Overview of Methotrexate Clinical Evaluations

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					Overview of Methotrexate
  Clinical Evaluations
        Malcolm Smith, MD, PhD
  Cancer Therapy Evaluation Program
        National Cancer Institute
FDA Pediatric ODAC Meeting - March 2006
    50 Years of Randomized Trials
    Evaluating Methotrexate for ALL
   Acute Leukemia Group B trial
    • Remission induction with prednisolone and
      vincristine, followed by randomization.
    • Comparison of 3 mg/m2 daily oral MTX versus
      30 mg/m2 twice-weekly IV MTX
    • Median CR duration: 17 months versus 3
      months favoring IV MTX
   50 years later still trying to learn how to
    use methotrexate


                                 JAMA 194: 187-193, 1965
            Complexities of Studying
                Methotrexate
   Standardizing high-dose methotrexate?
    •   1   gm/m2   over   24   hours   (POG),
    •   2   gm/m2   over   24   hours   (Dutch)
    •   5   gm/m2   over   24   hours   (BFM)
    •   8   gm/m2   over   24   hours   (NOPHO)
   Optimal timing of leucovorin rescue?
    • 36 hours? 42 hours? 48 hours?
   Number of courses of high-dose
    methotrexate (from 1 to 12)?
   Capizzi escalating dose methotrexate and
    role of asparaginase “rescue”?
Childhood ALL Collaborative Group
 Overview – Methotrexate Efficacy
   Meta-analysis: 8 randomized trials asking
    an IV MTX (+/-) question of therapy
   MTX doses from 0.5 gm/m2 to 8 gm/m2
   Addition of IV MTX to long-term IT
    therapy or radiotherapy with IT therapy
    reduced event rate by 17%
   IV MTX reduced non-CNS relapse rate
   No effect of IV MTX on CNS relapses


                   Clarke, et al. J Clin Oncol 21:1798-1809. 2003
Childhood ALL Collaborative Group
Overview – IV Methotrexate Efficacy




             Clarke, et al. J Clin Oncol 21:1798-1809. 2003
Recent Methotrexate Randomized
     Studies – POG-9005
   B-precursor ALL – Standard risk
   IV MTX 1.0 gm/m2 versus PO MTX 30
    mg/m2 every 6 hours for six doses
   CCR rate superior for IV MTX
    compared to PO MTX (p=0.013)
   Caveat: Too much leucovorin in the
    PO MTX arm??


            Mahoney, et al., J Clin Oncol, 16: 246-254, 1998
    Recent Methotrexate Randomized
         Studies – POG-9404
   T-cell ALL & lymphoblastic lymphoma
   Addition of IV MTX 5.0 gm/m2 to
    consolidation therapy
   3 EFS (SE) of 72.2% (SE 6.7%) vs. 86.0%
    (SE 5.6%) for the No HD-MTX and HD-
    MTX groups
   Primary difference in arms for CNS events
   Caveat: Delay of radiation in no HD-MTX
    arm may have increased CNS event rate
    for control patients

         Asselin, et al. Proc Am Soc Clin Oncol 20, Abstr #1464. 2001
    Recent Methotrexate Randomized
    Studies – CCG-1882 & CCG-1961
   Evaluated “Capizzi methotrexate” during “interim
    maintenance” as per “augmented” BFM regimen:
    • MTX escalating from 100 mg/m2 q 10 days x 5
    • Asparaginase 24 hours after MTX
    • Vincristine q 10 days x 5
   CCG-1882: Improved outcome for SER patients
    with augmented BFM compared to standard interim
    maintenance
   CCG-1961: Improved outcome for the “augmented”
    strategy with RER patients
   Caveat: Augmented BFM differs from standard COG
    BFM in ways other than “Capizzi methotrexate”.
                 Nachman, et al., N.Engl.J.Med., 338: 1663-1671, 1998
                      Seibel, et al. Blood 102 (11), Abstr #787, 2003
Recent Methotrexate Randomized
  Studies – EFS for CCG-1961
  1
0.95
                                                            Augmented BFM (N=644)
 0.9                                                        Standard BFM (N=640)
0.85
 0.8        Log rank p = .01
0.75
 0.7
0.65
                               5 Yr EFS    RHR
 0.6       Augmented BFM       80.5%       Baseline
0.55        Standard BFM       70.7%       1.42
 0.5
       0         1         2           3          4     5         6       7

                                       Years Followed

                                 Seibel, et al. Blood 102 (11), Abstr #787, 2003
      The Question of the Day
   In 2006, what is the best way to
    administer MTX during the post-
    remission, pre-maintenance phase of
    therapy????
ALL0232 Treatment Schema
 Standard ALL Treatment Schema
                              8 week treatment block:
    INDUCTION                 Capizzi MTX:
                              •IV 100 mg/m2 MTX q10d x 5
                              •VCR q10d x 5
  CONSOLIDATION               •PEG-Asparaginase x 2

                              High-dose Methotrexate
                              •5 gm/m2 MTX x 4
INTERIM MAINTENANCE           •VCR X 4
                              •6MP x 56 days

                      DELAYED
                  INTENSIFICATION



                                    MAINTENANCE
        ALL0232 for High-Risk
          B-Precursor ALL
   2 x 2 factorial design using an augmented
    intensity BFM backbone.
   Activated December, 2003
   Approximately 2000 randomized patients to
    enroll in 4+ years of accrual
   Randomization 1: Dexamethasone 10 mg/m2/d x
    14 days versus prednisone 60 mg/m2/d x 28
    days during Induction
   Randomization 2: HD-MTX (5 gm/m2) block
    versus Capizzi escalating methotrexate block
    during Interim Maintenance I.
        ALL0434 for T-cell ALL
   2 x 2 factorial design using an augmented
    intensity BFM backbone.
   To be activated in 2nd Quarter 2006
   Approximately 1200 randomized patients to
    enroll in 6 years of accrual
   Randomization 1: +/- nelarabine during the
    Consolidation, Delayed Intensification and
    Maintenance phases of therapy.
   Randomization 2: HD-MTX (5 gm/m2) blocks
    versus Capizzi escalating methotrexate blocks
    during Interim Maintenance I.
Potential Mediators of Methotrexate-
     Associated Neurotoxicity




            Vezmar, et al. Chemotherapy, 49: 92-104, 2003
    Methotrexate Neurological Toxicity
   Acute neurological toxicity (e.g., seizure) with
    HD-MTX
   Acute neurological toxicity can also be
    observed with low-dose oral MTX (Winick, et
    al. JNCI, 84: 252-256, 1992 )
   Chronic neurological toxicity severity ranges
    from severe leukoencephalopathy to subtle
    findings on neuropsychological testing
   With BPCA support, evaluation of neurological
    toxicity to become an important secondary
    objective of both AALL0232 and ALL0434
                Summary
   Despite more than 50 years of
    evaluation and treatment refinements,
    important questions remain to be
    addressed about how best to use
    methotrexate for children with ALL.
   Future use of methotrexate should be
    based on data from phase 3 trials
    evaluating both efficacy and
    neuropsychological endpoints.

				
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