Risk-adapted, MRD-directed Therapy for Young Adults With Newly Diagnosed Acute Myeloid Leukemia

Acute Myeloid Leukemia Clinical Trial

— AML1310  

Official title:

Risk-adapted, MRD-directed Therapy for Young Adults With Newly Diagnosed Acute Myeloid Leukemia. GIMEMA Protocol AML1310. EudraCT Number 2010-023809-36

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01452646
• Other study ID #: AML1310
• Status: Completed
• Phase: Phase 2
• Start date: January 2012
• Est. completion date: July 10, 2018

Study information

• Verified date: August 2018
• Source: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether a risk-adapted, minimal-residual-disease directed therapy for young adults with newly diagnosed acute myeloid leukemia has positive results in terms of overall survival at 24 months.

Description:

The general objective of this study is that of setting up a multicentre, risk-adapted study that relies on pre-treatment cytogenetic/genetic features and post-consolidation assessment of Minimal Residual Disease (MRD) to establish the final risk assignment and treatment of younger (≤ 60 years) patients with Acute Myeloid Leukemia (AML). Aim of this clinical trial is to verify whether the delivery of a post remission therapy whose intensity is risk-driven will improve the outcome in terms of both increased anti-leukemic efficacy and reduced therapy-related toxicity.

All patients will receive induction and consolidation chemotherapy according to the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) LAM99P protocol. After the first consolidation, patients belonging to the low-risk category (core binding factor positive AML without c-Kit mutations, NPM1 positive FLT3 negative AML) will receive autologous stem cell transplantation, patients with high-risk features (adverse-risk karyotype, FLT3-ITD mutations), will be assigned to allogeneic stem cell transplantation. Patients with FLT3-TKD mutations or c-Kit mutated core binding factor positive AML and those belonging to the intermediate-risk karyotype category will be stratified according to MRD by flow cytometry and will receive risk-adapted treatment (autologous vs. allogeneic stem cell transplantation). All patients who meet the criteria for high-risk definition will be offered the allogeneic transplantation option regardless of the availability of a Human Leukocyte Antigen (HLA) identical sibling. In fact, for those lacking a HLA identical sibling all the other sources of hematopoietic stem cells (matched unrelated donor from international registry, unrelated cord blood, family haploidentical donor) will be considered. Autologous or allogeneic stem cell transplantation will be performed within 3 months from the end of consolidation therapy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 515
• Est. completion date: July 10, 2018
• Est. primary completion date: July 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• Signed written informed consent according to ICH/EU/GCP and national/local laws

• Patients aged between 18 and 60 years

• Patients previously untreated for their AML by other chemotherapeutic agents (with the exception of no more than 7 days hydroxyurea (HU)), radiotherapy or more than 7 days corticosteroids

• Unequivocal diagnosis of untreated de novo AML according to WHO diagnostic criteria (at least 20% blasts in the bone marrow), with FAB classification other than M3 (acute promyelocytic leukemia), documented by bone marrow aspiration (or biopsy in case of dry tap) (not supervening after other myeloproliferative disease or myelodysplastic syndromes of more than 6 months duration)

• WHO performance status 0-3

• Adequate renal (serum creatinine < 2 x the institutional Upper Limit of Normal (ULN)) and liver (total serum bilirubin < 2 x ULN; serum ALT and AST = 3 x ULN) function, unless considered due to organ leukemic involvement

• Left Ventricular Ejection Fraction (LVEF) >50%, as determined by echocardiogram

• Absence of severe concomitant neurological or psychiatric diseases and congestive heart failure or active uncontrolled infection

• Absence of any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and the follow-up schedule.

