Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma

• ClinicalTrials.gov Identifier: NCT01700946
• Recruitment Status: Active, not recruiting
• First Posted: October 4, 2012
• Last Update Posted: July 21, 2020
• Sponsor: St. Jude Children's Research Hospital
• Collaborators: Cookies for Kids' Cancer; Assisi Foundation
• Information provided by (Responsible Party): St. Jude Children's Research Hospital

Tracking Information

• First Submitted Date: October 1, 2012
• First Posted Date: October 4, 2012
• Last Update Posted Date: July 21, 2020
• Actual Study Start Date: April 15, 2013
• Estimated Primary Completion Date: April 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 2, 2012)

• 3-year overall survival rate of patients with relapsed ALL [ Time Frame: At 3 years of follow-up since the on-study date of the last enrolled patient ]
  Estimate the 3-year survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.
• 3-year event-free survival rates in patients with relapsed ALL [ Time Frame: At 3 years of follow-up since the on-study date of the last enrolled patient ]
  Estimate the 3-year event-free survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 2, 2012)

• Proportion of participants with positive minimal residual disease [ Time Frame: At 3 months after the on-study date of the last enrolled patient ]
  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.
• Mean of CD20 expression levels [ Time Frame: approximately 5 weeks after the on-study date of the last enrolled patient ]
  To estimate mean 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.
• Median CD20 expression levels [ Time Frame: approximately 5 weeks after the on-study date of the last enrolled patient ]
  To estimate median 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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Brief Summary

The overall objective of this protocol is to improve the cure rate of relapsed precursor B-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma.

This phase II trial is studying risk-directed therapy for B-lymphoblastic leukemia or lymphoma in first relapse. Standard risk (SR) and high risk (HR) participants will receive different therapy. Treatment will consist of chemotherapy for SR participants, and chemotherapy followed by hematopoietic stem cell transplant (HSCT) for HR in first relapse. Induction therapy consists of three blocks of chemotherapy. The first block is a novel immunotherapy regimen that includes chemotherapy, rituximab and infusion of haploidentical natural killer (NK) cells. SR participants will continue to receive chemotherapy for a total duration of approximately 2 years. HR participants will be candidates for HSCT and will proceed to transplant once a suitable donor is found and their minimal residual disease (MRD) is negative.

Detailed Description

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 of 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 CliniMACS 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 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 on days 6 and 20 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, courses 1-5.

Due to the unavailability of the drug Teniposide (VM-26), etoposide (VP-16) will be substituted for the remaining doses for patients currently on this study. The protocol Section 5.1.3 allows this substitution.

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Recurrent B-Cell Childhood Acute Lymphoblastic Leukemia
• Recurrent Childhood B-Lymphoblastic Lymphoma

Intervention

• Drug: dexamethasone
  given intravenously or orally
  Other Name: Decadron(R)
• Drug: vincristine sulfate
  given intravenously
  Other Name: Oncovin(R)
• Biological: rituximab
  given intravenously
  Other Name: Rituxan(R)
• Drug: clofarabine
  given intravenously
  Other Names:

  • Clolar(TM)
  • clofarex
• Drug: cyclophosphamide
  given intravenously
  Other Name: Cytoxan(R)
• Drug: etoposide
  given intravenously
  Other Names:

  • VP-16
  • Vepesid(R)
• Biological: aldesleukin
  given subcutaneously
  Other Names:

  • IL-2
  • interleukin-2
  • Proleukin (R)
• Drug: pegaspargase
  given intravenously
  Other Names:

  • PEG-ASP
  • Peg-L-asparaginase
  • PEG-asparaginase
  • Oncaspar(R)
• Drug: methotrexate
  given intrathecally or intravenously
  Other Names:

  • MTX
  • HDMTX
• Drug: mercaptopurine
  given orally
  Other Names:

  • 6-MP
  • Purinethol(R)
• Drug: cytarabine
  given intrathecally or intravenously
  Other Names:

  • Ara-C
  • Cytosar-U(R)
• Drug: mitoxantrone
  given intravenously
  Other Name: Novantrone(R)
• Drug: teniposide
  given intravenously
  Other Names:

  • VM-26
  • Vumon(R)
• Drug: vinblastine
  given intravenously
  Other Name: Velban(R)
• Biological: natural killer cell infusion
  undergo allogeneic natural killer cell infusion
  Other Name: NK cell infusion
• Other: laboratory biomarker analysis
  correlative studies
• Drug: therapeutic hydrocortisone
  given intrathecally
  Other Name: Cortef
• Procedure: allogeneic hematopoietic stem cell transplantation
  undergo allogeneic HSCT
  Other Name: HSCT
• Device: CliniMACS
  The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.
  Other Name: Cell Selection System

Study Arms

• Active Comparator: Standard Risk

  Interventions: dexamethasone, vincristine sulfate, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, teniposide, vinblastine, natural killer cell infusion, laboratory biomarker analysis, therapeutic hydrocortisone

  Cells for infusion are prepared using the CliniMACS System.

