Intrathecal DepoCyte and Lineage-targeted Minimal Residual Disease-oriented Therapy of Acute Lymphoblastic Leukemia

October 21, 2014 updated by: DR RENATO BASSAN, Northern Italy Leukemia Group

A Randomized Study on CNS Prophylaxis With Liposome-Encapsulated Cytarabine in Association With a Lineage-Targeted and MRD-Oriented Postremission Strategy in Adult ALL

The aim of this clinical study in adult ALL is to compare by risk category (1) the feasibility of two different CNS prophylaxis regimens and (2) the overall disease-free survival in relation to the achievement of an early MRD negative status and following consolidation with 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.

In this multicentric prospective pilot randomized phase II trial on CNS prophylaxis, all patients receive induction/consolidation therapy incorporating lineage-targeted high-dose methotrexate plus other drugs (with additional imatinib in Ph/BCR-ABL+ ALL), for the achievement of an early negative MRD status. The MRD study supports a risk/MRD-oriented final consolidation phase.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

A) Risk Classification

Newly diagnosed patients are hierarchically clustered into very high, high and standard risk cases (VHR, HR, SR) using international risk criteria modified according to NILG:

A1) VHR (any criterium): B-precursor: WBC count >100x109/L; adverse cytogenetics/molecular biology such as t(9;22)/BCR-ABL, t(4;11)/MLL rearrangement at 11q23, +8, -7, del6q, t(8;14), low hypodiploidy with 30-39 chromosomes, near triploidy with 60-78 chromosomes, complex with >5 unrelated anomalies. T-precursor: WBC count >100x109/L; early/late non-cortical immunophenotype (CD1a-); adverse cytogenetics/molecular biology (as above).

A2) HR (any criterium, VHR excluded): B-precursor: WBC count >30x109/L; pro-B immunophenotype; complete remission after cycle 2. T-precursor: complete remission after cycle 2.

A3) SR (all criteria, VHR/HR excluded): B-precursor: WBC count <30x109/L; T-precursor: WBC count <100x109/L; cortical immunophenotype (CD1a+).

B) CNS Prophylaxis Stratification before randomisation

  1. by immunophenotype, i.e. B-precursor vs. T-precursor
  2. by risk class, i.e. SR vs. non-SR (using only known factors) Randomisation: intrathecal (IT) CNS prophylaxis with standard triple therapy (TIT, 12 total injections) vs. DepoCyte (6-8 total injections by disease subset). Cranial irradiation is omitted in both arms, and all patients receive the same chemotherapy program including CNS-crossing agents.

C)Induction/Early Consolidation and MRD Study

Randomised patients receive homogeneous induction/early consolidation chemotherapy, including subset-specific elements for B-precursor ALL (3x targeted-infusion methotrexate 2.5 g/m2), T-precursor ALL (3x targeted-infusion methotrexate 5 g/m2), age >55 years (methotrexate reduced to 1.5 g/m2), Ph/BCR-ABL+ ALL (imatinib, reduced-intensity chemotherapy), radiation therapy (LL). Patients not in CR after cycles 1-2 are off study. For CR evaluation bone marrow is checked on days 28 and/or 56. Consolidation cycles are administered at 21-28 day intervals Concurrent MRD analysis is performed at four timepoints (weeks 4, 10, 16 and 22 of induction/consolidation), to optimize risk classification and support risk/MRD-oriented therapy:

C1) MRD negative (M-NEG): negative MRD study (<10-4 at timepoints #2 and #3, and negative at timepoint #4) C2) MRD positive (M-POS): positive MRD study (>10-4 at timepoints #2 or #3, or positive at timepoint #4)

D)MRD/Risk-Oriented Final Therapy D1) VHR patients are candidate to an early allogeneic SCT (related/unrelated donor/cord blood; ablative/non-ablative conditioning according to current protocols/guidelines) after CR, regardless MRD study results.

D2) M-POS as well as HR patients with unknown MRD are allocated to allogeneic SCT after MRD timepoint 2 (M-POS >10-4) or MRD timepoint 4 (others). When an allogeneic SCT is not possible, patients complete consolidation and receive autologous-type SCT followed by maintenance.

D3) M-NEG as well as SR patients with unknown MRD are allocated to maintenance therapy.

Age-limited therapeutic procedures: Patients aged >55 years are treated with age-adapted therapy, and when indicated will be included in SCT programs whenever possible and according to performance status and comorbidity.

