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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Untreated Philadelphia Positive Acute Lymphoblastic Leukemia, De Novo, Secondary, Low-dose Corticosteroids Pretreatment

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study population<br>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<br> <br> Drug: Cycle 1 Induction<br> <br> * Other names: VCR + IDR + DXM + ASP + IT;Drug: Cycle 2 Induction / Early consolidation<br> <br> * Other names: IDR + CY + ARA-C + ASP + 6MP + DXM + IT;Drug: Cycle 3 Early consolidation<br> <br> * Other names: MTX + ARA-C;Drug: Cycle 4 Consolidation<br> <br> * Other names: VCR + IDR + CY + ARA-C + 6-MP + DXM + IT;Drug: Cycle 5 Consolidation<br> <br> * Other names: MTX + ASP + 6-MP;Drug: Cycle 6 Consolidation<br> <br> * Other names: VCR + IDR + CY + ARA-C + ASP + 6MP + DXM + IT;Drug: Cycle 7 Consolidation<br> <br> * Other names: MTX + ARA-C;Drug: Cycle 8 Reinduction<br> <br> * Other names: VCR + IDR + DXM + PDN + CY + IT;Drug: Maintenance<br>* If MRD negative MRD u/k SR<br>* Other names: CY or VP and 6MP/MTX + 12 cycles of 6MP/MTX;Procedure: Allogeneic SCT or Autologous SCT<br>* If MRD positive MRD u/k HR<br>* Other names: + Maintenance;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| Overall Survival (OS) estimation. |  | At two years from diagnosis. | 
| Cumulative Incidence of Relapse (CIR) estimation. |  | At two years from CR achievement. | 
| The rate of patients dead due Treatment-related mortality (TRM). |  | By the end of the study (4.5 years from first centre opened). | 
| 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. | 
| Number of Severe Infections (SI) during treatment. | Description: Number and type. | At the end of the study (4.5 years from first centre opened). | 
| Rate of Adverse Events (AE). | Excluding SI. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Untreated philadelphia positive acute lymphoblastic leukemia, De novo, Secondary, Low-dose corticosteroids pretreatment, Pegylated asparaginase, Lineage-targeted risk and minimal residual disease