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

Phase 3

Recruiting

• Conditions: Testicular Leukemia; B Lymphoblastic Lymphoma; B Acute Lymphoblastic Leukemia; Mixed Phenotype Acute Leukemia; Central Nervous System Leukemia
• Interventions: Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Drug: Calaspargase Pegol; Procedure: Bone Scan; Drug: Cyclophosphamide; Drug: Cytarabine; Procedure: Computed Tomography; Drug: Daunorubicin Hydrochloride; Drug: Dexamethasone; Drug: Doxorubicin Hydrochloride; Drug: Leucovorin Calcium; Biological: Inotuzumab Ozogamicin; Drug: Mercaptopurine; Drug: Methotrexate; Drug: Pegaspargase; Procedure: Magnetic Resonance Imaging; Drug: Prednisolone; Other: Questionnaire Administration; Radiation: Radiation Therapy; Procedure: Positron Emission Tomography; Drug: Thioguanine; Drug: Vincristine Sulfate

• Registration Number: NCT03959085
• Lead Sponsor: Children's Oncology Group

Brief Summary

This phase III trial studies whether inotuzumab ozogamicin added to post-induction chemotherapy for patients with High-Risk B-cell Acute Lymphoblastic Leukemia (B-ALL) improves outcomes. 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. Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab, linked to a type of chemotherapy called calicheamicin. Inotuzumab attaches to cancer cells in a targeted way and delivers calicheamicin 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. This trial will also study the outcomes of patients with mixed phenotype acute leukemia (MPAL) and disseminated B lymphoblastic lymphoma (B-LLy) when treated with high-risk ALL chemotherapy.

The overall goal of this study is to understand if adding inotuzumab ozogamicin to standard of care chemotherapy maintains or improves outcomes in High Risk B-cell Acute Lymphoblastic Leukemia (HR B-ALL). The first part of the study includes the first two phases of therapy: Induction and Consolidation. This part will collect information on the leukemia, as well as the effects of the initial treatment, to classify patients into post-consolidation treatment groups. On the second part of this study, patients with HR B-ALL will receive the remainder of the chemotherapy cycles (interim maintenance I, delayed intensification, interim maintenance II, maintenance), with some patients randomized to receive inotuzumab. The patients that receive inotuzumab will not receive part of delayed intensification. Other aims of this study include investigating whether treating both males and females with the same duration of chemotherapy maintains outcomes for males who have previously been treated for an additional year compared to girls, as well as to evaluate the best ways to help patients adhere to oral chemotherapy regimens. 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 5-year disease-free survival (DFS) for children and young adults with High Risk (HR) B-cell acute lymphoblastic leukemia (B-ALL) treated with modified Berlin-Frankfurt-Munster (mBFM) chemotherapy without delayed intensification (DI) part 2, but with the addition of two blocks of inotuzumab ozogamicin, versus those treated with full mBFM chemotherapy backbone including DI Part 2 without the addition of inotuzumab ozogamicin.

SECONDARY OBJECTIVES:

I. To describe the 5-year 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.

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.

EXPLORATORY OBJECTIVES:

I. 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).

II. 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.

III. To determine the impact of proposed adherence-enhancing interventions on adherence to oral 6-mercaptopurine in patients with ALL.

OUTLINE: All patients receive the same Induction and Consolidation chemotherapy. Patients with HR-Fav B-ALL are assigned to Arm I. Patients with HR B-ALL are randomized to Arm II or III. Patients with MPAL are assigned to Arm IV, and patients with B-LLy are assigned to Arm V.

All patients with B-ALL receive Induction and Consolidation therapy:

INDUCTION: Patients receive cytarabine intrathecally (IT) on day 1 and central nervous system (CNS)2 patients also receive cytarabine IT on days 4, 5 or 6 and 11 or 12. 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 CNS3 patients). Patients \< 10 years old receive dexamethasone orally (PO) twice daily (BID) or IV on days 1-14; patients \>= 10 years old receive prednis(ol)one 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.

