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NCT03959085 · CITED IN SOURCE DOCUMENTS

Inotuzumab Ozogamicin and Post-Induction Chemotherapy in Treating Patients With High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and B-LLy

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
RECRUITING
Registry last update
2026-08-25

This phase III trial studies whether inotuzumab ozogamicin added to post-induction chemotherapy and immunotherapy (chemo-immunotherapy) for patients with High-Risk B-cell Acute Lymphoblastic Leukemia (B-ALL) improves outcomes. Inotuzumab ozogamicin is a monoclonal antibody, which is a type of protein that can bind to certain targets on the surface of cells. Inotuzumab ozogamicin is a monoclonal antibody that is linked to a type of chemotherapy called calicheamicin. Inotuzumab attaches to cancer cells by binding to the CD22 protein on the surface of the cancer cell and delivering calicheamicin inside the cells to kill them. Other drugs used in the chemotherapy regimen, such as cyclophosphamide, cytarabine, dexamethasone, doxorubicin, daunorubicin, methotrexate, leucovorin, mercaptopurine, prednisone, thioguanine, vincristine, and pegaspargase or calaspargase pegol work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Blinatumomab is a specialized type of monoclonal antibody known as a bispecific T-cell engager (BiTE). It works by simultaneously binding to CD19 on cancer cells and CD3 on normal immune cells, bringing them together to destroy leukemia cells. Blinatumomab is a standard part of chemo-immunotherapy treatment for B-ALL. This trial also studies the outcomes of patients with mixed phenotype acute leukemia (MPAL), and B-lymphoblastic lymphoma (B-LLy) when treated with ALL therapy without inotuzumab ozogamicin or blinatumomab. The overall goal of this study is to understand if adding inotuzumab ozogamicin to standard of care chemo-immunotherapy maintains or improves outcomes in High Risk B-cell Acute Lymphoblastic Leukemia (HR B-ALL). The first part of the study includes the first phase of therapy: Induction. This part will collect information on the leukemia, as well as the effects of the initial treatment, to classify patients into post-induction treatment groups. On the second part of this study, patients with HR B-ALL will receive the remainder of the chemotherapy cycles (consolidation, blinatumomab block 1, interim maintenance 1, blinatumomab block 2, delayed intensification, interim maintenance 2, maintenance), with some patients randomized to receive inotuzumab. The patients that receive inotuzumab will not receive part of consolidation or part of delayed intensification. Other aims of this study include evaluating 1) side effects of treatment using patient-reported outcomes and health-related quality of life, 2) the best ways to help patients adhere to oral chemotherapy regimens, 3) the relationship between levels of inotuzumab ozogamicin in the blood and side effects, 4) the impact of chemo-immunotherapy on the immune system and risk of infection, and 5) the impact of social determinants of health on outcomes. Finally, this study will be the first to track the outcomes of subjects with disseminated B-cell Lymphoblastic Leukemia (B-LLy) or Mixed Phenotype Acute Leukemia (MPAL) when treated with B-ALL chemotherapy.

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part
eligibility Criteria
Inclusion Criteria: * B-ALL and MPAL patients must be enrolled on APEC14B1 and consented to eligibility studies (Part A) prior to treatment and enrollment on AALL1732. Note that central confirmation of MPAL diagnosis must occur within 22 days of enrollment for suspected MPAL patients. If not performed within this time frame, patients will be taken off protocol. * APEC14B1 is not a requirement for B-LLy patients but for institutional compliance every patient should be offered participation in APEC14B1. B-LLy patients may directly enroll on AALL1732. * Patients must be \> 365 days and \< 25 years of age * Initial white blood cell count (WBC) criteria for patients with B-ALL (within 7 days prior to the start of protocol-directed systemic therapy): * Age 1-9.99 years: WBC \>= 50,000/uL * Age 10-24.99 years: Any WBC * Age 1-9.99 years: WBC \< 50,000/uL with one or more of the following: * Testicular leukemia * CNS leukemia (CNS3) * Steroid pretreatment. * Initial white blood cell count (WBC) criteria for patients with MPAL (within 7 days prior to the start of protocol-directed systemic therapy): * Age 1-24.99 years: any WBC NOTE: Patients enrolled as suspected MPAL but found on central confirmatory testing to have B-ALL must meet the B-ALL criteria above (age, WBC, extramedullary disease, steroid pretreatment) to switch to the B-ALL stratum before the end of induction. * Patient has newly diagnosed B-ALL or MPAL (by World Health Organization \[WHO\] 2016 criteria) with \>= 25% blasts on a bone marrow (BM) aspirate; * OR If a BM aspirate is not obtained or is not diagnostic of acute leukemia, the diagnosis can be established by a pathologic diagnosis of acute leukemia on a BM biopsy; * OR A complete blood count (CBC) documenting the presence of at least 1,000/uL circulating leukemic cells