e Terapia Cellulare e Genica - Ospedale Pediatrico "Bambino Gesù"	Roma
Italy	Policlinico Umberto I Università "LA Sapienza" - Dip. Biotecnologie cellulari ed ematologia UOS Ematologia Pediatrica	Roma
Italy	Ospedale "Casa Sollievo della Sofferenza" - UO Oncoematologia Pediatrica	San Giovanni Rotondo	Foggia
Italy	AOU Città della Salute e della Scienza di Torino - Presidio Infantile Regina Margherita	Torino
Netherlands	VU medisch centrum	Amsterdam
Portugal	Centro Hospitalar Universitário de Coimbra - Hospital Pediátrico de Coimbra	Coimbra
Portugal	Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE	Lisbon
Portugal	Instituto Português de Oncologia do Porto Francisco Gentil, E. P. E.	Porto
Spain	Valencia University Medical School University Hospital La Fe	Valencia
Sweden	Childrens hematology and oncology Uppsala University	Uppsala

Sponsors (1)

Lead Sponsor	Collaborator
Associazione Italiana Ematologia Oncologia Pediatrica

Countries where clinical trial is conducted

Belgium,  Czechia,  Denmark,  France,  Germany,  Ireland,  Israel,  Italy,  Netherlands,  Portugal,  Spain,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event Free Survival (EFS) probability	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	Rate of hematological CR/CRi after induction	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
Secondary	Rate of molecular CR/CRi after induction	To evaluate the rate of molecular CR/CRi (defined as the absence of PML/RARa fusion transcript in bone marrow assessed by RQ-PCR, with an assay sensitivity of at least 10^-4).	5 years
Secondary	Rate of early death during induction	To evaluate the rate of early death during induction (defined as any death occurring within 14 days from diagnosis from any cause).	5 years
Secondary	Probability of overall survival (OS) at 3 years	To evaluate the rate of overall survival	3 years
Secondary	Cumulative incidence of relapse (CIR) at 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/RARa fusion transcript in two successive samples taken at least 2 weeks apart in patients previously in molecular remission).	3 years
Secondary	Incidence of hematological and non-hematological toxicity	Incidence of treatment-related hematological and non-hematological toxicity assessed by CTCAE v4.0	5 years
Secondary	Rate of molecular remission after 3 consolidation cycles	To evaluate the rate of molecular remission (defined as the absence of PML/RARa fusion transcript in bone marrow assessed by RQ-PCR, with an assay sensitivity of at least 10^-4) after 3 consolidation cycles.	5 years
Secondary	Assessment of PML/RARa transcription level reduction during treatment	To evaluate the reduction of PML/RARa fusion transcript in bone marrow by means of RQ-PCR during treatment.	5 years
Secondary	Pediatric Quality of Life assessment	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
Secondary	Total hospitalization days during therapy	Number of total hospitalization days during the treatment.	5 years