MRD/Risk-oriented Therapy of Adult Ph- ALL Including Pegylated Asparaginase and Lineage-targeted Methotrexate

Secondary Clinical Trial

— LAL1913  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02067143
• Other study ID #: LAL1913
• Status: Completed
• Phase: Phase 2
• Start date: May 20, 2014
• Est. completion date: December 7, 2020

Study information

• Verified date: September 2021
• Source: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 204
• Est. completion date: December 7, 2020
• Est. primary completion date: October 7, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• De Novo
• Leukemia
• Leukemia, Lymphoid
• Low-dose Corticosteroids Pretreatment
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Secondary
• Untreated Philadelphia Positive Acute Lymphoblastic Leukemia

Intervention

Drug:
• Prephase PDN + CY

• Cycle 1 Induction

• Cycle 2 Induction / Early consolidation

• Cycle 3 Early consolidation

• Cycle 4 Consolidation

• Cycle 5 Consolidation

• Cycle 6 Consolidation

• Cycle 7 Consolidation

• Cycle 8 Reinduction

• Maintenance
If MRD negative MRD u/k SR

Procedure:
• Allogeneic SCT or Autologous SCT
If MRD positive MRD u/k HR

Locations

Country	Name	City	State
Italy	S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo	Alessandria
Italy	Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. LANCISI - G. SALESI	Ancona
Italy	U.O.C. Ematologia e Terapia Cellulare - Ospedale "C. e G. Mazzoni" di Ascoli Piceno	Ascoli Piceno
Italy	Az.Ospedaliera S.G.Moscati	Avellino
Italy	UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro	Bari
Italy	Azienda Ospedaliera - Papa Giovanni XXIII	Bergamo
Italy	Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi	Bologna
Italy	Comprensorio Sanitario di Bolzano - Azienda Sanitaria dell'Alto Adige - Ematologia e Centro TMO - Ospedale S.Maurizio	Bolzano
Italy	Spedali Civili - Brescia - Azienda Ospedaliera - U.O. Ematologia	Brescia
Italy	Divisione di Ematologia Ospedale A. Perrino	Brindisi
Italy	Ao Brotzu, Presidio Ospedaliero A. Businco - Cagliari - Sc Ematologia E Ctmo	Cagliari
Italy	CTMO - Ematologia - Ospedale "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	Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova	Cona
Italy	Sezione di Ematologia C.T.M.O. Istituti Ospitalieri	Cremona
Italy	S.C. Ematologia ASO S. Croce e Carle	Cuneo
Italy	IRCCS_AOU San Martino-IST.Clinica Ematologica	Genova
Italy	ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE	Lecce
Italy	Divisione di Ematologia - Azienda Ospedaliera Ospedali Riuniti "Papardo Piemonte" P.O. Papardo	Messina
Italy	U.O. di Ematologia- Ospedale dell'Angelo - Mestre	Mestre
Italy	Fondazione Irccs Ca' Granda, Ospedale Maggiore Policlinico - Milano - Ematologia - Padiglione Marcora	Milano
Italy	Ospedale Niguarda " Ca Granda" - SC Ematologia Blocco SUD, Ponti Est, Scala E, 4° piano	Milano
Italy	U.O. Ematologia e Trapianto di MIdollo - Ist.Scientifico Ospedale San Raffaele	Milano
Italy	UO Ematologia - AOU Policlinico di Modena	Modena
Italy	Azienda Ospedaliera "S.Gerardo"	Monza
Italy	Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli"	Napoli
Italy	S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro	Novara
Italy	U.O. CTMO Ematologia - Osp. S.Francesco	Nuoro
Italy	Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2	Orbassano
Italy	Università degli Studi di Padova - Ematologia ed Immunologia Clinica	Padova
Italy	Ospedali Riuniti "Villa Sofia-Cervello"	Palermo
Italy	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"	Palermo
Italy	Casa Di Cura La Maddalena S.P.A. - Dipartimento Oncologico Di Iii Livello - Palermo - Uo Oncoematologia E Tmo	Palmero
Italy	Day Hospital dell'U.O.C di Ematologia e CTMO Padiglione 1 TORRE DELLE MEDICINE, 6° piano	Parma
Italy	S.C. Ematologia - Fondazione IRCCS Policlinico S. Matteo	Pavia
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	U.O. Ematologia Clinica - Azienda USL di Pescara	Pescara
Italy	Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto	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	Dipartimento Oncologico - 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
Italy	S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena	Roma
Italy	U.O.C. Ematologia - Ospedale S.Eugenio	Roma
Italy	Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia	Roma
Italy	Sezione di Ematologia Cancer Center Humanitas	Rozzano
Italy	UOC di Ematologia e Trapianti di Cellule Staminali Emopoietiche - AOU San Giovanni di Dio e Ruggi D'Aragona	Salerno
Italy	Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo
Italy	U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"	Siena
Italy	Dipartimento di Oncologia ed Ematologia S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino San Giovanni Battista	Torino
Italy	Divisione di Ematologia dell' Università degli Studi di Torino - "Città della Salute e della Scienza di Torino"	Torino
Italy	Ospedale Mauriziano Umberto I - Torino - Scdu Ematologia	Torino
Italy	U.L.S.S. 9 UOC Ematologia - Ospedale Ca' Foncello	Treviso
Italy	Clinica Ematologica-Centro Trapianti e Terapie cellulari Azienda Ospedaliero-Universitaria, Udine	Udine
Italy	Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi	Verona

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	Number of patients on disease free survival (DFS).	DFS is defined as the time interval between the evaluation of CR and relapse of the disease or death in first Complete Response (CR); patients still alive, in first CR, will be censored at the time of the last follow-up. In this case, the DFS will be truncated at 2 years.	At two years.
Secondary	The rate of patients in complete remission (CR).		After approximately two months from start of treatment.
Secondary	The rate of early bone marrow MRD negativity.		At 4 timepoints (week 4, 10, 16 22).
Secondary	Early bone marrow MRD response (<10-4).		At 4 weeks following induction cycle 1 with Peg-ASP.
Secondary	Overall Survival (OS) estimation.		At two years from diagnosis.
Secondary	Cumulative Incidence of Relapse (CIR) estimation.		At two years from CR achievement.
Secondary	The rate of patients dead due Treatment-related mortality (TRM).		By the end of the study (4.5 years from first centre opened).
Secondary	Composite DFS, OS, CIR.		At two years from CR achievement and rate of TRM in LL patients.
Secondary	Description of Minimal Residual Disease (MRD) monitoring.		During treatment at time point 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12.
Secondary	Number of Severe Infections (SI) during treatment.	Description: Number and type.	At the end of the study (4.5 years from first centre opened).
Secondary	Rate of Adverse Events (AE).	Excluding SI.	By the end of the study (4.5 years from first centre opened)
Secondary	Composite evaluation of impact of age (=55 and >55) and risk category group (SR, HR, VHR - as defined) on outcomes: DFS, CIR.		At two years for CR achievement, OS at two years from diagnosis and TRM.

External Links

•   GIMEMA Foundation