A Study of Children With Refractory or Relapsed ALL

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Brief Title

A Study of Children With Refractory or Relapsed ALL

Official Title

A Study of Children With Refractory or Relapsed Acute Lymphoblastic Leukemia (ALLR16)

Brief Summary

      The main purpose of this study is to find out which form of asparaginase (the native E.
      coli/Erwinia) or PEG-asparaginase) is more effective during induction treatment for children
      with acute lymphoblastic leukemia that has come back after treatment (relapsed) or is
      resistant to treatment (refractory)
    

Detailed Description

      The present protocol will compare the biologic effects of PEG-asparaginase vs native-forms of
      asparaginase in a randomized trial using the same dosages and schedules used in the POG 9411
      study. Comprehensive studies, including the measurement of antibodies and asparagine levels
      as well as the pharmacokinetics of L-asparaginase, will be performed. This protocol will also
      study the changes in topoisomerase I and topoisomerase II levels and the fractions of
      topoisomerase I/II translocations in malignant lymphoblasts after upfront window topotecan
      therapy, and correlate oncolytic response with these changes.

      Secondary objectives include:

        -  To compare changes in asparagine levels 28 days after initiation of treatment with
           asparaginase between the two groups.

        -  To estimate the pharmacokinetics of L-asparaginase, compare the pharmacokinetics between
           the two groups of patients, and correlate the pharmacokinetics with the development of
           antibody to asparaginase and depletion of asparagine.

        -  To measure the pharmacokinetics and pharmacodynamics of topotecan in patients with
           recurrent acute lymphoblastic leukemia

        -  To determine whether the frequency of recombinogenesis in lymphocytes is increased
           during or after etoposide therapy relative to the pre-therapy level, and to explore
           whether etoposide pharmacokinetics are related to the Day 7 or post-therapy level of
           recombinogenesis.

      Detailed Description of Treatment Plan

      WINDOW Topotecan 2.4 mg/m2 ; IV over 30 min in 5 doses Days 1-5

      STANDARD INDUCTION Dexamethasone 6 mg/m2/day orally Days 8-35 Vincristine 1.5 mg/m2 (max 2.0
      mg) days 8, 15, 22, 29

      RANDOMIZE E. coli asparaginase 10,000 U/m2/day IM (or Erwinia if previous allergy to E. coli)
      Days 8, 11, 13, 15, 18, 20, 22, 25, 27, 29, 32, 34

      OR

      PEG-Asparaginase 2500 U/m2/day IM Days 8, 15, 22, 29

      ITHMA Days 8, 22, 36

      CONSOLIDATION

      Fludarabine: 15 mg/m2 IV over 30 min; days 1,2,3,4 Ara-C: 2 g/m2 IV days 1,2,3,4

      Patients who achieve remission on R16 induction or consolidation may be eligible for either a
      matched sibling or a fully matched/one-antigen-mismatched unrelated donor transplant

      For patients not undergoing bone marrow transplant:

      SECONDARY CONSOLIDATION

      VP 16: 50 mg/m2 PO qd for 14 days. Vincristine: 1.5 mg/m2 (max 2.0 mg) IV; days 1, 8. IT MHA
      day 1

      CONTINUATION CHEMOTHERAPY

      Cycle 1:

      Cyclophosphamide 1 g/m2 IV on days 1 and 2 Vincristine 1.5 mg/m2 IV on day 1 (max 2.0 mg)

      Cycle 2:

      VP-16 50 mg/m2 day PO daily x 14 days Decadron 6 mg/m2 PO daily ) TID x 14 days Vincristine
      1.5 mg/m2 IV (max 2 mg) on days 1 and 8.

      Cycle 3:

      HD MTX 5 gm/m2 continuous infusion over 24 hrs E. coli Asparaginase 10,000 U/m2/dose IM qod
      x3 or PEG Asparaginase 2500 U/m2/dose IM x 1 (maintain same randomization for Asparaginase
      preparation as during induction)

      Cycle 4:

      High Dose Ara-C 2 g/m2/dose IV over 2 hrs q 12 hrs x 3 doses.[Total dose 6 gm/m2] Idarubicin
      12 mg/m2 IV over 30 min X 1 [after completion of first dose of Ara-C] IT MHA on day 1 prior
      to the HDARA-C (dose of ITMHA is age adjusted as outlined in section 7.3)

      STANDARD CONTINUATION CHEMOTHERAPY

      Patients will receive 4-week rotational cycles of chemotherapy with the following pairs of
      drugs for total treatment duration of 17 months.

      Week #1 Cyclophosphamide (300 mg/m2 IV) + VCR (1.5 mg/m2 IV; max 2 mg). Week #2 VM26 (200
      mg/m2 IV) + Ara C (300 mg/m2 IV). Week #3 MTX (MTX should be given IM or as a 2 hr IV
      infusion if the patient has had previous cranial iradiation) (40 mg/m2 IV/IM) + 6 MP (75
      mg/m2 PO q HS x 7) Week #4 MTX (MTX should be given IM or as a 2 hr IV infusion if the
      patient has had previous cranial irradiation)(40 mg/m2 IV/IM) + 6 MP (75 mg/m2 PO q HS x 7)

      IT MHA: Given every 8 weeks throughout standard continuation chemotherapy for patients with
      CNS 1 status Given every 4 weeks for patients with CNS 2/3 status who will receive CSI at the
      end of chemotherapy
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

To compare in a randomized trial the depletion of asparagine in patients who receive the native form of asparaginase or PEG-asparaginase during induction therapy.


Condition

Acute Lymphoblastic Leukemia

Intervention

Topotecan, dexamethasone, vincristine

Study Arms / Comparison Groups

 1
Description:  Native asparaginase

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

40

Start Date

February 1997

Completion Date

December 2003

Primary Completion Date

December 2003

Eligibility Criteria

        Inclusion Criteria

        For patients treated on frontline protocols at St. Jude:

          -  ALL in isolated bone marrow relapse, or combined marrow and extramedullary relapse,
             during or after treatment with multi-agent chemotherapy (TOTAL XI, XII, XIIIA, XIIIB),
             or isolated extramedullary relapse after treatment on TOTXII.

          -  Patients with recurrent T-Cell non-Hodgkin's lymphoma who relapse in the bone marrow
             with >25% blasts

        For patients not treated on front-line St. Jude protocols:

        • ALL in isolated bone marrow relapse, or isolated extramedullary relapse, or combined
        marrow and extramedullary relapse.

        All patients:

          -  First relapse after receiving primary therapy or during primary therapy

          -  Life expectance of at least 8 weeks

          -  ECOG score 0-2 Exclusion criteria

          -  Life expectancy < 8 weeks
      

Gender

All

Ages

N/A - 18 Years

Accepts Healthy Volunteers

No

Contacts

Sima Jeha, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00187083

Organization ID

ALLR16



Study Sponsor

St. Jude Children's Research Hospital


Study Sponsor

Sima Jeha, MD, Principal Investigator, St. Jude Children's Research Hospital


Verification Date

June 2008