Clinical trial NCT02067143: MRD/Risk-oriented Therapy of Adult Ph- ALL Including Pegylated Asparaginase and Lineage-targeted Methotrexate
Official title: National Treatment Program of Philadelphia Chromosome-negative Adult Acute Lymphoblastic Leukemia With Pegylated Asparaginase Added to a Lineage-Targeted Risk- and Minimal Residual Disease-Oriented Strategy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Untreated Philadelphia Positive Acute Lymphoblastic Leukemia
De Novo
Secondary
Low-dose Corticosteroids Pretreatment
Keywords: Untreated philadelphia positive acute lymphoblastic leukemia
De novo
Secondary
Low-dose corticosteroids pretreatment
Pegylated asparaginase
Lineage-targeted risk and minimal residual disease
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2014-02-20
Enrollment: 204
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study will be conducted in different centres and will study adult patients with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL). The study treatment will include a induction/consolidation therapy incorporating pegylated Asparaginase (Peg-ASP) and lineage-targeted high-dose methotrexate plus other antileukemic drugs, for the achievement of an early negative minimal residual disease (MRD) status. The MRD study supports a risk/MRD-oriented final consolidation phase.

Detailed description: The aim of this clinical study in adult ALL is to improve , by risk category, the overall disease-free survival in relation to the achievement of an early MRD negative status and following induction/consolidation with Peg-ASP, lineage-targeted methotrexate infusions and other disease-specific therapeutic elements, with or without the application of allogeneic or autologous SCT depending on risk class and MRD study results. A survey of severe infections occurring along the entire chemotherapy and stem cell transplant program and until 2 years from the achievement of CR will be performed with the aim to increase the knowledge of these complications and to evaluate their impact on the antileukemic program and on the long term outcome of the underlying malignancy. The prospective survey of severe infections will be performed as an ancillary observational objective of the present study.

Eligibility criteria: Inclusion Criteria:

* Signed written informed consent according to ICH/EU/GCP and national local laws.
* Age 18-65 years.
* A diagnosis of untreated Ph- ALL or LL is required, either de novo or secondary to chemo-radiotherapy for other cancer. Pretreatment with low-dose corticosteroids in patients presenting with hyperleukocytosis is allowed. All diagnostic procedures need to be performed on freshly obtained bone marrow (BM) and peripheral blood (PB) samples. The diagnosis must be one of: de novo ALL, secondary ALL, B-/T-cell LL Full cytological, cytochemical, cytogenetic and immunobiological disease characterization according to EGIL and WHO classifications. Bone marrow and peripheral blood sampling (ALL) or biopsy specimen (LL) are required for MRD study. Detailed indications on patient registration, storage of representative diagnostic material and diagnostic work-up, including the forwarding of samples for MRD study are given in Appendix B.
* Bone marrow and peripheral blood sampling (ALL) or biopsy specimen (LL) for MRD study.
* ECOG performance status 0-2, unless a performance of 3 is unequivocally caused by the disease itself and not by preexisting comorbidity, and is considered and/or documented to be reversible following the application of antileukemic therapy and appropriate supportive measures.

Exclusion Criteria:

* Diagnosis of Burkitt's leukemia or lymphoma.
* Down's syndrome
* Pre-existing, uncontrolled pathology such as heart failure (congestive/ischemic, acute myocardial infarction within the past 3 months, untreatable arrhythmias, NYHA classes III and IV), severe liver disease with serum bilirubin \>3 mg/dL and/or ALT \>3 x upper normal limit (unless attributable to ALL), kidney function impairment with serum creatinine \>2 mg/dL (unless attributable to ALL), and severe neuropsychiatric disorder that impairs the patient's ability to understand and sign the informed consent, or to cope with the intended treatment plan. N.B. For altered liver and kidney function tests, eligibility criteria can be reassessed at 24-96 hours, following the institution of adequate supportive measures.
* Pre-existing HIV positive serology (i.e. already known before enrolment). If HIV positivity is detected after enrolment, the patient is sent off study.
* A history of cancer that is not in a remission phase following surgery and/or radiotherapy and/or chemotherapy, with life expectancy \<1 year.
* Pregnancy declared by the patient herself, unless a decision is taken with the patient to induce a therapeutic abortion in order to carry on with ALL therapy. A pregnancy test is performed at diagnosis but does not preclude the enrolment into study. Fertile patients will be advised to adopt contraceptive methods while on treatment.

