AALL0932

Principal Investigator: Phillip Barnette
Keywords: Pediatric , Oncology , Leukemia Department: Pediatric Administration
IRB Number: 00044149 Co Investigator:  
Specialty: Oncology
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Jennifer Craig
jennifer.craig@imail.org
8016624715

Brief Summary

Primary Objectives

1.To determine if a Maintenance regimen containing weekly oral methotrexate at 40 mg/m²/week will result in an improved disease free survival (DFS) compared to that containing weekly oral methotrexate at 20 mg/m²/week in the AR subset of patients with Standard Risk B-ALL.

2. To determine whether a reduced-pulses Maintenance regimen with vincristine/dexamethasone pulses delivered every 12 weeks can be used without adversely impacting DFS as compared to pulses given every 4 weeks in the AR subset of patients with Standard Risk B-ALL.

3. To confirm that patients in the LR subset of Standard Risk B-ALL, based on clinical and cytogenetic features and minimal residual disease (MRD) criteria, can attain a 5-year DFS of at least 95% with either a P9904-based regimen that includes 6 courses of intermediate dose (1 g/m2 over 24 hours) methotrexate without alkylating agents or anthracyclines (Arm LR-M), or an outpatient based regimen identical to that of AR patients with reduced vincristine/dexamethasone pulses at 12 week intervals during Maintenance (Arm LR-C)

4. To provide standardized treatment and enhanced supportive care to children with SR DS B-ALL in order to improve outcomes and facilitate further study of this biologically and clinically unique patient subgroup.

5.  To improve understanding of the biology of localized B-LLy and DS B-LLy by obtaining biologic data, including FISH for recurrent cytogenetic lesions on paraffin specimen, and banking tissue for future research.

6. To describe the 5-year EFS and overall survival (OS) of patients with Murphy Stage I and II B-LLy receiving modified AR B-ALL therapy.

Secondary Objectives

1.To assess the burden of AR B-ALL therapy as measured by surveys of the child‘s quality of life, missed days of school/daycare/work by children and parents, family functioning, parental perception of the child‘s health vulnerability, physical functioning, and emotional distress, 1) overall at different time points during and at the end of therapy, and by 2) comparing children randomized to every 4 week vs. every 12 week dexamethasone/vincristine pulses during Maintenance

2. To characterize the onset, severity, and natural history of vincristine associated neuropathy by physical therapists (or occupational therapists) in children undergoing therapy for AR B-ALL, 1) overall at different time points during and at the end of therapy, and by 2) comparing children randomized to every 4 week vs. every 12 week dexamethasone/vincristine pulses during Maintenance.   (The Leukemia Physical Functioning Study is closed to further accrual as of 3/15/2013.) 

 Edited with Amendment 3A:

Exploratory Obective (Previously secondary objective 1.2.3) To explore the correlation of minimal marrow disease (MMD) at diagnosis and outcome for patients with B-LLy.

Detailed Description

AALL0932 will explore the delivery of Maintenance therapy for children with AR B-precursor ALL. This study will compare 2 different doses of methotrexate during Maintenance administered with and without a reduced frequency of vincristine/dexamethasone (VCR/DEX) pulses, every 12 weeks compared to every 4 weeks, respectively, in a 2 x 2 design. Average Risk-ALL patients will be randomized to 1 of 4 Maintenance regimens: (A): VCR/DEX pulses at 4-week intervals and oral methotrexate at 20 mg/m²/week (standard arm); (B): VCR/DEX pulses at 4-week intervals and oral methotrexate at 40 mg/m²/week; (C): VCR/DEX pulses at 12-week intervals and oral methotrexate at 20 mg/m²/week; and (D): VCR/DEX pulses at 12-week intervals and oral methotrexate at 40 mg/m²/week. Patients on all arms will receive intrathecal methotrexate every 12 weeks during Maintenance and the duration of therapy will continue to be gender-based. AALL0932 also seeks to confirm that children with LR-ALL can obtain outstanding outcomes using either a P9904-based regimen that includes 6 courses of intermediate dose (1 g/m2 over 24 hours) methotrexate without alkylating agents or anthracyclines (Arm LR-M), or one identical to that of AR patients receiving regimen C Maintenance as above (Arm LR-C). Low-risk patients will be randomized between these 2 treatments arms. The goal will not be to prove superiority of 1 regimen, but rather to determine if excellent outcomes (at least 95% 5-year disease-free survival) are obtained. If both regimens meet this benchmark, then physicians and families can select the treatment that they prefer for low-risk patients in the future. Another important goal of this study is to provide safe and standardized therapy to DS patients with SR-ALL, and to facilitate further study of this biologically and clinically unique subgroup. This trial will also incorporate prospective, standardized assessments of health related quality of life (HRQOL) among children with AR-ALL using parent-reported measurements. These data will serve as the basis for future screening and intervention strategies to minimize the morbidity of ALL and its therapy in the growing proportion of children with ALL that are cured.

Inclusion Criteria

INCLUSION CRITERIA
 
1. Classification study: B-ALL patients must be enrolled on AALL08B1 (IRB 44134) prior to treatment and enrollment on AALL0932.

Please note: B-LLy patients are not eligible for AALL08B1, and can enroll directly onto AALL0932.


 
2. Age and WBC Criteria Patients must be > 365 days and < 10 years of age (for B-ALL patients).  Patients must be >365 days and 30.99 years of age (for B-LLy patients)

B-ALL patients must have an initial white blood cell count < 50 000/μL.
 

 
3. Diagnosis: Patients must have newly diagnosed NCI Standard Risk B-ALL or B-LLy Murphy Stages I or II (See Appendix V for staging). Patients with Down syndrome are also eligible.

Note: For B-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to B-ALL. For tissue processed by other means (i.e. paraffin blocks), the methodology and  criteria for immunophenotypic analysis to establish the diagnosis of B-LLy defined by the submitting  institution will be accepted.

 

Exclusion Criteria

EXCLUSION CRITERIA
 

 
1. Prior Therapy: With the exception of steroid pretreatment (defined below) or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for either the current diagnosis of B-ALL or B-LLy or for any cancer diagnosed prior to initiation of protocol therapy on AALL0932.

Patients receiving prior steroid therapy may be eligible for AALL0932 as defined below (Section 3.3).

 
2. Patients with CNS3 leukemia (see definition in Section 3.3 below). CNS status must be known prior to enrollment because NCI SR patients with CNS disease (CNS3) are not eligible for AALL0932 (but are eligible for the COG (HR) ALL protocol). (Note: The CNS status must be determined based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment as discussed in Section 3.3.). B-LLy patients with CNS3 disease are not eligible for this protocol or the COG HR ALL protocol.   It is recommended that intrathecal cytarabine be administered at the time of the diagnostic lumbar puncture. This is usually done at the time of the diagnostic bone marrow or venous line placement to avoid a second lumbar puncture. This is allowed prior to registration. Systemic chemotherapy must begin within 72 hours of the first dose of intrathecal therapy.
 

 
3. B-ALL patients with testicular leukemia are not eligible for AALL0932.

4.  For B-LLy patients the following additional exclusion criteria apply:

• T-Lymphoblastic Lymphoma.

• Morphologically unclassifiable lymphoma.

• Absence of both B-cell and T-cell phenotype markers in a case submitted as lymphoblastic  lymphoma.

• CNS3-positive disease (see Section 3.3 for details) or testicular involvement.

• M2 (5%-25% blasts) or M3 (> 25% blasts) marrow.