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Summary

for people ages 1–30 (full criteria)
at Oakland, California and other locations
study started

Description

Summary

This randomized phase III trial studies how well blinatumomab works compared with standard combination chemotherapy in treating patients with B-cell acute lymphoblastic leukemia that has returned after a period of improvement (relapsed). Monoclonal antibodies, such as blinatumomab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether standard combination chemotherapy is more effective than blinatumomab in treating relapsed B-cell acute lymphoblastic leukemia.

Official Title

Risk-Stratified Randomized Phase III Testing of Blinatumomab (NSC#765986) in First Relapse of Childhood B-Lymphoblastic Leukemia (B-ALL)

Details

PRIMARY OBJECTIVES:

  1. To compare disease free survival (DFS) of high-risk (HR) and intermediate-risk (IR) relapse B-cell acute lymphoblastic leukemia (B-ALL) patients who are randomized following induction block 1 chemotherapy to receive either two intensive chemotherapy blocks or two 5-week blocks of blinatumomab (HR/IR randomization).

II. To compare the DFS of low risk (LR) relapse B-ALL patients who are randomized following block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR randomization).

SECONDARY OBJECTIVES:

  1. To compare overall survival (OS) of HR and IR relapse B-ALL patients who are randomized following induction block 1 chemotherapy to receive either two intensive chemotherapy blocks or two 5-week blocks of blinatumomab (HR/IR randomization).

II. To compare OS of LR relapse B-ALL patients who are randomized following block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR randomization).

TERTIARY OBJECTIVES:

  1. To compare the rates of minimal residual disease (MRD) >= 0.01% at the end of block 2 and block 3 for HR and IR relapse B-ALL patients in HR/IR randomization.

II. To estimate, for treatment failure (TF) patients not previously receiving blinatumomab, the hematologic complete remission rate (CR), rate of MRD < 0.01%, and proportion able to proceed to hematopoietic stem cell transplant (HSCT) in CR after treatment with blinatumomab.

III. To assess the feasibility and safety of rapid taper of immune suppression for the subset of HSCT patients with MRD >= 0.01% pre- and/or post-HSCT with no acute graft versus host disease (aGVHD).

IV. To evaluate blinatumomab pharmacokinetics (PK) and explore exposure-response relationships for measures of safety and effectiveness.

OUTLINE:

All patients receive Block 1 over 4 weeks.

BLOCK 1: Patients receive dexamethasone orally (PO) twice daily (BID) or intravenously (IV) on days 1-5 and 15-19; vincristine sulfate IV over 1 minute on days 1, 8, 15, and 22; pegaspargase IV over 1-2 hours on days 3 and 17; and mitoxantrone hydrochloride IV over 15-30 minutes on days 1-2. Patients with central nervous system (CNS) 1 or CNS2 also receive methotrexate intrathecally (IT) on days 1 and 8. Patients with CNS3 or isolated CNS relapse also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 1, 8, 15, and 22. High risk and intermediate risk patients are then assigned to randomization R1. Low risk patients are assigned to randomization R2.

RANDOMIZATION R1 (HR and IR patients): Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT.

ARM B: Patients receive Blinatumomab Block 1 over 5 weeks, Blinatumomab Block 2 over 5 weeks, and then undergo allogeneic HSCT.

RANDOMIZATION R2 (LR patients): Patients are then randomized to 1 of 2 treatment arms.

ARM C: Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.

ARM D: Patients receive Block 2 over 4 weeks, Blinatumomab Block 2 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Block 3 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Block 3 over 5 weeks, and then Maintenance.

BLOCK 2: Patients receive dexamethasone PO BID or IV on days 1-5; vincristine sulfate IV over 1 minute on day 1; methotrexate IV over 36 hours on day 8; leucovorin calcium IV or PO on days 10-11; pegaspargase IV over 1-2 hours on day 9 or 10; cyclophosphamide IV over 15-30 minutes on days 15-19; and etoposide IV over 1-2 hours on days 15-19. Patients with CNS1 or CNS2 also receive methotrexate IT on day 8. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 8 and 22.

BLOCK 3: Patients receive dexamethasone PO BID or IV on days 1-5; vincristine sulfate IV over 1 minute on day 1; cytarabine IV over 3 hours every 12 hours on days 1, 2, 8, and 9; asparaginase intramuscularly (IM) or IV over 1 hour on days 2, 4, 9, 11, and 23; methotrexate IT on day 1 and IV over 36 hours on day 22; leucovorin calcium PO or IV on days 24-25. Patients with CNS1 or CNS2 also receive methotrexate IT on day 22. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 22.

