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

Sponsor
St. Jude Children's Research Hospital (Other)
Overall Status
Completed
CT.gov ID
NCT01700946
Collaborator
Cookies for Kids' Cancer (Other), Assisi Foundation (Other)
94
Enrollment
3
Locations
2
Arms
99.3
Actual Duration (Months)
31.3
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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 Design

Study Type:
Interventional
Actual Enrollment :
94 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase II Study of Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma
Actual Study Start Date :
Apr 15, 2013
Actual Primary Completion Date :
Jul 24, 2021
Actual Study Completion Date :
Jul 24, 2021

Arms and Interventions

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.

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-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 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

    • Other: laboratory biomarker analysis
    correlative studies

    Drug: therapeutic hydrocortisone
    given intrathecally
    Other Names:
  • Cortef

    • 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

    		•
    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.

    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-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 Names:
  • Novantrone(R)

    • Biological: natural killer cell infusion
    undergo allogeneic natural killer cell infusion
    Other Names:
  • NK cell infusion

    • Other: laboratory biomarker analysis
    correlative studies

    Drug: therapeutic hydrocortisone
    given intrathecally
    Other Names:
  • Cortef

    • Procedure: allogeneic hematopoietic stem cell transplantation
    undergo allogeneic HSCT
    Other Names:
  • 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 Names:
  • Cell Selection System

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 3-year overall survival rate of patients with relapsed ALL [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.

    2. 3-year event-free survival rates in patients with relapsed ALL [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.

    Secondary Outcome Measures

    1. Proportion of participants with positive minimal residual disease [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.

    2. Mean of CD20 expression levels [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.

    3. Median CD20 expression levels [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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 21 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Rady Children's Hospital and Health Center San Diego California United States 92123
    2 St. Jude Children's Research Hospital Memphis Tennessee United States 38105
    3 Cook Children's Medical Center Fort Worth Texas United States 76104

    Sponsors and Collaborators

    • St. Jude Children's Research Hospital
    • Cookies for Kids' Cancer
    • Assisi Foundation

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    St. Jude Children's Research Hospital
    ClinicalTrials.gov Identifier:
    NCT01700946
    Other Study ID Numbers:
    • ALLR18
    • NCI-2012-00587
    First Posted:
    Oct 4, 2012
    Last Update Posted:
    Aug 24, 2021
    Last Verified:
    Aug 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    Yes
    Keywords provided by St. Jude Children's Research Hospital
    leukemia
    lymphoma
    Non-Hodgkins
    Additional relevant MeSH terms:
    Lymphoma
    Leukemia
    Precursor Cell Lymphoblastic Leukemia-Lymphoma
    Leukemia, Lymphoid
    Recurrence
    Cytarabine
    Aldesleukin
    Dexamethasone
    Hydrocortisone
    Hydrocortisone 17-butyrate 21-propionate
    Hydrocortisone acetate
    Hydrocortisone hemisuccinate
    Cyclophosphamide
    Rituximab
    Methotrexate
    Etoposide
    Vincristine
    Interleukin-2
    Asparaginase
    Mitoxantrone
    Mercaptopurine
    Clofarabine
    Vinblastine
    Pegaspargase
    Teniposide

    Study Results

    No Results Posted as of Aug 24, 2021