Study Type

Interventional

Enrollment (Actual)

145

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
    • (al)
      • Alessandria, (al), Italy
        • USC Ematologia, Ospedale Civile
    • (bg)
      • Bergamo, (bg), Italy, 24128
        • USC Ematologia, Ospedali Riuniti
    • (bs)
      • Brescia, (bs), Italy
        • Divisione di Ematologia - Spedali Civili
    • (bz)
      • Bolzano, (bz), Italy
        • Divisione di Ematologia e TMO, Ospedale San Maurizio
    • (ca)
      • Cagliari, (ca), Italy
        • Ematologia e centro TMO - Ospedale Armando Businco
    • (cn)
      • Cuneo, (cn), Italy
        • S.C. Ematologia - Azienda Ospedaliera S. Croce e Carle
    • (cr)
      • Cremona, (cr), Italy
        • Ematologia e centro TMO, Istituti Ospedalieri
    • (fi)
      • Firenze, (fi), Italy
        • Ematologia - AOU Careggi
    • (mi)
      • Milano, (mi), Italy
        • Ematologia e centro TMO - IRCSS Mangiagalli Regina Elena
      • Milano, (mi), Italy
        • Ematologia e centro TMO, Ospedale San Raffaele
      • Monza, (mi), Italy
        • Ematologia e centro TMO, Ospedale San Gerardo
    • (pa)
      • Palermo, (pa), Italy
        • Oncoematologia e TMO - Dipartimento Oncologico La Maddalena
    • (to)
      • Torino, (to), Italy
        • Ematologia 2 - Ospedale San Giovanni Battista
    • (va)
      • Varese, (va), Italy
        • Medicina Interna I - Ospedale di Circolo
    • (ve)
      • Noale, (ve), Italy
        • Onco-Ematologia - Ospedale Civile
    • (vi)
      • Vicenza, (vi), Italy
        • Ematologia - Ospedale San Bortolo

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 63 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age 18-65 years.
  • Diagnosis of untreated ALL with B-/T-precursor phenotype or B-cell lymphoblastic lymphoma (B-LL), either de novo or secondary to chemo-radiotherapy for other cancer.
  • Full cytological, cytochemical, cytogenetic and immunobiological disease characterization by revised FAB, EGIL and WHO criteria.
  • Bone marrow and peripheral blood sampling (ALL) or biopsy specimen (LL) for MRD study.
  • ECOG performance status 0-2 or reversible ECOG 3 score following intensive care of complications.
  • Signed informed consent.

Exclusion Criteria:

  • Diagnosis of B-ALL (FAB L3 ALL/Burkitt's leukemia or lymphoma) and T-LL (T-cell lymphoblastic lymphoma).
  • Down's syndrome.
  • Pre-existing, uncontrolled pathology such as cardiac disease (congestive/ischemic, acute myocardial infarction within the past 3 months, untreatable arrythmias, 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/LL), kidney function impairment with serum creatinine >2 mg/dL (unless attributable to ALL/LL), and severe neurological or psychiatric disorder that impairs the patient's ability to understand and sign the informed consent, or to cope with the intended treatment plan.
  • Known HIV positive serology.
  • Other active hematological or non-hematological cancer with life expectancy <1 year.
  • Pregnancy (fertile women will be advised not to become pregnant while on treatment; and male patients to adopt contraceptive methods), unless therapeutic aborption/early discharge is carried out.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Intrathecal DepoCyte
I.t. DepoCyte 50 mg admninistered x6-8 (depending on immunophenotypic disease subset) during induction/consolidation/eraly maintenance phases
Drug: liposome-encapsulated cytarabine (DepoCyte)
DepoCyte 50 mg injected intrathecally x6-8 (6: B-lineage, 8: T-lineage) during induction/consolidation phases
Other Names:
  • DepoCyt
  • DepoCyte
Active Comparator: Triple intrathecal therapy (TIT)
Methotrexate 12,5 mg + Cytarabine 50 mg + Prednisolone 40 mg injected intrathecally x12 during indiction/consolidation phases
Drug: Triple intrathecal therapy (TIT)
Methotrexate 12,5 mg + Cytarabine 50 mg + Prednisolone 40 mg. injected intrathecally x12 during induction/consolidation therapy
Other Names:
  • Cytosar
  • Cytosine arabinoside
  • Methotrexate

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Comparative analysis of feasibility/toxicity of IT DepoCyte vs. TIT
Time Frame: weeks 5, 11, 17 and 23
weeks 5, 11, 17 and 23

Secondary Outcome Measures

Outcome Measure
Time Frame
Comparative analysis of isolated and combined CNS recurrence following TIT vs DepoCyte prophylaxis
Time Frame: During study follow-up
During study follow-up
Complete remission (CR)
Time Frame: After study chemotherapy cycles 1 and 2
After study chemotherapy cycles 1 and 2
Bone marrow MRD negativity rates
Time Frame: Four time-points at weeks 4-22
Four time-points at weeks 4-22
Lenght of remission
Time Frame: Study follow-up
Study follow-up
Overall survival
Time Frame: Study follow-up
Study follow-up

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Northern Italy Leukemia Group

Investigators

  • Study Chair: Renato Bassan, MD, USC Ematologia, Ospedali Riuniti, Bergamo (Italy)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2008

Primary Completion (Actual)

October 1, 2013

Study Completion (Actual)

October 1, 2013

Study Registration Dates

First Submitted

November 19, 2008

First Submitted That Met QC Criteria

November 20, 2008

First Posted (Estimate)

November 21, 2008

Study Record Updates

Last Update Posted (Estimate)

October 22, 2014

Last Update Submitted That Met QC Criteria

October 21, 2014

Last Verified

October 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NILG-ALL 10/07

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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