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MRD/Risk-oriented Therapy of Adult Ph- ALL Including Pegylated Asparaginase and Lineage-targeted Methotrexate (LAL1913)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02067143
Recruitment Status : Completed
First Posted : February 20, 2014
Last Update Posted : April 20, 2021
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Untreated Philadelphia Positive Acute Lymphoblastic Leukemia De Novo Secondary Low-dose Corticosteroids Pretreatment 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 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 204 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 20, 2014
Actual Primary Completion Date : October 7, 2016
Actual Study Completion Date : December 7, 2020

Arm Intervention/treatment
Experimental: Study population
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.
Drug: Prephase PDN + CY
Drug: Cycle 1 Induction
Other Name: VCR + IDR + DXM + ASP + IT

Drug: Cycle 2 Induction / Early consolidation
Other Name: IDR + CY + ARA-C + ASP + 6MP + DXM + IT

Drug: Cycle 3 Early consolidation
Other Name: MTX + ARA-C

Drug: Cycle 4 Consolidation
Other Name: VCR + IDR + CY + ARA-C + 6-MP + DXM + IT

Drug: Cycle 5 Consolidation
Other Name: MTX + ASP + 6-MP

Drug: Cycle 6 Consolidation
Other Name: VCR + IDR + CY + ARA-C + ASP + 6MP + DXM + IT

Drug: Cycle 7 Consolidation
Other Name: MTX + ARA-C

Drug: Cycle 8 Reinduction
Other Name: VCR + IDR + DXM + PDN + CY + IT

Drug: Maintenance
If MRD negative MRD u/k SR
Other Name: CY or VP and 6MP/MTX + 12 cycles of 6MP/MTX

Procedure: Allogeneic SCT or Autologous SCT
If MRD positive MRD u/k HR
Other Name: + Maintenance

Primary Outcome Measures :
  1. Number of patients on disease free survival (DFS). [ Time Frame: 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 :
  1. The rate of patients in complete remission (CR). [ Time Frame: After approximately two months from start of treatment. ]
  2. The rate of early bone marrow MRD negativity. [ Time Frame: At 4 timepoints (week 4, 10, 16 22). ]
  3. Early bone marrow MRD response (<10-4). [ Time Frame: At 4 weeks following induction cycle 1 with Peg-ASP. ]
  4. Overall Survival (OS) estimation. [ Time Frame: At two years from diagnosis. ]
  5. Cumulative Incidence of Relapse (CIR) estimation. [ Time Frame: At two years from CR achievement. ]
  6. The rate of patients dead due Treatment-related mortality (TRM). [ Time Frame: By the end of the study (4.5 years from first centre opened). ]
  7. Composite DFS, OS, CIR. [ Time Frame: At two years from CR achievement and rate of TRM in LL patients. ]
  8. Description of Minimal Residual Disease (MRD) monitoring. [ Time Frame: During treatment at time point 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12. ]
  9. Number of Severe Infections (SI) during treatment. [ Time Frame: At the end of the study (4.5 years from first centre opened). ]
    Description: Number and type.

  10. Rate of Adverse Events (AE). [ Time Frame: By the end of the study (4.5 years from first centre opened) ]
    Excluding SI.

  11. Composite evaluation of impact of age (≤55 and >55) and risk category group (SR, HR, VHR - as defined) on outcomes: DFS, CIR. [ Time Frame: At two years for CR achievement, OS at two years from diagnosis and TRM. ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02067143

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Sponsors and Collaborators
Gruppo Italiano Malattie EMatologiche dell'Adulto
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Study Chair: Renato Bassan, Pr. Azienda ULSS 12 Veneziana
Study Director: Roberto Foà, Pr. Policlinico Umberto I, Hematology Department.
Additional Information:
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Responsible Party: Gruppo Italiano Malattie EMatologiche dell'Adulto Identifier: NCT02067143    
Other Study ID Numbers: LAL1913
First Posted: February 20, 2014    Key Record Dates
Last Update Posted: April 20, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Gruppo Italiano Malattie EMatologiche dell'Adulto:
Untreated philadelphia positive acute lymphoblastic leukemia
De novo
Low-dose corticosteroids pretreatment
Pegylated asparaginase
Lineage-targeted risk and minimal residual disease
Additional relevant MeSH terms:
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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs