Blinatumomab in Treating Younger Patients W/Relapsed B-cell ALL

Risk-Stratified Randomized Phase III Testing of Blinatumomab (IND# 117467, NSC#765986) in First Relapse of Childhood B-Lymphoblastic Leukemia (B-ALL)

November 22, 2017

  • Clinical Trial Information

    Trial Contact: El-Shami, Jessica

    Trial Phone: 321.841.3837

  • IRB No: AALL1331

    Principal Investigator: Vincent F. Giusti, MD

    Sub Investigators: AguilarBonilla, Ana MD; Eslin, Don MD; Kelly, Susan MD; Levy, Alejandro MD; Pope, Michele ARNP; Smith, Amy MD; Story, Allison ARNP; Sullivan, Kelly ARNP; Sutphin, Robert MD; Wieber, Laura ARNP

    Phase: Drug: Phase III

    Age Group: Pediatric

    Secondary Protocol No: AALL1331

    Treatment: Chemotherapy

    Applicable Disease Sites: First Relapse B-ALL

    Therapies Involved: Intrathecal Medication; Chemotherapy ; Radiaition

    ClinicalTrials.gov ID: NCT02101853

  • Objective

    Primary Aims To compare disease free survival (DFS) 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). To compare DFS of LR relapse B-ALL patients who are randomized following Block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR Randomization). Secondary Aims 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). 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 Exploratory Aims To compare the rates of MRD ≥ 0.01% at the end of Block 2 and Block 3 for HR and IR relapse B-ALL patients in HR/IR randomization. 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. 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). To evaluate blinatumomab pharmacokinetics (PK) and explore exposure-response relationships for measures of safety and effectiveness.

  • Key Eligibility

    INCLUSION CRITERIA
    Age
    Patients ≥1 year and < 31 years of age at the time of relapse will be eligible.

    Diagnosis
    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.
    Please refer to Section 3.3 for definitions of relapse and
    criteria for risk classification.

    Prior Therapy
    Review- concomitant therapy restrictions for patients during
    treatment.
    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, .
    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 3.2.3.5 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) 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).
    Performance Status
    Patients must have a performance status corresponding to
    ECOG scores of 0, 1, or 2. Use Karnofsky for patients > 16
    years of age and Lansky for patients ≤ 16 years of age.
    Organ Function Requirements
    Adequate Renal Function Defined As:
    - Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or
    - A serum creatinine based on age/gender as follows:
    Age
    Maximum Serum Creatinine (mg/dL)
    Male Female
    1 to < 2 years
    0.6 0.6
    2 to < 6 years
    0.8 0.8
    6 to < 10 years
    1 1
    10 to < 13 years
    1.2 1.2
    13 to < 16 years
    1.5 1.4
    ≥ 16 years
    1.7 1.4

    Adequate liver function defined as a direct bilirubin < 3.0 mg/dL.
    Adequate Cardiac Function Defined As:
    Shortening fraction of ≥ 27% by echocardiogram, or
    Ejection fraction of ≥ 50% by radionuclide angiogram.
    Exclusion Criteria
    Patients with Philadelphia chromosome positive/BCR-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, an 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 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 since fetal toxicities and teratogenic
    effects have been noted for several of the study drugs. A
    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.)