Trial Information

A Phase II Study of Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma

Primary objective

- To estimate the 3-year survival rate of participants with first relapse or primary
refractory precursor B-cell ALL and lymphoblastic lymphoma treated with risk-directed
therapy.

Secondary objectives

- To determine minimal residual disease (MRD) levels at the end of remission induction
therapy for participants with relapsed precursor B-cell ALL and compare the results
with those in protocol ALLR17

- To estimate levels of CD20 expression at baseline, during treatment with
dexamethasone-containing chemotherapy and following rituximab treatment in Block 1 of
remission induction therapy for relapsed precursor B-cell ALL.

STUDY DESCRIPTION:

The general treatment plan will consist of chemotherapy for standard-risk participants and
chemotherapy followed by HSCT for high risk participants in first relapse of B-precursor ALL
or lymphoblastic lymphoma. Remission induction for all participants consists of three blocks
of therapy, wherein the first block is a novel immunotherapy regimen that includes cytotoxic
chemotherapy, rituximab and infusion of haploidentical natural killer (NK) cells.
Standard-risk patients will continue to receive chemotherapy for a total duration of
approximately 2 years. High-risk patients will be candidates for HSCT and will proceed to
transplant once a suitable donor is found and the patient achieves negative MRD.

Participants will be assigned to the standard arm if they experience late relapse (> or = 6
months after completion of frontline therapy) AND maximum residual disease (MRD) is <0.01%
at the end of Block II or remission induction therapy. Provisional standard risk
participants (i.e., late relapse) will be re-assigned to high risk if MRD is > or = 0.01% at
the end of Block II. participants with lymphoma must be in complete remission at the end of
Block III.

High risk participants will meet one of the following criteria:

- Early relapse (on therapy or <6 months after completion of frontline therapy), OR

- Any relapse after hematopoietic stem cell transplant, OR

- MRD > or = 0.01% at the end of Block II of remission induction therapy, OR

- Re-emergence of MRD at any time after attaining negative MRD on this clinical trial.

Natural killer (NK) cell collection: Donors who meet eligibility criteria will undergo
apheresis once. The cells obtained will be purified for CD56+ cells utilizing the
ClinicMACS selection system. The NK cell product will undergo quality control testing
following standard operating procedures of the St. Jude Human Applications Laboratory.

OUTLINE (STANDARD RISK):

REMISSION INDUCTION:

BLOCK I: Patients receive dexamethasone orally (PO) or intravenously (IV) thrice daily (TID)
on days 1-8 and 21-28; vincristine sulfate IV on days 1, 21, 28, and 35; rituximab IV on
days 4, 13, 20, and 27; clofarabine, cyclophosphamide, and etoposide IV on days 6-10;
aldesleukin subcutaneously (SC) once every other day (QOD) on days 11-19; and pegaspargase
IV on days 21, 28, and 35. Patients also undergo natural killer (NK) cell infusion on day
12. Patients may receive triple intrathecal therapy comprising methotrexate, therapeutic
hydrocortisone, and cytarabine on days 1, 5, 8, 11, 21, and 28. Patients continue on to
Block II after count recovery.

BLOCK II: Patients receive methotrexate IV over 24 hours on days 1 and 8 and mercaptopurine
PO on days 1-21. Patients also receive triple intrathecal therapy on day 1. High-risk
patients with negative MRD continue on to transplantation. All patients with positive MRD
continue on to Block III after count recovery.

BLOCK III: Patients receive cytarabine IV over 2 hours twice daily (BID) on days 1-4 and
mitoxantrone hydrochloride IV over 1 hour on days 3-5. Patients also receive triple
intrathecal therapy on day 7.

INTERIM CONTINUATION (for patients unable to tolerate dose intensive chemotherapy): Patients
receive etoposide and cyclophosphamide IV on day 1, methotrexate IV on day 8, mercaptopurine
PO on days 8-14, teniposide and cytarabine IV on day 15, dexamethasone PO TID on days 22-26,
and vinblastine IV on day 22.

RE-INDUCTION THERAPY: Patients receive clofarabine, cyclophosphamide, and etoposide IV on
days 1-5; dexamethasone PO on days 1-6; and pegaspargase and vincristine sulfate IV on days
6, 13, and 20.Patients may also receive triple intrathecal therapy on days 1 and 15.
Patients continue on to continuation treatment after count recovery.

CONTINUATION TREATMENT: Patients receive methotrexate IV over 2 hours on day 1 and
mercaptopurine PO on days 1-7 of weeks 1, 2, 5, and 6; teniposide and cytarabine IV on day 1
of weeks 3 and 7; vincristine sulfate IV on day 1 of week 4; dexamethasone PO TID on days
1-5 of weeks 4 and 8; and vinblastine IV on day 1 of week 8. Treatment repeats every 8 weeks
for up to 10 courses in the absence of disease progression or unacceptable toxicity.
Patients may also receive triple intrathecal therapy on day 1 of week 1 of all courses and
day 1 of week 5 of courses 6-10.

OUTLINE: GROUP 2 (high risk defined as participants not meeting the standard risk criteria
noted above):

Patients receive Remission Induction (Blocks I, II, and III) treatment as described above
for Group 1. Patients then undergo allogeneic hematopoietic stem cell transplantation (HSCT)
as soon as they have negative MRD. Patients with negative MRD may continue chemotherapy
until a suitable donor is found.

After completion of study treatment, patients are followed up every 4 months for 1 year,
every 6 months for 1 year, and then yearly for up to 10 years.