Principal Investigator: Phillip Barnette
Keywords: Pediatric , Oncology , Leukemia , B-cell ALL Department: Pediatric Administration
IRB Number: 00052541
Specialty: Oncology
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Jennifer Craig
jennifer.craig@imail.org
8016624715

Brief Summary

Primary Objectives

1.To determine if the administration of post-Induction age adjusted ITT on an MBFM-IMHDM backbone will improve 5-year DFS of children with HR B-ALL compared to age adjusted IT MTX. (Completed effective March 19, 2018)

2. To determine, in a randomized fashion, if the cyclophosphamide + etoposide containing regimen (Experimental Arm 1) or the clofarabine + cyclophosphamide + etoposide combination regimen (Experimental Arm 2) will improve the 4-year DFS of children, adolescents, and young adults with VHR B-ALL compared to a modified MBFM-IMHDM regimen that contains a second IM (Control Arm). (Completed effective February 15, 2017)

Secondary Objectives

1.To determine the toxicity and tolerability of post-Induction age adjusted ITT compared to age adjusted IT MTX in children with HR B-ALL. (Completed effective March 19, 2018)

2.To determine the toxicity and tolerability of Experimental Arms 1 and 2 compared to the Control Arm in children, adolescents, and young adults with VHR B-ALL. (Completed effective February 15, 2017)

3. To determine whether a single-arm, modified Induction with limited anthracycline exposure and post-Induction therapy regimen with MBFM-IMIDM and reduced vincristine/steroid pulse frequency and enhanced supportive care in children with DS and HR B-ALL will result in a ≥ 65% 5-year DFS and < 10% Induction mortality.

4. To describe the outcomes for children and young adults with Ph-like B-ALL and a predicted TKI-sensitive mutation treated with dasatinib plus MBFM-IMHDM. 

5. To determine the toxicity and tolerability of MBFM-IMIDM in children with DS and HR B-ALL.

6. To estimate overall survival (OS) rates both overall and by regimen a) for HR B-ALL and b) VHR B-ALL patients.

7. To determine the incidence of ON, defined by MR imaging, and to characterize the natural history of clinically silent ON in children, adolescents and young adults 10 years of age and greater and to assess the role of drugs (i.e., asparaginase and methotrexate) in addition to corticosteroids, in the risk for development of ON. (Completed accrual July 2016)

8. To determine if the prevalence of cognitive deficits measured by CogState, in children (ages 6 to <13 years) with HR- and VHR B-ALL at 1 year off therapy, is significantly higher than the normative population (> 14%) in the following domains: working memory, executive function, visual motor, processing speed, and visual attention.

9. To compare the drug delivery of vincristine, pegaspargase and methotrexate during Induction, Consolidation, Delayed Intensification and Interim Maintenance II in 16-30 year olds treated on the control arm of the VHR study to that of adolescents and young adults (AYAs) with ALL treated with the same therapy on the C10403 adult cooperative group trial.

Added with Amendment 3B:

1.3 Exploratory Obejctive

1.3.1 To determine if the reduction of MRD from end-Induction to end-Consolidation is greater for children, adolescents, and young adults with VHR B-ALL receiving Experimental Arm 1 compared to the Control Arm. (Closed effective Amendment #6)

 

Inclusion Criteria

3.2.1 Classification study Patients must be enrolled on APEC14B1 and consented to Eligibility Screening on the Part A consent form prior to enrollment on AALL1131.

3.2.2 Age Patients must be > 365 days and < 31 years of age

3.2.3 White Blood Cell Count (WBC) Criteria

Age 1-9.99 years: WBC ≥ 50 000/μL

Age 10-30.99 years: Any WBC

Age 1-30.99 years: Any WBC with: a) Testicular leukemia b) CNS leukemia (CNS3) c) Steroid pretreatment (see Section 3.3 )

3.2.4 Diagnosis Patients must have newly diagnosed B lymphoblastic leukemia (2008 WHO classification) (also termed B-precursor acute lymphoblastic leukemia). Patients with Down syndrome are also eligible. See the next page for organ function reuires for patients with Ph-like ALL and a predicted TKI-sensitive mutation.

