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

Phase 2

Completed

• Conditions: Untreated Philadelphia Positive Acute Lymphoblastic Leukemia; Low-dose Corticosteroids Pretreatment; De Novo; Secondary
• Interventions: Drug: Prephase PDN + CY; Drug: Cycle 1 Induction; Drug: Cycle 2 Induction / Early consolidation; Drug: Cycle 3 Early consolidation; Drug: Cycle 4 Consolidation; Drug: Cycle 5 Consolidation; Drug: Cycle 6 Consolidation; Drug: Cycle 7 Consolidation; Drug: Cycle 8 Reinduction; Drug: Maintenance; Procedure: Allogeneic SCT or Autologous SCT

• Registration Number: NCT02067143
• Lead Sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto

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.

Study Timeline

• Study First Submitted: 2014-02-17
• Study First Submitted QC: 2014-02-18
• Study First Posted: 2014-02-20
• Study Start: 2014-05-20
• Primary Completion: 2016-10-07
• Study Completion: 2020-12-07
• Status Verified: 2021-09
• Last Update Submitted: 2021-09-06
• Last Update Posted: 2021-09-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 204

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Study population	Prephase PDN + CY	In this phase II multicentric trial, eligible patients with Ph- ALL/LL will receive homogeneous supportive care and chemotherapy and will be homogeneously analyzed for response at prefixed timepoints from induction day 1. For risk-/MRD-oriented therapy, CR patients will be stratified by risk class according to diagnostic characteristics, MRD study and CT/PET (LL only) results during early consolidation.
Study population	Cycle 4 Consolidation	In this phase II multicentric trial, eligible patients with Ph- ALL/LL will receive homogeneous supportive care and chemotherapy and will be homogeneously analyzed for response at prefixed timepoints from induction day 1. For risk-/MRD-oriented therapy, CR patients will be stratified by risk class according to diagnostic characteristics, MRD study and CT/PET (LL only) results during early consolidation.
Study population	Maintenance	In this phase II multicentric trial, eligible patients with Ph- ALL/LL will receive homogeneous supportive care and chemotherapy and will be homogeneously analyzed for response at prefixed timepoints from induction day 1. For risk-/MRD-oriented therapy, CR patients will be stratified by risk class according to diagnostic characteristics, MRD study and CT/PET (LL only) results during early consolidation.
Study population	Allogeneic SCT or Autologous SCT	In this phase II multicentric trial, eligible patients with Ph- ALL/LL will receive homogeneous supportive care and chemotherapy and will be homogeneously analyzed for response at prefixed timepoints from induction day 1. For risk-/MRD-oriented therapy, CR patients will be stratified by risk class according to diagnostic characteristics, MRD study and CT/PET (LL only) results during early consolidation.
Study population	Cycle 1 Induction	In this phase II multicentric trial, eligible patients with Ph- ALL/LL will receive homogeneous supportive care and chemotherapy and will be homogeneously analyzed for response at prefixed timepoints from induction day 1. For risk-/MRD-oriented therapy, CR patients will be stratified by risk class according to diagnostic characteristics, MRD study and CT/PET (LL only) results during early consolidation.
Study population	Cycle 2 Induction / Early consolidation	In this phase II multicentric trial, eligible patients with Ph- ALL/LL will receive homogeneous supportive care and chemotherapy and will be homogeneously analyzed for response at prefixed timepoints from induction day 1. For risk-/MRD-oriented therapy, CR patients will be stratified by risk class according to diagnostic characteristics, MRD study and CT/PET (LL only) results during early consolidation.
Study population	Cycle 3 Early consolidation	In this phase II multicentric trial, eligible patients with Ph- ALL/LL will receive homogeneous supportive care and chemotherapy and will be homogeneously analyzed for response at prefixed timepoints from induction day 1. For risk-/MRD-oriented therapy, CR patients will be stratified by risk class according to diagnostic characteristics, MRD study and CT/PET (LL only) results during early consolidation.
Study population	Cycle 5 Consolidation	In this phase II multicentric trial, eligible patients with Ph- ALL/LL will receive homogeneous supportive care and chemotherapy and will be homogeneously analyzed for response at prefixed timepoints from induction day 1. For risk-/MRD-oriented therapy, CR patients will be stratified by risk class according to diagnostic characteristics, MRD study and CT/PET (LL only) results during early consolidation.
Study population	Cycle 8 Reinduction	In this phase II multicentric trial, eligible patients with Ph- ALL/LL will receive homogeneous supportive care and chemotherapy and will be homogeneously analyzed for response at prefixed timepoints from induction day 1. For risk-/MRD-oriented therapy, CR patients will be stratified by risk class according to diagnostic characteristics, MRD study and CT/PET (LL only) results during early consolidation.
Study population	Cycle 6 Consolidation	In this phase II multicentric trial, eligible patients with Ph- ALL/LL will receive homogeneous supportive care and chemotherapy and will be homogeneously analyzed for response at prefixed timepoints from induction day 1. For risk-/MRD-oriented therapy, CR patients will be stratified by risk class according to diagnostic characteristics, MRD study and CT/PET (LL only) results during early consolidation.
Study population	Cycle 7 Consolidation	In this phase II multicentric trial, eligible patients with Ph- ALL/LL will receive homogeneous supportive care and chemotherapy and will be homogeneously analyzed for response at prefixed timepoints from induction day 1. For risk-/MRD-oriented therapy, CR patients will be stratified by risk class according to diagnostic characteristics, MRD study and CT/PET (LL only) results during early consolidation.