  Interventions:

  • Drug: dexamethasone
  • Drug: vincristine sulfate
  • Biological: rituximab
  • Drug: clofarabine
  • Drug: cyclophosphamide
  • Drug: etoposide
  • Biological: aldesleukin
  • Drug: pegaspargase
  • Drug: methotrexate
  • Drug: mercaptopurine
  • Drug: cytarabine
  • Drug: mitoxantrone
  • Drug: teniposide
  • Drug: vinblastine
  • Biological: natural killer cell infusion
  • Other: laboratory biomarker analysis
  • Drug: therapeutic hydrocortisone
  • Device: CliniMACS
• Active Comparator: High Risk

  Interventions: dexamethasone, vincristine, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, natural killer cell infusion, allogeneic hematopoietic stem cell transplantation, laboratory biomarker analysis, therapeutic hydrocortisone

  Cells for infusion are prepared using the CliniMACS System.

  Interventions:

  • Drug: dexamethasone
  • Drug: vincristine sulfate
  • Biological: rituximab
  • Drug: clofarabine
  • Drug: cyclophosphamide
  • Drug: etoposide
  • Biological: aldesleukin
  • Drug: pegaspargase
  • Drug: methotrexate
  • Drug: mercaptopurine
  • Drug: cytarabine
  • Drug: mitoxantrone
  • Biological: natural killer cell infusion
  • Other: laboratory biomarker analysis
  • Drug: therapeutic hydrocortisone
  • Procedure: allogeneic hematopoietic stem cell transplantation
  • Device: CliniMACS

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 27, 2019): 94
• Original Estimated Enrollment (submitted: October 2, 2012): 40
• Estimated Study Completion Date: April 2021
• Estimated Primary Completion Date: April 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

INCLUSION CRITERIA:

• Must have relapsed or refractory precursor B-cell acute lymphoblastic leukemia or acute lymphoblastic lymphoma.

• Participants with leukemia must meet one of the following:

  1. In first hematologic relapse, defined as the reappearance (in a patient who has previously achieved remission) of leukemia blasts in the bone marrow or peripheral blood, OR
  2. Refractory to one or two courses of frontline induction therapy (≥ 5% blasts in the bone marrow or peripheral blood confirmed by flow cytometric analysis).

• Participant with lymphoma must meet one of the following:

  1. In first relapse, OR

  2. Refractory to one or two courses of frontline induction therapy with measurable disease

     • Should flow cytometric analyses suggest relapse (by the reappearance of a similar immunophenotype to the original leukemia) in the presence of <5% blasts morphologically, a repeat bone marrow test is recommended to confirm relapse.
     • Molecular or genetic relapse is characterized by the reappearance of a cytogenetic or molecular abnormality.
     • Early relapse is defined as relapse on therapy or < 6 months after completion of frontline therapy. Late relapse is defined as relapse occurring ≥ 6 months after completion of frontline therapy.
• Participant's age is < 22 years at time of enrollment (e.g. participant is eligible until 22nd birthday).

• Prior therapy:

  1. There is no waiting period for participants who relapse while receiving frontline therapy and are free from side effects attributable to such therapy.
  2. Emergent radiation therapy, one dose of intrathecal chemotherapy, and up to 7 days of steroids for treatment of relapse are permitted before start of treatment in participants who relapse after completion of frontline therapy.
  3. At least 90 days have elapsed since bone marrow transplant and participant is off immune suppression for a minimum of 2 weeks, if applicable. Participants with ALL or NHL who were transplanted in first remission are eligible for this study.

Organ function requirements

• Hepatic: Total bilirubin ≤ upper limit of normal (ULN) for age, or if total bilirubin is > ULN, direct bilirubin ≤ 1.4 mg/dl
• Cardiac: Shortening fraction ≥ 28%

• Renal: Glomerular filtration rate >50cc/min/1.73 m^2, OR maximum serum creatinine (SC) based on age as follows:

  • If age is 1 to 2 years, then maximum SC is 0.6 mg/dL
  • If age is 2 to 6 years, then maximum SC is 0.8 mg/dL
  • If age is 6 to 10 years, then maximum SC is 1 mg/dL
  • If age is 10 to <13 years, then maximum SC is 1.2 mg/dL
  • If age is 13 to 16 years, then maximum SC is 1.5 mg/dL for males and 1.4 mg/dL for females
  • If age is >16 years, then maximum SC is 1.7 mg/dL for males and 1.4 mg/dL for females

EXCLUSION CRITERIA:

• Leukemia participants ages 1 to 5 years with induction failure AND favorable cytogenetics (i.e., hyperdiploidy defined as DNA index ≥1.16 or modal chromosome number ≥51, or ETV6-RUNXI).
• Hepatitis B or HIV infection.
• Pregnant or breast-feeding
• Inability or unwillingness or research participant or legal guardian/representative to give written informed consent.

INCLUSION CRITERIA FOR NK CELL DONORS:

• Donor is at least 18 years of age.
• Donor is a family member.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01700946
• Other Study ID Numbers: ALLR18; NCI-2012-00587 ( Registry Identifier: NCi Clinical Trial Registration Program )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes

• IPD Sharing Statement: Not Provided
• Responsible Party: St. Jude Children's Research Hospital
• Study Sponsor: St. Jude Children's Research Hospital

Collaborators

• Cookies for Kids' Cancer
• Assisi Foundation

Investigators

• Principal Investigator: Sima Jeha, MD; St. Jude Children's Research Hospital

• PRS Account: St. Jude Children's Research Hospital
• Verification Date: July 2020