BLINATUMOMAB BLOCK 1: Patients dexamethasone PO or IV on day 1 and blinatumomab IV continuously on days 1-28. Patients with CNS1 or CNS2 also receive methotrexate IT on days 15 and 29. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 15 and 29.

BLINATUMOMAB BLOCK 2: Patients blinatumomab IV continuously on days 1-28. Patients with CNS1 or CNS2 also receive methotrexate IT on days 8 and 29. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 8 and 29.

BLINATUMOMAB BLOCK 3: Patients blinatumomab IV continuously on days 1-28 and dexamethasone PO or IV on day 1.

CONTINUATION 1 & 2: Patients receive dexamethasone PO BID or IV on days 1-5; vincristine sulfate IV over 1 minute on day 1; mercaptopurine tablet PO on days 1-42; methotrexate PO on days 8, 15, 29, and 36; leucovorin calcium PO or IV on day 24-25 (patients with CNS1, CNS2, or CNS3); cyclophosphamide IV over 15-30 minutes on days 43 and 50; etoposide IV over 1-2 hours on days 43 and 50; thioguanine PO once daily on days 43-49; and cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 44-47 and 51-54. Patients with CNS1 or CNS2 also receive methotrexate IT on days 1 and 43. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 1 and 43; methotrexate PO every 6 hours on day 22; and methotrexate IV over 36 hours on day 22.

MAINTENANCE: Patients receive dexamethasone PO BID or IV on days 1-5, 29-33, and 57-61; vincristine sulfate IV over 1 minute on days 1, 29, and 57; mercaptopurine tablet PO on days 1-84; and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Patients with CNS1 or CNS2 also receive methotrexate IT on day 1. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 1. Courses repeat every 12 weeks for up to 2 years since the beginning of treatment in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up annually for 10 years.

Keywords

B Acute Lymphoblastic Leukemia Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Burkitt Lymphoma Hydrocortisone 17-butyrate 21-propionate Cortisol succinate Hydrocortisone acetate Dexamethasone acetate Dexamethasone Hydrocortisone Pegaspargase Blinatumomab Etoposide phosphate Cyclophosphamide Methotrexate Etoposide Cytarabine Vincristine Mitoxantrone Asparaginase 6-Mercaptopurine Thioguanine Podophyllotoxin Muromonab-CD3 Antibodies Immunoglobulins Antibodies, Monoclonal Antibodies, Bispecific Calcium, Dietary BB 1101 2-Aminopurine Leucovorin Levoleucovorin Folic Acid

Eligibility

You can join if…

Open to people ages 1–30

  • First relapse of B-ALL, allowable sites of disease include isolated bone marrow,combined bone marrow and CNS and/or testicular, and isolated CNS and/or testicular;extramedullary sites are limited to the CNS and testicles
  • No waiting period for patients who relapse while receiving standard maintenance therapy
  • Patients who relapse on frontline therapy in phases other than maintenance must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy,or radiotherapy prior to entering this study
  • Cytotoxic therapy: at least 14 days since the completion of cytotoxic therapy with the exception of hydroxyurea, which is permitted up to 24 hours prior to the start of protocol therapy, or maintenance chemotherapy, or intrathecal chemotherapy(methotrexate strongly preferred) administered at the time of the required diagnostic lumbar puncture to establish baseline CNS status
  • Biologic (anti-neoplastic) agent: at least 7 days since the completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
  • Stem cell transplant or rescue: patient has not had a prior stem cell transplant or rescue
  • Patient has not had prior treatment with blinatumomab
  • With the exception of intrathecal chemotherapy (methotrexate strongly preferred;cytarabine is permissible) administered at the time of the required diagnostic lumbar puncture to establish baseline CNS status, patient has not received prior relapse-directed therapy (i.e., this protocol is intended as the INITIAL treatment of first relapse)
  • Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m2 or a serum creatinine based on age/gender as follows:

  • 1 to < 2 years: =< 0.6 mg/dL
  • 2 to < 6 years: =< 0.8 mg/dL
  • 6 to < 10 years: =< 1 mg/dL
  • 10 to < 13 years: =< 1.2 mg/dL
  • 13 to < 16 years: =< 1.5 mg/dL (males) and =< 1.4 mg/dL (females)
  • >= 16 years: =< 1.7 mg/dL (males) and =< 1.4 mg/dL (females)
  • Direct bilirubin < 3.0 mg/dL
  • Shortening fraction of >= 27% by echocardiogram, or
  • Ejection fraction of >= 50% by radionuclide angiogram
  • All patients and/or their parent or legal guardian must sign a written informed consent
  • All institutional, Food and Drug Administration (FDA), and National Cancer Institute(NCI) requirements for human studies must be met

You CAN'T join if...