if a bone marrow aspirate or biopsy cannot be performed. * Patient has newly diagnosed B-LLy Murphy stages III or IV. * Patient has newly diagnosed B-LLy Murphy stages I or II with steroid pretreatment. * Note: For B-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to B-ALL. For tissue processed by other means (i.e., paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of B-LLy defined by the submitting institution will be accepted. * Central nervous system (CNS) status must be determined prior to enrollment based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment and cytoreduction. Note that once cerebrospinal fluid (CSF) has been collected, protocol therapy can be initiated while final determination of CNS status is pending. It is recommended that intrathecal cytarabine be administered at the time of the diagnostic lumbar puncture. This is usually done at the time of the diagnostic bone marrow or venous line placement to avoid a second lumbar puncture. This is allowed prior to enrollment. Systemic chemotherapy must begin within 72 hours of this intrathecal therapy. * Direct bilirubin \< 2.0 mg/dL (34 micromoles/L) * Alanine aminotransferase (ALT) ≤ 10x upper limit of normal (ULN). For the purposes of this study, the ULN for ALT is defined as 45 U/L * Exceptions to this include patients with known Gilbert's Syndrome, or those with hepatic involvement from leukemic or lymphomatous infiltration * All patients and/or their parents or legal guardians must sign a written informed consent. * All institutional, Food and Drug Administration (FDA), and NCI requirements for human studies must be met. Exclusion Criteria: * Patients with Down syndrome are not eligible * With the exception of steroid pretreatment and steroid cytoreduction or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for the current diagnosis of B-ALL, MPAL, or B-LLy or for any cancer diagnosed prior to initiation of protocol therapy on AALL1732. * Patients who have received \> 72 hours of hydroxyurea within one week prior to start of systemic protocol therapy. * Patients with B-ALL or MPAL who do not have sufficient diagnostic bone marrow submitted for APEC14B1 testing and who do not have a peripheral blood sample submitted containing \> 1,000/uL circulating leukemia cells. * Patients with acute undifferentiated leukemia (AUL) are not eligible. * For Murphy stage III/IV B-LLy patients, or stage I/II patients with steroid pretreatment, the following additional exclusion criteria apply: * T-lymphoblastic lymphoma. * Morphologically unclassifiable lymphoma. * Absence of both B-cell and T-cell phenotype markers in a case submitted as lymphoblastic lymphoma. * Patients with known Charcot-Marie-Tooth disease. * Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL, regardless of blast immunophenotype. * Patients requiring radiation at diagnosis. * Female 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. * Lactating women who plan to breastfeed their infants while on study and for 2 months after the last dose of inotuzumab ozogamicin. * Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of study participation. For those patients randomized to inotuzumab ozogamicin, there is a minimum of 8 months after the last dose of inotuzumab ozogamicin for females and 5 months after the last dose of inotuzumab ozogamicin for males.
healthy Volunteers
false
maximum Age
25 Years
minimum Age
365 Days
sex
ALL
std Ages
  1. CHILD
  2. ADULT
Treatment arms and interventions
arm Groups
  1. description
    See detailed description for Arm D.
    intervention Names
    1. Procedure: Biospecimen Collection
    2. Biological: Blinatumomab
    3. Procedure: Bone Marrow Aspiration
    4. Procedure: Bone Marrow Biopsy
    5. Drug: Calaspargase Pegol
    6. Drug: Cyclophosphamide
    7. Drug: Cytarabine
    8. Drug: Daunorubicin Hydrochloride
    9. Drug: Dexamethasone
    10. Drug: Doxorubicin Hydrochloride
    11. Drug: Leucovorin Calcium
    12. Drug: Mercaptopurine
    label
    Arm D (CD 22 positive HR B-ALL)
    type
    ACTIVE_COMPARATOR
  2. description
    See detailed description for Arm E.
    intervention Names
    1. Procedure: Biospecimen Collection
    2. Biological: Blinatumomab
    3. Procedure: Bone Marrow Aspiration
    4. Procedure: Bone Marrow Biopsy
    5. Drug: Calaspargase Pegol
    6. Drug: Cyclophosphamide
    7. Drug: Cytarabine
    8. Drug: Daunorubicin Hydrochloride
    9. Drug: Dexamethasone
    10. Drug: Doxorubicin Hydrochloride
    11. Biological: Inotuzumab Ozogamicin
    12. Drug: Leucovorin Calcium
    label
    Arm E (CD22 positive HR B-ALL)
    type
    EXPERIMENTAL
  3. description
    See Detailed Description for Arm I.
    intervention Names
    1. Procedure: Biospecimen Collection
    2. Procedure: Bone Marrow Aspiration
    3. Procedure: Bone Marrow Biopsy
    4. Drug: Calaspargase Pegol
    5. Drug: Cyclophosphamide
    6. Drug: Cytarabine
    7. Drug: Daunorubicin Hydrochloride
    8. Drug: Dexamethasone
    9. Drug: Leucovorin Calcium
    10. Drug: Mercaptopurine
    11. Drug: Methotrexate
    12. Drug: Pegaspargase
    label
    Arm I (MPAL)
    type
    EXPERIMENTAL
  4. description
    See Detailed Description for Arm II.
    intervention Names
    1. Procedure: Biospecimen Collection
    2. Procedure: Bone Marrow Aspiration
    3. Procedure: Bone Marrow Biopsy
    4. Procedure: Bone Scan
    5. Drug: Calaspargase Pegol
    6. Procedure: Computed Tomography
    7. Drug: Cyclophosphamide
    8. Drug: Cytarabine
    9. Drug: Daunorubicin Hydrochloride
    10. Drug: Dexamethasone
    11. Drug: Doxorubicin Hydrochloride
    12. Drug: Leucovorin Calcium
    label
    Arm II (B-LLy)
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. Arm D (CD 22 positive HR B-ALL)
    2. Arm E (CD22 positive HR B-ALL)
    3. Arm I (MPAL)
    4. Arm II (B-LLy)
    description
    Undergo blood sample collection
    name
    Biospecimen Collection
    other Names
    1. Biological Sample Collection
    2. Biospecimen Collected
    3. Sample Collection
    4. Specimen Collection
    type
    PROCEDURE
  2. arm Group Labels
    1. Arm D (CD 22 positive HR B-ALL)
    2. Arm E (CD22 positive HR B-ALL)
    description
    Given IV
    name
    Blinatumomab
    other Names
    1. AMG 103
    2. AMG-103
    3. AMG103
    4. Anti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody
    5. Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103
    6. Blincyto
    7. MEDI 538
    8. MEDI-538
    9. MEDI538
    10. MT 103
    11. MT-103
    12. MT103
    type
    BIOLOGICAL
  3. arm Group Labels
    1. Arm D (CD 22 positive HR B-ALL)
    2. Arm E (CD22 positive HR B-ALL)
    3. Arm I (MPAL)
    4. Arm II (B-LLy)
    description
    Undergo bone marrow aspiration
    name
    Bone Marrow Aspiration
    type
    PROCEDURE
  4. arm Group Labels
    1. Arm D (CD 22 positive HR B-ALL)
    2. Arm E (CD22 positive HR B-ALL)
    3. Arm I (MPAL)
    4. Arm II (B-LLy)
    description
    Undergo bone marrow biopsy
    name
    Bone Marrow Biopsy
    other Names
    1. Biopsy of Bone Marrow
    2. Biopsy, Bone Marrow
    type
    PROCEDURE
  5. arm Group Labels
    1. Arm II (B-LLy)
    description
    Undergo bone scan
    name
    Bone Scan
    other Names
    1. Bone Scintigraphy
    type
    PROCEDURE
  6. arm Group Labels
    1. Arm D (CD 22 positive HR B-ALL)
    2. Arm E (CD22 positive HR B-ALL)
    3. Arm I (MPAL)
    4. Arm II (B-LLy)
    description
    Given IV
    name
    Calaspargase Pegol
    other Names
    1. Asparaginase (Escherichia coli Isoenzyme II), Conjugate with alpha-(((2,5-Dioxo-1-pyrrolidinyl)oxy)carbonyl)-omega-methoxypoly(oxy-1,2-ethanediyl)
    2. Asparlas
    3. Calaspargase Pegol-mknl
    4. EZN-2285
    5. SC-PEG E. Coli L-Asparaginase
    6. Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase
    type
    DRUG
  7. arm Group Labels
    1. Arm II (B-LLy)
    description
    Undergo CT
    name
    Computed Tomography
    other Names
    1. CAT
    2. CAT Scan
    3. Computed Axial Tomography
    4. Computerized Axial Tomography
    5. Computerized axial tomography (procedure)
    6. Computerized Tomography
    7. Computerized Tomography (CT) scan
    8. CT
    9. CT Scan
    10. Diagnostic CAT Scan
    11. Diagnostic CAT Scan Service Type
    12. tomography
    type
    PROCEDURE
  8. arm Group Labels
    1. Arm D (CD 22 positive HR B-ALL)
    2. Arm E (CD22 positive HR B-ALL)
    3. Arm I (MPAL)
    4. Arm II (B-LLy)
    description
    Given IV
    name
    Cyclophosphamide
    other Names
    1. (-)-Cyclophosphamide
    2. 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    3. Asta B 518
    4. B 518
    5. B-518
    6. B518
    7. Carloxan
    8. Ciclofosfamida
    9. Ciclofosfamide
    10. Cicloxal
    11. Clafen
    12. Claphene
    type
    DRUG
  9. arm Group Labels
    1. Arm D (CD 22 positive HR B-ALL)
    2. Arm E (CD22 positive HR B-ALL)
    3. Arm I (MPAL)
    4. Arm II (B-LLy)
    description
    Given IV, IT, or SC
    name
    Cytarabine
    other Names
    1. .beta.-Cytosine arabinoside
    2. 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
    3. 1-.beta.-D-Arabinofuranosylcytosine
    4. 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
    5. 1-Beta-D-arabinofuranosylcytosine
    6. 1.beta.-D-Arabinofuranosylcytosine
    7. 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
    8. 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
    9. Alexan
    10. Ara-C
    11. ARA-cell
    12. Arabine
    type
    DRUG
  10. arm Group Labels
    1. Arm D (CD 22 positive HR B-ALL)
    2. Arm E (CD22 positive HR B-ALL)
    3. Arm I (MPAL)
    4. Arm II (B-LLy)
    description
    Given IV
    name
    Daunorubicin Hydrochloride
    other Names
    1. Cerubidin
    2. Cerubidine
    3. Cloridrato de Daunorubicina
    4. Daunoblastin
    5. Daunoblastina
    6. Daunoblastine
    7. Daunomycin Hydrochloride
    8. Daunomycin, hydrochloride
    9. Daunorubicin.HCl
    10. Daunorubicini Hydrochloridum
    11. FI-6339
    12. Ondena
    type
    DRUG
  11. arm Group Labels
    1. Arm D (CD 22 positive HR B-ALL)
    2. Arm E (CD22 positive HR B-ALL)
    3. Arm I (MPAL)
    4. Arm II (B-LLy)
    description
    Given PO or IV
    name
    Dexamethasone
    other Names
    1. Aacidexam
    2. Adexone
    3. Aknichthol Dexa
    4. Alba-Dex
    5. Alin
    6. Alin Depot
    7. Alin Oftalmico
    8. Amplidermis
    9. Anemul mono
    10. Auricularum
    11. Auxiloson
    12. Baycadron
    type
    DRUG
  12. arm Group Labels
    1. Arm D (CD 22 positive HR B-ALL)
    2. Arm E (CD22 positive HR B-ALL)
    3. Arm II (B-LLy)
    description
    Given IV
    name
    Doxorubicin Hydrochloride
    other Names
    1. 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
    2. ADM
    3. Adriacin
    4. Adriamycin
    5. Adriamycin Hydrochloride
    6. Adriamycin PFS
    7. Adriamycin RDF
    8. ADRIAMYCIN, HYDROCHLORIDE
    9. Adriamycine
    10. Adriblastina
    11. Adriblastine
    12. Adrimedac
    type
    DRUG
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
5951
type
ESTIMATED
Registered outcome plans (not posted results)
other Outcomes
  1. description
    OS rates will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto.
    measure
    Overall survival (OS)
    time Frame
    Time from study entry to death or date of last contact for those alive at last contact, assessed up to 5 years
  2. description
    Will be described.
    measure
    Therapy administered to patients with MPAL who come off protocol therapy due to poor disease response to ALL therapy
    time Frame
    Up to 5 years
  3. description
    Will be described.
    measure
    Disease response in patients with MPAL who come off protocol therapy due to poor disease response to ALL therapy
    time Frame
    Up to 5 years
  4. description
    Will be described.
    measure
    Survival outcomes of patients with MPAL who come off protocol therapy due to poor disease response to ALL therapy
    time Frame
    Up to 5 years
  5. description
    Percentages with MMD at induction and MRD positivity at end of Induction will be described.
    measure
    Prevalence and significance of minimal marrow disease (MMD) at diagnosis and bone marrow MRD in disseminated B-LLy
    time Frame
    Up to 5 years
  6. description
    The main analyses will use mixed models including random effects to account for the multiple sites and longitudinal observations within patients. Will examine unadjusted associations of the primary outcome (MEMS-based adherence rate) with demographic, clinical and sociodemographic variables for the entire cohort (across 3 intervention arms). Those patient-level factors associated with the outcome will be included in the main model as fixed effects to improve the precision of the estimates. The basic model for adherence will include time and mean adherence during the baseline pre-intervention period and treatment group. It will also include interactions between time and both baseline adherence and intervention group to allow for intervention-specific trends and normal changes in adherence over time.
    measure
    Impact of four proposed interventions of varying intensities to enhance adherence to oral 6 mercaptopurine, with a randomization based upon baseline adherence measured during the first cycle of maintenance therapy
    time Frame
    Up to 5 years
  7. description
    Estimates of DFS and the corresponding 95% confidence intervals by sex.
    measure
    DFS by sex
    time Frame
    Up to 5 years
  8. description
    Estimates of DFS and the corresponding 95% confidence intervals by race.
    measure
    DFS by race
    time Frame
    Up to 5 years
  9. description
    Estimates of DFS and the corresponding 95% confidence intervals by ethnicity.
    measure
    DFS by ethnicity
    time Frame
    Up to 5 years
  10. description
    PK of inotuzumab ozogamicin will be described with the Area Under the Curve (AUC) (in the PK model).
    measure
    Pharmacokinetics (PK) of inotuzumab ozogamicin when administered in the setting of first remission in pediatric and young adult patients with HR B-ALL
    time Frame
    Up to 5 years
  11. description
    Will explore associations between family-reported social determinants of health and survival outcomes, toxicities, and blinatumomab patterns of delivery.