3.2.5 Organ Function Requirements for Patients with Ph-like ALL and a Predicted TKI-Sensitive Mutation Patients identified as Ph-like with a TKI-sensitive kinase mutation must have assessment of organ function performed within 3 days of study entry onto the dasatinib arm of AALL1131. To be eligible for the Dasatinib Arm (For patients who are Ph-like with a predicted TKI-sensitive mutation), patients must have:

3.2.5.1 Adequate Renal Function Defined As - Creatinine clearance or radioisotope GFR >70 mL/min/1.73 m2 or - A serum creatinine based on age/gender as follows:

Age                                       Maximum Serum Creatinine (mg/dL)

                                             Male                              Female

1 month to < 6 months          0.4                                0.4 6

months to < 1 year                0.5                                0.5

1 to < 2 years                        0.6                                0.6

2 years < 6 years                  0.8                                0.8

6 to < 10 years                      1.0                                1.0

10 to < 13 years                    1.2                                1.2

13 to < 16 years                    1.5                                1.4

> 16 years                             1.7                                1.4

The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC.117

3.2.5.2 Adequate Liver Function Defined As - Direct bilirubin ≤3 x upper limit of normal (ULN) for age, and - SGPT (ALT) ≤10x upper limit of normal (ULN) for age.

3.2.5.3 Adequate Cardiac Function** Defined As - Shortening fraction ≥27% by echocardiogram, or - Ejection fraction ≥ 50% by gated radionuclide study. ** Patients must have an EKG fewer than 6 days prior to enrollment on the dasatinib arm. Patients who have had cardiac assessments by echocardiogram or radionuclide scan at the beginning of Induction do not need to have these repeated prior to study entry.-QTc < 450 msec on baseline electrocardiogram as measured by the Frederica or Bazett formula - No major conduction abnormality (unless a cardiac pacemaker is present)

3.2.5.4 Adequate Pulmonary Function Defined As - No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% at sea level if there is clinical indication for determination.

3.2.5.5 Central Nervous System Function Defined As - Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled. However, drugs that induce CYP3A4/5 (carbamazepine, oxcarbazepine, phenytoin, primidone, phenobarbital) should be avoided.

Exclusion Criteria

With the approval of Amendment 3B, patients may enroll concurrently on COG AALL1421.

3.2.6 Prior Therapy With the exception of steroid pretreatment (defined in Section 3.3) or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for either the current

diagnosis of B-ALL or any cancer diagnosed prior to the initiation of protocol therapy on AALL1131. Patients cannot have secondary B-ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy. Patients receiving prior steroid therapy may be eligible for AALL1131 as defined below (Section 3.3).

3.2.7 Post Induction

3.2.7.1 Patients with BCR-ABL1 fusion are not eligible for post-Induction therapy on this study but may be eligible to enroll in a successor COG Ph+ ALL trial by Day 15 Induction.

3.2.7.2 DS HR B-ALL patients with Induction failure or BCR-ABL1

3.2.8 Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs.

3.2.9 Lactating females are not eligible unless they have agreed not to breastfeed their infant.

3.2.10 Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.

3.2.11 Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation.

3.2.12 Eligibility criteria for the Longitudinal, Computerized Assessment of Neurocognitive Functioning study

• Patients must be aged 6 to 13 years at time of B-ALL diagnosis, enrolled on AALL1131

• Patients must be English-, French- or Spanish-speaking (languages in which the assessment is available)

• Patients must have no known history of neurodevelopmental disorder prior to diagnosis of BALL (e.g., Down syndrome, Fragile X, William’s Syndrome, mental retardation)

• Patients must have no significant visual impairment that would prevent computer use and recognition of the visual test stimuli

3.2.13 Eligibility criteria for the NCI standard risk patients from AALL0932 enrolling on this study at the end of Induction.

 3.2.14.1 Effective March 19, 2018, patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 or the HR B-ALL stratum of this study at the end of Induction: a) Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with Day 8 PB MRD ≥ 1% and Day 29 BM MRD < 0.01%. b) With favorable cytogenetics (ETV6-RUNX1 or double trisomies 4+10), with any Day 8 PB MRD and Day 29 BM MRD > 0.01%. Both NCI SR and HR patients without Down syndrome and with testicular disease at diagnosis, who do not meet other VHR criteria.

3.2.14.2 Effective Amendment 6, patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 or the VHR stratum of AALL1131.

a) iAMP21

b) MLL rearrangement

c) Hypodiploidy (n< 44 chromosomes and/or a DNA index < 0.81)

d) Induction Failure (M3 BM at Day 29)

e) Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with Day 29 BM MRD > 0.01%

3.2.14.3 Patients enrolled on AALL0932, with Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the DS HR B-ALL stratum of this study at the end of Induction:

a) Day 29 MRD ≥ 0.01%

b) MLL rearrangement

c) Hypodiploidy (n< 45 chromosomes and/or DNA index < 0.81) DS HR B-ALL patients initially enrolled on AALL0932 or this study who have Induction Failure (M3 BM Day 29) or Philadelphia chromosome (BCR-ABL1) will not be eligible for post-Induction therapy on either trial (AALL0932 or AALL1131). REGULATORY REQUIREMENTS

3.2.15 All patients and/or their parents or legal guardians must sign a written informed consent.

3.2.16 All institutional, FDA, and NCI requirements for human studies must be met