Primary Outcome Measures

Name	Time	Method
Number of patients on disease free survival (DFS).	At two years.	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.

Secondary Outcome Measures

Name	Time	Method
Number of Severe Infections (SI) during treatment.	At the end of the study (4.5 years from first centre opened).	Description: Number and type.
Rate of Adverse Events (AE).	By the end of the study (4.5 years from first centre opened)	Excluding SI.
The rate of patients in complete remission (CR).	After approximately two months from start of treatment.
The rate of early bone marrow MRD negativity.	At 4 timepoints (week 4, 10, 16 22).
Early bone marrow MRD response (<10-4).	At 4 weeks following induction cycle 1 with Peg-ASP.
The rate of patients dead due Treatment-related mortality (TRM).	By the end of the study (4.5 years from first centre opened).
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.
Cumulative Incidence of Relapse (CIR) estimation.	At two years from CR achievement.
Composite DFS, OS, CIR.	At two years from CR achievement and rate of TRM in LL patients.
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.
Overall Survival (OS) estimation.	At two years from diagnosis.

Trial Locations

Locations (60)

Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. LANCISI - G. SALESI; 🇮🇹 Ancona, Italy

S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo; 🇮🇹 Alessandria, Italy

UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro; 🇮🇹 Bari, 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

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

Ospedale Niguarda " Ca Granda" - SC Ematologia Blocco SUD, Ponti Est, Scala E, 4° piano; 🇮🇹 Milano, 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

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

Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia; 🇮🇹 Roma, Italy

Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia; 🇮🇹 Roma, Italy

Sezione di Ematologia Cancer Center Humanitas; 🇮🇹 Rozzano, Italy

U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"; 🇮🇹 Siena, Italy

Divisione di Ematologia dell' Università degli Studi di Torino - "Città della Salute e della Scienza di Torino"; 🇮🇹 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, 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

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

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; 🇮🇹 Reggio Emilia, 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

Fondazione Irccs Ca' Granda, Ospedale Maggiore Policlinico - Milano - Ematologia - Padiglione Marcora; 🇮🇹 Milano, Italy

U.O. Ematologia e Trapianto di MIdollo - Ist.Scientifico Ospedale San Raffaele; 🇮🇹 Milano, Italy

UO Ematologia - AOU Policlinico di Modena; 🇮🇹 Modena, 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

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

S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena; 🇮🇹 Roma, Italy

Dipartimento Oncologico - Ospedale S.Maria delle Croci; 🇮🇹 Ravenna, Italy

Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"; 🇮🇹 Reggio Calabria, Italy

Ospedale "Infermi"; 🇮🇹 Rimini, 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

Dipartimento di Oncologia ed Ematologia S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino San Giovanni Battista; 🇮🇹 Torino, Italy

Complesso Ospedaliero S. Giovanni Addolorata; 🇮🇹 Roma, Italy

U.O.C. Ematologia - Ospedale S.Eugenio; 🇮🇹 Roma, Italy

Ospedale Mauriziano Umberto I - Torino - Scdu Ematologia; 🇮🇹 Torino, Italy