Primary outcomes:
measure: Number of patients on disease free survival (DFS).
timeFrame: At two years.
Secondary outcomes:
measure: The rate of patients in complete remission (CR).
timeFrame: After approximately two months from start of treatment.
measure: The rate of early bone marrow MRD negativity.
timeFrame: At 4 timepoints (week 4, 10, 16 22).
measure: Early bone marrow MRD response (<10-4).
timeFrame: At 4 weeks following induction cycle 1 with Peg-ASP.
measure: Overall Survival (OS) estimation.
timeFrame: At two years from diagnosis.
measure: Cumulative Incidence of Relapse (CIR) estimation.
timeFrame: At two years from CR achievement.
measure: The rate of patients dead due Treatment-related mortality (TRM).
timeFrame: By the end of the study (4.5 years from first centre opened).
measure: Composite DFS, OS, CIR.
timeFrame: At two years from CR achievement and rate of TRM in LL patients.
measure: Description of Minimal Residual Disease (MRD) monitoring.
timeFrame: During treatment at time point 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12.
measure: Number of Severe Infections (SI) during treatment.
timeFrame: At the end of the study (4.5 years from first centre opened).
measure: Rate of Adverse Events (AE).
timeFrame: By the end of the study (4.5 years from first centre opened)
measure: Composite evaluation of impact of age (≤55 and >55) and risk category group (SR, HR, VHR - as defined) on outcomes: DFS, CIR.
timeFrame: At two years for CR achievement, OS at two years from diagnosis and TRM.
Other outcomes:
Locations:
city: Alessandria
country: Italy
facility: S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo
city: Ancona
country: Italy
facility: Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. LANCISI - G. SALESI
city: Ascoli Piceno
country: Italy
facility: U.O.C. Ematologia e Terapia Cellulare - Ospedale "C. e G. Mazzoni" di Ascoli Piceno
city: Avellino
country: Italy
facility: Az.Ospedaliera S.G.Moscati
city: Bari
country: Italy
facility: UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro
city: Bergamo
country: Italy
facility: Azienda Ospedaliera - Papa Giovanni XXIII
city: Bologna
country: Italy
facility: Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi
city: Bolzano
country: Italy
facility: Comprensorio Sanitario di Bolzano - Azienda Sanitaria dell'Alto Adige - Ematologia e Centro TMO - Ospedale S.Maurizio
city: Brescia
country: Italy
facility: Spedali Civili - Brescia - Azienda Ospedaliera - U.O. Ematologia
city: Brindisi
country: Italy
facility: Divisione di Ematologia Ospedale A. Perrino
city: Cagliari
country: Italy
facility: Ao Brotzu, Presidio Ospedaliero A. Businco - Cagliari - Sc Ematologia E Ctmo
city: Cagliari
country: Italy
facility: CTMO - Ematologia - Ospedale "Binaghi"
city: Caserta
country: Italy
facility: Unità Operativa Complessa di Onco-Ematologia - A.O. S.Anna e S.Sebastiano
city: Catania
country: Italy
facility: Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
city: Cona
country: Italy
facility: Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova
city: Cremona
country: Italy
facility: Sezione di Ematologia C.T.M.O. Istituti Ospitalieri
city: Cuneo
country: Italy
facility: S.C. Ematologia ASO S. Croce e Carle
city: Genova
country: Italy
facility: IRCCS_AOU San Martino-IST.Clinica Ematologica
city: Lecce
country: Italy
facility: ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE
city: Messina
country: Italy
facility: Divisione di Ematologia - Azienda Ospedaliera Ospedali Riuniti "Papardo Piemonte" P.O. Papardo
city: Mestre
country: Italy
facility: U.O. di Ematologia- Ospedale dell'Angelo - Mestre
city: Milano
country: Italy
facility: Fondazione Irccs Ca' Granda, Ospedale Maggiore Policlinico - Milano - Ematologia - Padiglione Marcora
city: Milano
country: Italy
facility: Ospedale Niguarda " Ca Granda" - SC Ematologia Blocco SUD, Ponti Est, Scala E, 4° piano
city: Milano
country: Italy
facility: U.O. Ematologia e Trapianto di MIdollo - Ist.Scientifico Ospedale San Raffaele
city: Modena
country: Italy
facility: UO Ematologia - AOU Policlinico di Modena
city: Monza
country: Italy
facility: Azienda Ospedaliera "S.Gerardo"
city: Napoli
country: Italy
facility: Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli"
city: Novara
country: Italy
