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

September 13, 2022 updated by: St. Jude Children's Research Hospital

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Enrollment (Actual)

80

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • San Diego, California, United States, 92123
        • Rady Children's Hospital and Health Center
    • Tennessee
      • Memphis, Tennessee, United States, 38105
        • St. Jude Children's Research Hospital
    • Texas
      • Fort Worth, Texas, United States, 76104
        • Cook Children's Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 21 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
Other: laboratory biomarker analysis
correlative studies
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 Names:
  • Cell Selection System
Drug: dexamethasone
given intravenously or orally
Other Names:
  • Decadron(R)
Drug: vincristine sulfate
given intravenously
Other Names:
  • Oncovin(R)
Biological: rituximab
given intravenously
Other Names:
  • Rituxan(R)
Drug: clofarabine
given intravenously
Other Names:
  • Clolar(TM)
  • clofarex
Drug: cyclophosphamide
given intravenously
Other Names:
  • 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-asparaginase
  • Peg-L-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 Names:
  • Novantrone(R)
Drug: teniposide
given intravenously
Other Names:
  • VM-26
  • Vumon(R)
Drug: vinblastine
given intravenously
Other Names:
  • Velban(R)
Biological: natural killer cell infusion
undergo allogeneic natural killer cell infusion
Other Names:
  • NK cell infusion
Drug: therapeutic hydrocortisone
given intrathecally
Other Names:
  • Cortef
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.
Other: laboratory biomarker analysis
correlative studies
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 Names:
  • Cell Selection System
Drug: dexamethasone
given intravenously or orally
Other Names:
  • Decadron(R)
Drug: vincristine sulfate
given intravenously
Other Names:
  • Oncovin(R)
Biological: rituximab
given intravenously
Other Names:
  • Rituxan(R)
Drug: clofarabine
given intravenously
Other Names:
  • Clolar(TM)
  • clofarex
Drug: cyclophosphamide
given intravenously
Other Names:
  • 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-asparaginase
  • Peg-L-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 Names:
  • Novantrone(R)
Biological: natural killer cell infusion
undergo allogeneic natural killer cell infusion
Other Names:
  • NK cell infusion
Drug: therapeutic hydrocortisone
given intrathecally
Other Names:
  • Cortef
Procedure: allogeneic hematopoietic stem cell transplantation
undergo allogeneic HSCT
Other Names:
  • HSCT

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
3-year Overall Survival Rate of Patients With Relapsed ALL
Time Frame: 3 years of follow-up since the on-study date
Estimate the 3-year survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.
3 years of follow-up since the on-study date
3-year Event-free Survival Rates in Patients With Relapsed ALL
Time Frame: 3 years of follow-up since the on-study date
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.
3 years of follow-up since the on-study date

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of Participants With Positive Minimal Residual Disease
Time Frame: At end of induction (approximately 3 months)
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 (NCT00186875).
At end of induction (approximately 3 months)
Mean of CD20 Expression Levels
Time Frame: Baseline and at the end of Block I (approximately 5 weeks after the on-study date)
To estimate mean levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block I of remission induction therapy for relapsed precursor B-cell ALL.
Baseline and at the end of Block I (approximately 5 weeks after the on-study date)
Median CD20 Expression Levels
Time Frame: Baseline and at the end of Block I (approximately 5 weeks after the on-study date)
To estimate median levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block I of remission induction therapy for relapsed precursor B-cell ALL.
Baseline and at the end of Block I (approximately 5 weeks after the on-study date)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

St. Jude Children's Research Hospital

Collaborators

Assisi Foundation
Cookies for Kids' Cancer

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 15, 2013

Primary Completion (Actual)

July 24, 2021

Study Completion (Actual)

July 24, 2021

Study Registration Dates

First Submitted

October 1, 2012

First Submitted That Met QC Criteria

October 2, 2012

First Posted (Estimate)

October 4, 2012

Study Record Updates

Last Update Posted (Actual)

September 28, 2022

Last Update Submitted That Met QC Criteria

September 13, 2022

Last Verified

September 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ALLR18
  • NCI-2012-00587 (Registry Identifier: NCi Clinical Trial Registration Program)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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