Overview of Methotrexate Overview of Methotrexate Clinical EvaluationsClinical Evaluations

Malcolm Smith, MD, PhDMalcolm Smith, MD, PhDCancer Therapy Evaluation ProgramCancer Therapy Evaluation Program

National Cancer InstituteNational Cancer InstituteFDA Pediatric ODAC Meeting - March 2006FDA Pediatric ODAC Meeting - March 2006

50 Years of Randomized Trials 50 Years of Randomized Trials Evaluating Methotrexate for ALL Evaluating Methotrexate for ALL

Acute Leukemia Group B trialAcute Leukemia Group B trial• Remission induction with prednisolone and Remission induction with prednisolone and

vincristine, followed by randomization.vincristine, followed by randomization.

• Comparison of 3 mg/mComparison of 3 mg/m22 daily oral MTX versus 30 daily oral MTX versus 30 mg/mmg/m22 twice-weekly IV MTX twice-weekly IV MTX

• Median CR duration: 17 months versus 3 Median CR duration: 17 months versus 3 months favoring IV MTXmonths favoring IV MTX

50 years later still trying to learn how to use 50 years later still trying to learn how to use methotrexatemethotrexate

JAMA 194: 187-193, 1965

Complexities of Studying Complexities of Studying MethotrexateMethotrexate

Standardizing high-dose methotrexate?Standardizing high-dose methotrexate?• 1 gm/m1 gm/m22 over 24 hours (POG), over 24 hours (POG),• 2 gm/m2 gm/m22 over 24 hours (Dutch) over 24 hours (Dutch)• 5 gm/m5 gm/m22 over 24 hours (BFM) over 24 hours (BFM)• 8 gm/m8 gm/m22 over 24 hours (NOPHO) over 24 hours (NOPHO)

Optimal timing of leucovorin rescue?Optimal timing of leucovorin rescue?• 36 hours? 42 hours? 48 hours? 36 hours? 42 hours? 48 hours?

Number of courses of high-dose Number of courses of high-dose methotrexate (from 1 to 12)?methotrexate (from 1 to 12)?

Capizzi escalating dose methotrexate and Capizzi escalating dose methotrexate and role of asparaginase “rescue”?role of asparaginase “rescue”?

Childhood ALL Collaborative Group Childhood ALL Collaborative Group Overview – Methotrexate EfficacyOverview – Methotrexate Efficacy

Meta-analysis: 8 randomized trials asking Meta-analysis: 8 randomized trials asking an IV MTX (+/-) question of therapyan IV MTX (+/-) question of therapy

MTX doses from 0.5 gm/m2 to 8 gm/m2MTX doses from 0.5 gm/m2 to 8 gm/m2 Addition of IV MTX to long-term IT therapy Addition of IV MTX to long-term IT therapy

or radiotherapy with IT therapy reduced or radiotherapy with IT therapy reduced event rate by 17%event rate by 17%

IV MTX reduced non-CNS relapse rateIV MTX reduced non-CNS relapse rate No effect of IV MTX on CNS relapses No effect of IV MTX on CNS relapses

Clarke, et al. J Clin Oncol 21:1798-1809. 2003

Childhood ALL Collaborative Group Childhood ALL Collaborative Group Overview – IV Methotrexate EfficacyOverview – IV Methotrexate Efficacy

Clarke, et al. J Clin Oncol 21:1798-1809. 2003

Recent Methotrexate Randomized Recent Methotrexate Randomized Studies – POG-9005Studies – POG-9005

B-precursor ALL – Standard riskB-precursor ALL – Standard risk IV MTX 1.0 gm/mIV MTX 1.0 gm/m22 versus PO MTX 30 versus PO MTX 30

mg/mmg/m22 every 6 hours for six doses every 6 hours for six doses CCR rate superior for IV MTX CCR rate superior for IV MTX

compared to PO MTX (p=0.013)compared to PO MTX (p=0.013) Caveat: Too much leucovorin in the Caveat: Too much leucovorin in the

PO MTX arm??PO MTX arm??

Mahoney, et al., J Clin Oncol, 16: 246-254, 1998

Recent Methotrexate Randomized Recent Methotrexate Randomized Studies – POG-9404Studies – POG-9404

T-cell ALL & lymphoblastic lymphomaT-cell ALL & lymphoblastic lymphoma Addition of IV MTX 5.0 gm/mAddition of IV MTX 5.0 gm/m22 to to

consolidation therapy consolidation therapy 3 EFS (SE) of 72.2% (SE 6.7%) vs. 86.0% 3 EFS (SE) of 72.2% (SE 6.7%) vs. 86.0%

(SE 5.6%) for the No HD-MTX and HD-MTX (SE 5.6%) for the No HD-MTX and HD-MTX groups groups

Primary difference in arms for CNS eventsPrimary difference in arms for CNS events Caveat: Delay of radiation in no HD-MTX Caveat: Delay of radiation in no HD-MTX

arm may have increased CNS event rate arm may have increased CNS event rate for control patientsfor control patients

Asselin, et al. Proc Am Soc Clin Oncol 20, Abstr #1464. 2001

Recent Methotrexate Randomized Recent Methotrexate Randomized Studies – CCG-1882 & CCG-1961Studies – CCG-1882 & CCG-1961

Evaluated “Capizzi methotrexate” during “interim Evaluated “Capizzi methotrexate” during “interim maintenance” as per “augmented” BFM regimen:maintenance” as per “augmented” BFM regimen:• MTX escalating from 100 mg/mMTX escalating from 100 mg/m22 q 10 days x 5 q 10 days x 5• Asparaginase 24 hours after MTXAsparaginase 24 hours after MTX• Vincristine q 10 days x 5Vincristine q 10 days x 5

CCG-1882: Improved outcome for SER patients with CCG-1882: Improved outcome for SER patients with augmented BFM compared to standard interim augmented BFM compared to standard interim maintenance maintenance

CCG-1961: Improved outcome for the “augmented” CCG-1961: Improved outcome for the “augmented” strategy with RER patients strategy with RER patients

Caveat: Augmented BFM differs from standard COG Caveat: Augmented BFM differs from standard COG BFM in ways other than “Capizzi methotrexate”. BFM in ways other than “Capizzi methotrexate”.