Exclusion Criteria:

• Patients aged less than 18 or more than 60 years

• Patients already treated for their AML by other chemotherapeutic agents (with the exception of no more than 7 days HU), radiotherapy or more than 7 days corticosteroids

• Acute promyelocytic leukaemia

• Blast crisis of chronic myeloid leukaemia

• AML supervening after other myeloproliferative disease

• AML supervening after antecedent myelodysplastic syndromes of more than 6 months duration

• Other progressive malignant diseases. However, secondary AML following previously cured malignancies may be included as well as secondary AML following previous exposure to alkylating agents or radiation for other reason

• Inadequate renal or liver function (metabolic abnormalities > 3 times the normal upper limit)

• Severe heart failure requiring diuretics

• Ejection fraction < 50%

• Uncontrolled infections

• WHO performance status = 4

• Severe concomitant neurological or psychiatric diseases

• Patients who are pregnant or adults of reproductive potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of chemotherapy. Post-menopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Other:
• Risk-adapted, MRD-directed therapy
The general objective of this study is that of setting up a multicentre, risk-adapted study that relies on pre-treatment cytogenetic/genetic features and post-consolidation assessment of MRD to establish the final risk assignment and treatment of younger (= 60 years) patients with AML. Aim of this clinical trial is to verify whether the delivery of a post remission therapy whose intensity is risk-driven will improve the outcome in terms of both increased anti-leukemic efficacy and reduced therapy-related toxicity.

Locations

Country	Name	City	State
Italy	S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo	Alessandria
Italy	Azienda Ospedaliera - Nuovo Ospedale "Torrette"	Ancona
Italy	Az. Ospedaliera S. G. Moscati	Avellino
Italy	Unità Operativa Ematologia 1 - Università degli Studi di Bari	Bari
Italy	UOC Ematologia Ospedale " Monsignor Raffaele Dimiccoli"	Barletta
Italy	Ist.Ematologia e Oncologia Medica L.e A. Seragnoli	Bologna
Italy	Divisione di Ematologia Ospedale A. Perrino	Brindisi
Italy	Servizio di Ematologia - CTMO - ASL 8 P.O. Binaghi	Cagliari
Italy	Unità Operativa Complessa di Onco-Ematologia - A.O. S.Anna e S.Sebastiano	Caserta
Italy	Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"	Catania
Italy	Azienda Ospedaliera Pugliese Ciaccio	Catanzaro
Italy	Marche U.O. di Medicina Interna - ASUR Marche 8 - Ospedale Civile	Civitanova
Italy	Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi	Cona
Italy	Sezione di Ematologia C.T.M.O. Istituti Ospitalieri	Cremona
Italy	Sez.Ematologia e Dip. scienze Biomediche Arcispedale S. Anna	Ferrara
Italy	Struttura Complessa di Ematologia Ospedali Riuniti Foggia - Azienda Ospedaliero-Universitaria	Foggia
Italy	Clinica Ematologica - Università degli Studi	Genova
Italy	Divisione di Ematologia Ospedale "Santa Maria Goretti"	Latina
Italy	ASL Le/1 P.O. Vito Fazzi - U.O. di Ematol	Lecce
Italy	Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori- IRST	Meldola
Italy	Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina	Messina
Italy	Divisione di Ematologia - Azienda Ospedaliera Ospedali Riuniti "Papardo Piemonte"	Messina
Italy	Ospedale Niguarda " Ca Granda"	Milano
Italy	UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico	Milano
Italy	Centro Oncologico Modenese - Dipartimento di Oncoematologia	Modena
Italy	Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia	Napoli
Italy	Pr. Alfonso Maria D'Arco	Nocera Inferiore
Italy	S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro	Novara
Italy	Ospedale S. Luigi Gonzaga	Orbassano
Italy	Università degli Studi di Padova - Ematologia ed Immunologia Clinica	Padova
Italy	Divisione di Ematologia con trapianto di midollo - A.U. Policlinico "Paolo Giaccone"	Palermo
Italy	Ospedale Riuniti "Villa-Sofia-Cervello"	Palermo
Italy	Cattedra di Ematologia CTMO Università degli Studi di Parma	Parma
Italy	Sezione di Ematologia ed Immunologia Clinica - Ospedale S.Maria della MIsericordia	Perugia
Italy	Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore	Pesaro
Italy	Azienda ASL di Pescara	Pescara
Italy	Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza	Piacenza
Italy	Università di Pisa - Azienda Ospedaliera Pisana - Dipartimento di Oncologia, dei Trapianti e delle nuove Tecnologie in Medicina - Divisione di Ematologia	Pisa
Italy	Ematologia - Ospedale San Carlo	Potenza
Italy	Ospedale S.Maria delle Croci	Ravenna
Italy	Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"	Reggio Calabria
Italy	Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova	Reggio Emilia
Italy	Ospedale "Infermi"	Rimini
Italy	Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia	Roma
Italy	Complesso Ospedaliero S. Giovanni Addolorata	Roma	(rm)
Italy	Divisione Ematologia - Università Campus Bio-Medico	Roma
Italy	S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena	Roma
Italy	Università Cattolica del Sacro Cuore - Policlinico A. Gemelli	Roma
Italy	Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia	Roma
Italy	Ospedale S. Camillo	Rome
Italy	Policlinico di Tor Vergata	Rome	(rm)
Italy	U.O.C. Ematologia - Ospedale S.Eugenio	Rome
Italy	Sezione di Ematologia Cancer Center Humanitas	Rozzano
Italy	Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo
Italy	Serv. di Ematologia Ist. di Ematologia ed Endocrinologia	Sassari
Italy	U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"	Siena
Italy	UOC di Ematologia Generale P.O. S.Vincenzo	Taormina
Italy	U.O.C. di Ematolgia - A.O. " SS Annunziata" - P.O. S.G. Moscati	Taranto
Italy	Azienda U.L.S.S.9 - U.O. di Ematologia	Treviso
Italy	U.O. di Ematologia - Azienda Ospedaliera - Pia Fondazione di Culto e di Religione Card. G.Panico	Tricase	(le)
Italy	Policlinico Universitario - Clinica Ematologia	Udine