    measure
    Family-reported social determinants of health and survival outcomes, toxicities, and blinatumomab patterns of delivery
    time Frame
    Up to 5 years
  12. description
    Will describe short- and long-term impact of chemo-immunotherapy on measures of immune function and infectious toxicities.
    measure
    Short- and long-term impact of chemo-immunotherapy on measures of immune function and infectious toxicities
    time Frame
    Up to 5 years
primary Outcomes
  1. description
    Will compare in a randomized manner the post-induction 5-year EFS for children and young adults with High Risk (HR) B-cell acute lymphoblastic leukemia (B-ALL) treated with a modified Berlin-Frankfurt-Münster (mBFM) chemo-immunotherapy backbone that includes blinatumomab and replaces Consolidation Part 2 and Delayed Intensification (DI) Part 2 with two blocks of inotuzumab ozogamicin, versus those treated with a full mBFM chemo-immunotherapy backbone that includes blinatumomab and retains Consolidation Part 2 and DI Part 2 without the addition of inotuzumab ozogamicin.
    measure
    Post-induction 5-year event-free survival (EFS)
    time Frame
    From study entry to first event (induction failure, induction death, end of induction [EOI] minimal residual disease [MRD] ≥ 5%,EO consolidation [C] MRD ≥ 0.01%, relapse, second malignancy, remission death) or date of last contact, assessed up to 5 years
secondary Outcomes
  1. description
    Will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. Estimation of treatment effect will be done using ITT analysis based on randomized group.
    measure
    5-year DFS for favorable risk subset of NCI HR B-ALL (HR favorable) when treated with mBFM chemotherapy with a single high-dose methotrexate (HD MTX) Interim Maintenance (IM) phase and treatment duration of 2 years from the start of IM regardless of sex
    time Frame
    From EOC to first event (relapse, second malignant neoplasm, remission death) or date of last contact, assessed up to 5 years
  2. description
    Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Will be monitored and reported.
    measure
    Incidence of adverse events for the integration of inotuzumab ozogamicin into the mBFM chemotherapy backbone in HR B-ALL
    time Frame
    Up to 5 years
  3. description
    Will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. Estimation of treatment effect will be done using ITT analysis based on randomized group.
    measure
    5-year event-free survival (EFS) for patients with mixed phenotype acute leukemia (MPAL) receiving mBFM HR B-ALL therapy that includes a second IM phase with Capizzi escalating intravenous MTX without leucovorin rescue+pegaspargase or calaspargase pegol
    time Frame
    From study entry to first event (induction failure, Induction death, end of induction (EOI) minimal residual disease (MRD) >= 5%, EOC MRD >= 0.01%, relapse, second malignancy, remission death) or date of last contact, assessed up to 5 years
  4. description
    Will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. Estimation of treatment effect will be done using ITT analysis based on randomized group.
    measure
    5-year EFS for patients with disseminated (Murphy stage III-IV) B-cell lymphoblastic lymphoma (B-LLy) receiving mBFM HR B-ALL therapy that includes a second IM phase with C-MTX
    time Frame
    From study entry to first event (progressive disease, induction death, relapse, second malignancy, remission death) or date of last contact, assessed up to 5 years
  5. description
    Will compare by study arm.
    measure
    Health-related quality of life (HRQoL) for HR B-ALL
    time Frame
    Consolidation Part 2 Day 43 (Arm D)/Inotuzumab ozogamicin Block 1 Day 15 (Arm E) up to Day 1 of IM2 (Arms D and E)
  6. description
    Will compare by study arm using Patient Reported Outcome (PRO) Measures.
    measure
    Incidence of symptomatic AEs for patients with HR B-ALL
    time Frame
    Up to 5 years
Full study description
brief Summary
This phase III trial studies whether inotuzumab ozogamicin added to post-induction chemotherapy and immunotherapy (chemo-immunotherapy) for patients with High-Risk B-cell Acute Lymphoblastic Leukemia (B-ALL) improves outcomes. Inotuzumab ozogamicin is a monoclonal antibody, which is a type of protein that can bind to certain targets on the surface of cells. Inotuzumab ozogamicin is a monoclonal antibody that is linked to a type of chemotherapy called calicheamicin. Inotuzumab attaches to cancer cells by binding to the CD22 protein on the surface of the cancer cell and delivering calicheamicin inside the cells to kill them. Other drugs used in the chemotherapy regimen, such as cyclophosphamide, cytarabine, dexamethasone, doxorubicin, daunorubicin, methotrexate, leucovorin, mercaptopurine, prednisone, thioguanine, vincristine, and pegaspargase or calaspargase pegol work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Blinatumomab is a specialized type of monoclonal antibody known as a bispecific T-cell engager (BiTE). It works by simultaneously binding to CD19 on cancer cells and CD3 on normal immune cells, bringing them together to destroy leukemia cells. Blinatumomab is a standard part of chemo-immunotherapy treatment for B-ALL. This trial also studies the outcomes of patients with mixed phenotype acute leukemia (MPAL), and B-lymphoblastic lymphoma (B-LLy) when treated with ALL therapy without inotuzumab ozogamicin or blinatumomab. The overall goal of this study is to understand if adding inotuzumab ozogamicin to standard of care chemo-immunotherapy maintains or improves outcomes in High Risk B-cell Acute Lymphoblastic Leukemia (HR B-ALL). The first part of the study includes the first phase of therapy: Induction. This part will collect information on the leukemia, as well as the effects of the initial treatment, to classify patients into post-induction treatment groups. On the second part of this study, patients with HR B-ALL will receive the remainder of the chemotherapy cycles (consolidation, blinatumomab block 1, interim maintenance 1, blinatumomab block 2, delayed intensification, interim maintenance 2, maintenance), with some patients randomized to receive inotuzumab. The patients that receive inotuzumab will not receive part of consolidation or part of delayed intensification. Other aims of this study include evaluating 1) side effects of treatment using patient-reported outcomes and health-related quality of life, 2) the best ways to help patients adhere to oral chemotherapy regimens, 3) the relationship between levels of inotuzumab ozogamicin in the blood and side effects, 4) the impact of chemo-immunotherapy on the immune system and risk of infection, and 5) the impact of social determinants of health on outcomes. Finally, this study will be the first to track the outcomes of subjects with disseminated B-cell Lymphoblastic Leukemia (B-LLy) or Mixed Phenotype Acute Leukemia (MPAL) when treated with B-ALL chemotherapy.
detailed Description
PRIMARY OBJECTIVE: I. To compare in a randomized manner the post-induction 5-year event-free survival (EFS) for children and young adults with High Risk (HR) B-cell acute lymphoblastic leukemia (B-ALL) treated with a modified Berlin-Frankfurt-Münster (mBFM) chemo-immunotherapy backbone that includes blinatumomab and replaces Consolidation Part 2 and Delayed Intensification (DI) Part 2 with two blocks of inotuzumab ozogamicin, versus those treated with a full mBFM chemo-immunotherapy backbone that includes blinatumomab and retains Consolidation Part 2 and DI Part 2 without the addition of inotuzumab ozogamicin. SECONDARY OBJECTIVES: I. To describe the 5-year disease-free survival (DFS) for a favorable risk subset of National Cancer Institute (NCI) HR B-ALL (HR-Fav) when treated with mBFM chemotherapy with a single high-dose methotrexate (HD-MTX) interim maintenance (IM) phase and treatment duration of 2 years from the start of IM regardless of sex. (Pre-Amendment #7B) II. To determine the toxicity and tolerability of inotuzumab ozogamicin integrated into the mBFM chemotherapy backbone in HR B-ALL, including toxicity experienced during phases of therapy subsequent to inotuzumab ozogamicin. III. To describe the 5-year event-free survival (EFS) for patients with mixed phenotype acute leukemia (MPAL) receiving mBFM HR B-ALL therapy that includes a second IM phase with Capizzi intravenous (IV) methotrexate without leucovorin rescue plus pegaspargase or calaspargase pegol (C-MTX). IV. To describe the 5-year EFS for patients with disseminated (Murphy stage III-IV) B-cell lymphoblastic lymphoma (B-LLy) receiving mBFM HR B-ALL therapy that includes a second IM phase with C-MTX. V. To compare health-related quality of life (HRQoL) for randomized HR B-ALL patients by study arm at two defined time points: Consolidation Part 2 Day 43 (Arm D)/inotuzumab ozogamicin Block 1 Day 15 (Arm E) and day 1 of IM2 (Arms D and E). VI. To compare symptomatic adverse events (AEs) for patients with HR B-ALL by study arm using Patient Reported Outcome (PRO) Measures. EXPLORATORY OBJECTIVES: I. To describe the 5-year overall survival (OS) and cumulative incidence of relapse (CIR) for randomized patients with HR B-ALL. II. To describe the therapy administered, disease response, and survival outcomes of patients with MPAL who come off protocol therapy due to poor disease response to ALL therapy either during Induction, at end of induction (EOI), or at end of consolidation (EOC). III. To define the prevalence and significance of minimal marrow disease (MMD) at diagnosis and bone marrow minimal residual disease (MRD) at EOI in disseminated B-LLy. IV. To determine the impact of proposed adherence-enhancing interventions on adherence to oral mercaptopurine in patients with ALL. V. To characterize the pharmacokinetics (PK) of inotuzumab ozogamicin when administered in the setting of first remission in pediatric and young adult patients with HR B-ALL. VI. To explore associations between family-reported social determinants of health and survival outcomes, toxicities, and blinatumomab patterns of delivery. VII. To describe both the short- and long-term impact of chemo-immunotherapy on measures of immune function and infectious toxicities. OUTLINE: B-ALL: All patients with B-ALL receive Induction therapy: INDUCTION: Patients receive cytarabine intrathecally (IT) on day 1. Patients also receive vincristine intravenously (IV) on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase intramuscularly (IM) on day 4, and methotrexate IT on days 8 and 29 (and on days 15 and 22 for central nervous system \[CNS\]3 patients). Patients \< 10 years old receive dexamethasone orally (PO) twice daily (BID) or IV on days 1-14; patients \>= 10 years old receive prednisone or prednisolone PO BID or IV on days 1-28. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. After completion of Induction treatment, patients with HR Fav B-ALL discontinue study, and patients with HR B-ALL and CD22 positive at diagnosis are randomized to Arm D or Arm E. ARM D * CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO QD on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (also days 29 and 43 for CNS3 patients), vincristine IV on days 15, 22, 43, and 50, pegaspargase IM or IV over 1-2 hours OR calaspargase pegol (\< 22 years of age only) IV over 1-2 hours on days 15 and 43. Consolidation treatment continues for 57 days in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis also receive radiation therapy (RT) to the testes once daily (QD) over 12 treatment fractions. After completion of Consolidation treatment, patients with MRD ≥ 25% discontinue study treatment. * BLINATUMOMAB (BLINA) BLOCK 1: Patients receive dexamethasone PO or IV on day 1 (and day 8 for patients with MRD ≥ 5% - \<25% at end of Consolidation \[EOC\]), blinatumomab IV continuously on days 1-28, and methotrexate IT on day 1. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. After completion of Blina Block 1 treatment, patients with MRD ≥ 0.01% discontinue study treatment. * INTERIM MAINTENANCE 1: Patients receive vincristine IV on days 1, 15, 29, and 43, high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO QD on days 1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. * BLINA BLOCK 2: Patients receive blinatumomab IV continuously on days 1-28 and methotrexate IT on day 1. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. * DELAYED INTENSIFICATION PART 1: Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over 3-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase IM or IV over 1-2 hours OR calaspargase pegol (\< 22 years of age only) IV over 1-2 hours on day 4 in the absence of disease progression or unacceptable toxicity. Patients then proceed to Delayed Intensification Part 2. * DELAYED INTENSIFICATION PART 2: Patients receive cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO QD on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine IV on days 43 and 50, and pegaspargase IM or IV over 1-2 hours OR calaspargase pegol (\< 22 years of age only) IV over 1-2 hours on day 43. Delayed Intensification Part 1 and 2 treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. * INTERIM MAINTENANCE 2: Patients receive vincristine IV on days 1, 11, 21, 31 and 41, methotrexate IV over 2-5 or 10-15 minutes on days 1, 11, 21, 31 and 41, methotrexate IT on days 1 and 31, and pegaspargase IM or IV over 1-2 hours on days 2 and 22 OR calaspargase pegol (\< 22 years of age only) IV over 1-2 hours on days 2 and 23. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * MAINTENANCE: Patients receive vincristine IV on day 1 of each cycle, prednisone or prednisolone PO BID or IV on days 1-5 of each cycle, mercaptopurine PO QD on days 1-84 of each cycle, methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and methotrexate IT on day 1 of each cycle. Patients with CNS3 at diagnosis also receive cranial RT over 10 treatment fractions QD, 5 days per week, during the first 4 weeks of Maintenance treatment. Cycles repeat every 84 days until 2 years from start of Blina Block 1 treatment in the absence of disease progression or unacceptable toxicity. ARM E: * CONSOLIDATION PART 1: Patients receive cyclophosphamide IV over 30-60 minutes on day 1, cytarabine IV over 1-30 minutes or SC on days 1-4 and 8-11, mercaptopurine PO QD on days 1-14, methotrexate IT on days 1, 8, 15, and 22 (NOTE: Patients with CNS3 omit days 15 and 22), vincristine IV on days 15 and 22, and pegaspargase IM or IV over 1-2 hours OR calaspargase pegol (\< 22 years of age only) IV over 1-2 hours on day 15. Treatment continues for 29 days in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis also receive RT to the testes QD over 12 treatment fractions. * INOTUZUMAB OZOGAMICIN (InO) BLOCK 1: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15 and methotrexate IT on day 1 (and day 15 for patients with CNS3). Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. After completion of InO Block 1 treatment, patients with MRD ≥ 25% discontinue study treatment. * BLINA BLOCK 1: Patients receive dexamethasone PO or IV on day 1 (and day 8 for patients with MRD ≥ 5% - \<25% at end of InO Block 1), blinatumomab IV continuously on days 1-28, and methotrexate IT on day 1. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. After completion of Blina Block 1 treatment, patients with MRD ≥ 0.01% discontinue study treatment. * INTERIM MAINTENANCE 1: Patients receive vincristine IV on days 1, 15, 29, and 43, high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO QD on days 1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. * BLINA BLOCK 2: Patients receive blinatumomab IV continuously on days 1-28 and methotrexate IT on day 1. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. * DELAYED INTENSIFICATION PART 1: Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over 3-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase IM or IV over 1-2 hours OR calaspargase pegol (\< 22 years of age only) IV over 1-2 hours on day 4 in the absence of disease progression or unacceptable toxicity. Patients then proceed to Delayed Intensification Part 2. * InO BLOCK 2: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15 and methotrexate IT on day 1. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. * INTERIM MAINTENANCE 2: Patients receive vincristine IV on days 1, 11, 21, 31 and 41, methotrexate IV over 2-5 or 10-15 minutes on days 1, 11, 21, 31 and 41, methotrexate IT on days 1 and 31, and pegaspargase IM or IV over 1-2 hours on days 2 and 22 OR calaspargase pegol (\< 22 years of age only) IV over 1-2 hours on days 2 and 23. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * MAINTENANCE: Patients receive vincristine IV on day 1 of each cycle, prednisone or prednisolone PO BID or IV on days 1-5 of each cycle, mercaptopurine PO QD on days 1-84 of each cycle, methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and methotrexate IT on day 1 of each cycle. Patients with CNS3 at diagnosis also receive cranial RT over 10 treatment fractions QD, 5 days per week, during the first 4 weeks of Maintenance treatment. Cycles repeat every 84 days for 2 years in the absence of disease progression or unacceptable toxicity. ARM I: MPAL * INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4, and methotrexate IT on days 8 and 29 (and on days 15 and 22 for CNS3 patients). Patients \< 10 years old receive dexamethasone PO BID or IV on days 1-14; patients \>= 10 years old receive prednisone or prednisolone PO BID or IV on days 1-28. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. Patients with MRD ≥ 5% at EOI discontinue study treatment. * CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (excluded on days 15 and 22 for CNS3 patients), vincristine IV on days 15, 22, 43, and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on days 15 and 43. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis that does not resolve by EOC and continued evidence of testicular disease at end of induction (EOI) undergo testicular RT over 12 once-daily fractions. Calaspargase pegol can only be given to patients less than 22 years of age. Patients with MRD ≥ 0.01% at EOC discontinue study treatment. ARM II: B-LLY * INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4, and methotrexate IT on days 8 and 29 (and on days 15 and 22 for CNS3 patients). Patients \< 10 years old receive dexamethasone PO BID or IV on days 1-14; patients \>= 10 years old receive prednisone or prednisolone PO BID or IV on days 1-28. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. * CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (excluded on days 15 and 22 CNS3 patients), vincristine IV on days 15, 22, 43, and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on days 15 and 43. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis that does not resolve by the EOI will and continued evidence of testicular disease at EOI undergo testicular RT over 12 once-daily fractions. Calaspargase pegol can only be given to patients less than 22 years of age. Patients without complete response (CR) at EOC discontinue study treatment. ARM I AND II: MPAL AND B-LLY (POST-CONSOLIDATION THERAPY) * INTERIM MAINTENANCE 1: Patients receive vincristine IV on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, methotrexate IT on days 1 and 29 and mercaptopurine PO QD on days 1-14, 15-28, 29-42, and 43-56. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. * DELAYED INTENSIFICATION (PART 1): Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over 3-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4. Treatment (Parts 1 and 2 of Delayed Intensification) continues for 63 days in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. * DELAYED INTENSIFICATION (PART 2): Patients receive cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine IV or IV push over 1 minute on days 43 and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 43. Treatment (Parts 1 and 2 of Delayed Intensification) continues for 63 days in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. * INTERIM MAINTENANCE 2: Patients receive vincristine IV on days 1, 11, 21, 31, and 41, methotrexate IV or infusion over 2-15 minutes or 10-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase or calaspargase pegol IV over 1-2 hours on days 2 and 22 (pegaspargase) or (calaspargase) 23 or pegaspargase IM on days 2 and 22. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. * MAINTENANCE: Patients receive vincristine IV on days 1, prednisone or prednisolone PO BID or IV on days 1-5, mercaptopurine PO on days 1-84, methotrexate PO on days 8, 15, 22, 29 (excluded in cycles 1 and 2), 36, 43, 50, 57, 64, 71, and 78, and methotrexate IT on days 1 (and 29 of cycles 1-2 for patients who do not receive cranial radiation). Cycles repeat every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients with CNS3 disease at diagnosis undergo cranial radiation therapy for 10 fractions over 4 weeks. Patients undergo blood sample collection and bone marrow aspiration and biopsy on study. B-LLy patients undergo computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and/or bone scan on study. After completion of study treatment, patients are followed up at 4 weeks, then every 3 months for 2 years, every 4-6 months for the third year, then every 6-12 months for years 4-5.
Source references
references
  1. citation
    Davis KL, Yao CC, Zimmerman JAO, Rau RE. Immunotherapy in B-Cell Acute Lymphoblastic Leukemia. J Natl Compr Canc Netw. 2025 Dec;23(12):e257067. doi: 10.6004/jnccn.2025.7067.
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        April 21, 2025

    Preserved source evidence · Not medical advice