facility: S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro
city: Nuoro
country: Italy
facility: U.O. CTMO Ematologia - Osp. S.Francesco
city: Orbassano
country: Italy
facility: Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2
city: Padova
country: Italy
facility: Università degli Studi di Padova - Ematologia ed Immunologia Clinica
city: Palermo
country: Italy
facility: Ospedali Riuniti "Villa Sofia-Cervello"
city: Palermo
country: Italy
facility: U.O. di Ematologia con trapianto - Centro di Riferimento Regionale per le coagulopatie rare nel bambino e nell'adulto Dipart. Biomedico di Medicina Interna - A.U. Policlinico "Paolo Giaccone"
city: Palmero
country: Italy
facility: Casa Di Cura La Maddalena S.P.A. - Dipartimento Oncologico Di Iii Livello - Palermo - Uo Oncoematologia E Tmo
city: Parma
country: Italy
facility: Day Hospital dell'U.O.C di Ematologia e CTMO Padiglione 1 TORRE DELLE MEDICINE, 6° piano
city: Pavia
country: Italy
facility: S.C. Ematologia - Fondazione IRCCS Policlinico S. Matteo
city: Perugia
country: Italy
facility: Sezione di Ematologia ed Immunologia Clinica - Ospedale S.Maria della Misericordia
city: Pesaro
country: Italy
facility: Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore
city: Pescara
country: Italy
facility: U.O. Ematologia Clinica - Azienda USL di Pescara
city: Piacenza
country: Italy
facility: Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto
city: Pisa
country: Italy
facility: Università di Pisa - Azienda Ospedaliera Pisana - Dipartimento di Oncologia, dei Trapianti e delle nuove Tecnologie in Medicina - Divisione di Ematologia
city: Potenza
country: Italy
facility: Ematologia - Ospedale San Carlo
city: Ravenna
country: Italy
facility: Dipartimento Oncologico - Ospedale S.Maria delle Croci
city: Reggio Calabria
country: Italy
facility: Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
city: Reggio Emilia
country: Italy
facility: Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova
city: Rimini
country: Italy
facility: Ospedale "Infermi"
city: Roma
country: Italy
facility: Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia
city: Roma
country: Italy
facility: Complesso Ospedaliero S. Giovanni Addolorata
city: Roma
country: Italy
facility: S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena
city: Roma
country: Italy
facility: U.O.C. Ematologia - Ospedale S.Eugenio
city: Roma
country: Italy
facility: Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia
city: Rozzano
country: Italy
facility: Sezione di Ematologia Cancer Center Humanitas
city: Salerno
country: Italy
facility: UOC di Ematologia e Trapianti di Cellule Staminali Emopoietiche - AOU San Giovanni di Dio e Ruggi D'Aragona
city: San Giovanni Rotondo
country: Italy
facility: Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
city: Siena
country: Italy
facility: U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"
city: Torino
country: Italy
facility: Dipartimento di Oncologia ed Ematologia S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino San Giovanni Battista
city: Torino
country: Italy
facility: Divisione di Ematologia dell' Università degli Studi di Torino - "Città della Salute e della Scienza di Torino"
city: Torino
country: Italy
facility: Ospedale Mauriziano Umberto I - Torino - Scdu Ematologia
city: Treviso
country: Italy
facility: U.L.S.S. 9 UOC Ematologia - Ospedale Ca' Foncello
city: Udine
country: Italy
facility: Clinica Ematologica-Centro Trapianti e Terapie cellulari Azienda Ospedaliero-Universitaria, Udine
city: Verona
country: Italy
facility: Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi
Study officials:
affiliation: Azienda ULSS 12 Veneziana
name: Renato Bassan, Pr.
role: STUDY_CHAIR
affiliation: Policlinico Umberto I, Hematology Department.
name: Roberto Foà, Pr.
role: STUDY_DIRECTOR
References:
citation: Piciocchi A, Messina M, Elia L, Vitale A, Soddu S, Testi AM, Chiaretti S, Mancini M, Albano F, Spadano A, Krampera M, Bonifacio M, Cairoli R, Vetro C, Colella F, Ferrara F, Cimino G, Bassan R, Fazi P, Vignetti M. Prognostic impact of KMT2A-AFF1-positivity in 926 BCR-ABL1-negative B-lineage acute lymphoblastic leukemia patients treated in GIMEMA clinical trials since 1996. Am J Hematol. 2021 Sep 1;96(9):E334-E338. doi: 10.1002/ajh.26253. Epub 2021 Jun 9. No abstract available.