Sponsors (1)

Lead Sponsor	Collaborator
Gruppo Italiano Malattie EMatologiche dell'Adulto

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Treatment strategy in terms of Overall Survival (OS) at 24 months.	OS is defined as the time interval between the date of study entry and death for any cause; patients still alive will be censored at the time of the last follow-up.	24 months from study entry.
Secondary	Estimation of Disease Free Survival (DFS) from Complete Response (CR) evaluation.	DFS is defined as the time interval between the evaluation of CR -after induction phase- and relapse or death in CR; patients still alive, in first CR, will be censored at the time of the last follow-up.	At 24 months from study entry
Secondary	Estimation of Event Free Survival (EFS) from study entry.	EFS is defined as the time interval between the date of study entry dose and failure during induction phase, relapse or death whichever comes first; patients still alive, in first CR, will be censored at the time of the last follow-up.	at 24 months from study entry
Secondary	Rate of patients in CR after induction therapy		At 31 days from study entry if pts are in CR or at 69 days from study entry if pts are in PR after 1 induction cycle
Secondary	Toxicity according to Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0		From study entry to study completion (6 months therapy + 18 months follow-up)
Secondary	Estimation of OS, EFS, DFS and Cumulative Incidence of Relapse (CIR) according to risk groups (Low, Intermediate, High)	CIR is calculated from the date of achievement of the CR -after induction phase-, using the cumulative incidence method, considering death in CR as a competing risk. Patients still alive, without relapse, will be censored at the time of the last follow-up.	At 24 months from study entry
Secondary	Estimation of OS, EFS, DFS and CIR according to the Minimal Residual Disease (MRD) level at each evaluation step		At 24 months from study entry
Secondary	Rate of CR patients and estimation OS, EFS, DFS and CIR according to baseline characteristics such as age, performance status, white blood cell (WBC), morphology, cytogenetic and molecular features.		At 24 months from study entry
Secondary	Quality of Life evaluation	QoL should be measured at three different time points: At Baseline (before treatment starts).; At the end of Induction phase (after evaluation of response and before start of consolidation therapy for patients in CR or salvage therapy for patients not achieving a CR).; At one year after baseline evaluation.	Before treatment starts, after induction, at one year after baseline evaluation.

External Links

•   GIMEMA Foundation Website