# Presentation: 884482

## 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

**Notes:**
Fig 3. Comparison B: Addition of intravenous (IV) methotrexate to long-term intrathecal (IT) therapy or radiotherapy with IT therapy—effects on survival and event-free survival. Descriptive curves of survival and event-free survival rates by treatment. Annual numbers of deaths, events, and person-years at risk are given beneath the graph.

## 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”.

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

- Nachman, et al., N.Engl.J.Med., *338*: 1663-1671, 1998

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

**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

**Notes:**
Children with high risk (HR) ALL (age 1-9 years and WBC 350,000; or age 310 years and any WBC) have had a 60-70% event-free survival (EFS) with past therapies. CCG 1882 tested augmented, i.e., longer and stronger, versus standard CCG BFM-based post induction intensification therapy in HR patients with a slow early response (SER) to induction therapy (bone marrow (BM) blasts > 25% on Day 7). A-BFM featured additional vincristine (VCR) and L-asparaginase (LASP) during consolidation and delayed intensification (DI) and VCR, intravenous methotrexate, and LASP during interim maintenance (IM) (increased strength). The duration of intensification was also increased with 2nd IM and DI phases (increased length). Since A-BFM improved outcome for SER patients, CCG 1961 (open Nov 96; closed May 2002) examined the contributions of increased strength and increased length for HR patients with a RER, i.e., Day 7 BM blasts < 25% with 2x2 factoral design as shown below.

Regimen    A         B         C          D        
Intensity  Standard  Standard  Augmented  Augmented
Duration   1 DI      2 DI      1 DI       2 DI     

2077 patients were entered on study. 1356 patients had a RER and, of these, 1318 were M1 or M2 on day 28. 644 patients were randomized to the augmented arms (C+D) and 640 patients to standard intensity arms (A+B). Cranial irradiation was reserved for patients with overt CNS disease at diagnosis. Five-year EFS is 80% for patients assigned to augmented intensity arms versus 71% for patients on the standard intensity arms (p=0.01); 5 year survival is 88% and 84% (p=0.09). Augmented intensity arms show fewer BM relapses (N=23), fewer CNS relapses (N=5), and fewer testicular relapses (N=6) compared to standard intensity arms. There is no difference between infections and supportive care interventions between A-BFM and S-BFM. Surprisingly, EFS and survival outcomes are similar for patients assigned to standard (1 DI) or longer (2 DI) intensification (EFS 76% versus 75%, p=0.33). Younger children (1-12 years) derive the greatest EFS benefit from the augmented intensity arms (5-year EFS 81% vs 68%, p=.001). On the augmented arms, 53% of relapses have an extramedullary component; 34% were isolated CNS relapses. Augmented BFM with single DI will serve as the control arm in the upcoming COG HR ALL study.

## 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:**
**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 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.