  • Patients with Philadelphia chromosome positive/breakpoint cluster region protein(BCR)-Abelson murine leukemia viral oncogene homolog 1 (ABL1)+ ALL are not eligible
  • Patients with Burkitt leukemia/lymphoma or mature B-cell leukemia are not eligible
  • Patients with T-lymphoblastic leukemia (T-ALL)/lymphoblastic lymphoma (T-LL) are not eligible
  • Patients with B-lymphoblastic lymphoma (B-LL) are not eligible
  • Patients with known optic nerve and/or retinal involvement are not eligible; patients who are presenting with visual disturbances should have an ophthalmologic exam and, if indicated, a magnetic resonance imaging (MRI) to determine optic nerve or retinal involvement
  • Patients known to have one of the following concomitant genetic syndromes: Down syndrome, Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome,Shwachman syndrome or any other known bone marrow failure syndrome
  • Patients with known human immunodeficiency virus (HIV) infection
  • Patients with known allergy to mitoxantrone, cytarabine, or both etoposide and etoposide phosphate (Etopophos)
  • Lactating females who plan to breastfeed
  • Patients who are pregnant; pregnancy test is required for female patients of childbearing potential
  • Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
  • Patients with pre-existing significant central nervous system pathology that would preclude treatment with blinatumomab, including: history of severe brain injury,dementia, cerebellar disease, organic brain syndrome, psychosis, coordination/movement disorder, or autoimmune disease with CNS involvement are not eligible; patients with a history of cerebrovascular ischemia/hemorrhage with residual deficits are not eligible; (patients with a history of cerebrovascular ischemia/hemorrhage remain eligible provided all neurologic deficits have resolved)
  • Patients with uncontrolled seizure disorder are not eligible; (patients with seizure disorders that do not require antiepileptic drugs, or are well controlled with stable doses of antiepileptic drugs remain eligible)

Locations

  • Children's Hospital and Research Center at Oakland accepting new patients
    Oakland, California, 94609-1809, United States
  • UCSF Medical Center-Mission Bay accepting new patients
    San Francisco, California, 94158, United States
  • Kaiser Permanente-Oakland accepting new patients
    Oakland, California, 94611, United States
  • Lucile Packard Children's Hospital Stanford University accepting new patients
    Palo Alto, California, 94304, United States
  • Kaiser Permanente Medical Center - Santa Clara accepting new patients
    Santa Clara, California, 95051, United States
  • University of California Davis Comprehensive Cancer Center accepting new patients
    Sacramento, California, 95817, United States
  • Sutter Medical Center Sacramento accepting new patients
    Sacramento, California, 95816, United States
  • Santa Barbara Cottage Hospital accepting new patients
    Santa Barbara, California, 93102, United States
  • Children's Hospital Los Angeles accepting new patients
    Los Angeles, California, 90027, United States
  • Cedars Sinai Medical Center accepting new patients
    Los Angeles, California, 90048, United States
  • City of Hope Comprehensive Cancer Center accepting new patients
    Duarte, California, 91010, United States
  • Southern California Permanente Medical Group accepting new patients
    Downey, California, 90242, United States
  • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center accepting new patients
    Torrance, California, 90502, United States
  • Miller Children's and Women's Hospital Long Beach accepting new patients
    Long Beach, California, 90806, United States
  • Children's Hospital of Orange County accepting new patients
    Orange, California, 92868, United States
  • Loma Linda University Medical Center accepting new patients
    Loma Linda, California, 92354, United States
  • Summerlin Hospital Medical Center accepting new patients
    Las Vegas, Nevada, 89144, United States
  • Children's Specialty Center of Nevada II accepting new patients
    Las Vegas, Nevada, 89109, United States
  • Sunrise Hospital and Medical Center accepting new patients
    Las Vegas, Nevada, 89109, United States

Details

Status
accepting new patients
Start Date
Sponsor
National Cancer Institute (NCI)
ID
NCT02101853
Phase
Phase 3
Lead Scientist
Study Type
Interventional
Last Updated
October 16, 2017
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