Seibel, et al. Blood 102 (11), Abstr #787, 2003Nachman, et al., N.Engl.J.Med., 338: 1663-1671, 1998

Recent Methotrexate Randomized Recent Methotrexate Randomized Studies – EFS for CCG-1961Studies – EFS for CCG-1961

0.5

0.55

0.6

0.65

0.7

0.75

0.8

0.85

0.9

0.95

1

0 1 2 3 4 5 6 7

Augmented BFM (N=644)

Standard BFM (N=640)

Years Followed

5 Yr EFS RHR

Augmented BFM 80.5% Baseline

Standard BFM 70.7% 1.42

Log rank p = .01

Seibel, et al. Blood 102 (11), Abstr #787, 2003

The Question of the DayThe Question of the Day

In 2006, what is the best way to In 2006, what is the best way to administer MTX during the post-administer MTX during the post-remission, pre-maintenance phase of remission, pre-maintenance phase of therapy????therapy????

ALL0232 Treatment SchemaALL0232 Treatment Schema

Standard ALL Treatment SchemaStandard ALL Treatment Schema

INDUCTION

CONSOLIDATION

INTERIM MAINTENANCE

DELAYED INTENSIFICATION

MAINTENANCE

8 week treatment block: Capizzi MTX:•IV 100 mg/m2 MTX q10d x 5•VCR q10d x 5•PEG-Asparaginase x 2

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

ALL0232 for High-Risk ALL0232 for High-Risk B-Precursor ALLB-Precursor ALL

2 x 2 factorial design using an augmented 2 x 2 factorial design using an augmented intensity BFM backbone. intensity BFM backbone.

Activated December, 2003Activated December, 2003 Approximately 2000 randomized patients to Approximately 2000 randomized patients to

enroll in 4+ years of accrualenroll in 4+ years of accrual Randomization 1: Dexamethasone 10 mg/mRandomization 1: Dexamethasone 10 mg/m22/d x /d x

14 days versus prednisone 60 mg/m14 days versus prednisone 60 mg/m22/d x 28 days /d x 28 days during Induction during Induction

Randomization 2: HD-MTX (5 gm/mRandomization 2: HD-MTX (5 gm/m22) block ) block versus Capizzi escalating methotrexate block versus Capizzi escalating methotrexate block during Interim Maintenance I.during Interim Maintenance I.

ALL0434 for T-cell ALLALL0434 for T-cell ALL 2 x 2 factorial design using an augmented 2 x 2 factorial design using an augmented

intensity BFM backbone. intensity BFM backbone. To be activated in 2nd Quarter 2006To be activated in 2nd Quarter 2006 Approximately 1200 randomized patients to Approximately 1200 randomized patients to

enroll in 6 years of accrualenroll in 6 years of accrual Randomization 1: +/- nelarabine during the Randomization 1: +/- nelarabine during the

Consolidation, Delayed Intensification and Consolidation, Delayed Intensification and Maintenance phases of therapy.Maintenance phases of therapy.

Randomization 2: HD-MTX (5 gm/mRandomization 2: HD-MTX (5 gm/m22) blocks ) blocks versus Capizzi escalating methotrexate blocks versus Capizzi escalating methotrexate blocks during Interim Maintenance I.during Interim Maintenance I.

Potential Mediators of Methotrexate-Potential Mediators of Methotrexate-Associated NeurotoxicityAssociated Neurotoxicity

Vezmar, et al. Chemotherapy, 49: 92-104, 2003

Methotrexate Neurological ToxicityMethotrexate Neurological Toxicity Acute neurological toxicity (e.g., seizure) with Acute neurological toxicity (e.g., seizure) with

HD-MTXHD-MTX Acute neurological toxicity can also be Acute neurological toxicity can also be

observed with low-dose oral MTX (observed with low-dose oral MTX (Winick, et Winick, et al. JNCI, al. JNCI, 8484: 252-256, 1992 : 252-256, 1992 ))

Chronic neurological toxicity severity ranges Chronic neurological toxicity severity ranges from severe leukoencephalopathy to subtle from severe leukoencephalopathy to subtle findings on neuropsychological testingfindings on neuropsychological testing

With BPCA support, evaluation of neurological With BPCA support, evaluation of neurological toxicity to become an important secondary toxicity to become an important secondary objective of both AALL0232 and ALL0434objective of both AALL0232 and ALL0434

SummarySummary

Despite more than 50 years of Despite more than 50 years of evaluation and treatment refinements, evaluation and treatment refinements, important questions remain to be important questions remain to be addressed about how best to use addressed about how best to use methotrexate for children with ALL.methotrexate for children with ALL.

Future use of methotrexate should be Future use of methotrexate should be based on data from phase 3 trials based on data from phase 3 trials evaluating both efficacy and evaluating both efficacy and neuropsychological endpoints.neuropsychological endpoints.