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 once daily (QD) on days 1-14 and 29-42, and methotrexate IT on days 1, 8, 15, and 22 (CNS3 patients receive methotrexate IT on days 1 and 8). Patients also receive 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 8 weeks in the absence of disease progression or unacceptable toxicity. Additionally, patients with testicular disease at diagnosis that does not resolve by the end of induction will undergo radiation therapy over 12 once daily fractions. Calaspargase pegol can only be given to patients less than 22 years of age.

POST-CONSOLIDATION THERAPY: After Consolidation, based on clinical features and response, patients with B-ALL are designated as HR-Fav or HR B-ALL. Patients with HR-Fav B-ALL are assigned to Arm I. Patients with HR B-ALL are randomized to Arm II or III. Patients with MPAL and B-LLy are assigned to therapy arms (Arms IV and V) that are identical to Arm II. Patients that are \< 10 years, have CNS1, no testicular leukemia, with favorable cytogenetics (ETV6 RUNX1 fusion or double trisomies \[4 and 10\]), =\< 24 hours of steroids in the two weeks prior to diagnosis, and EOI MRD \< 0.01% are assigned to Arm I. Patients with HR B-ALL who are surface CD22 positive at diagnosis and have MRD \< 0.01% by the end of Consolidation, are randomized to either Arm II or III.

ARM I: HR-FAV B-ALL (Patients that are \< 10 years, have CNS1 status, no testicular leukemia, with favorable cytogenetics (ETV6 RUNX1 fusion or double trisomies \[4 and 10\]), =\< 24 hours of steroids in the two weeks prior to diagnosis, and EOI MRD \< 0.01%)

INTERIM MAINTENANCE: 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 9 weeks in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION (PART I): 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 1-15 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 I and II of Delayed Intensification) continues for 9 weeks 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 II): 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 on days 43 and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 43. Treatment (Parts I and II of Delayed Intensification) continues for 9 weeks 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 methotrexate IT on days 1 and 29 for cycles 1-4, and day 1 for subsequent cycles. Patients also receive vincristine IV on day 1, prednisolone PO BID or IV on days 1-5, mercaptopurine PO QD on days 1-84, and methotrexate PO on days 8, 15, 22, 29 (excluded in cycles 1-4), 36, 43, 50, 57, 64, 71, and 78. Cycles repeat every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.

Patients with HR B-ALL who have MRD \< 0.01% by the end of Consolidation, and leukemic blasts positive for surface CD22 at diagnosis are randomized to Arm II or Arm III.

ARM II: HR B-ALL (CONTROL) INTERIM MAINTENANCE I: 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, 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 9 weeks in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION (PART I): 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 1-15 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 I and II of Delayed Intensification) continues for 9 weeks 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 II): 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 on days 43 and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 43. Treatment (Parts I and II of Delayed Intensification) continues for 9 weeks 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 II: Patients receive vincristine on days 1, 11, 21, 31 and 41, methotrexate IV 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 23 (calaspargase) or pegaspargase IM on days 2 and 22. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.

ARM III: HR B-ALL (EXPERIMENTAL) 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. Treatment continues for 4 weeks in the absence of disease progression or unacceptable toxicity.

INTERIM MAINTENANCE I: 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 on days 1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION (Part I): 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 1-15 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 I and II of Delayed Intensification) 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.

InO BLOCK 2: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15. Treatment continues for 4 weeks in the absence of disease progression or unacceptable toxicity.

INTERIM MAINTENANCE II: Patients receive vincristine IV on days 1, 11, 21, 31, and 41, methotrexate IV 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 23 (calaspargase) or pegaspargase IM on days 2 and 22. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.

ARMS II AND III: HR B-ALL MAINTENANCE: Patients receive vincristine IV on day 1, 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 undergo cranial radiation therapy over 10 fractions during the first 4 weeks.

ARM IV: MPAL INDUCTION: Patients receive cytarabine IT on day 1 and CNS2 patients also receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive 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 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.

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 8 weeks in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis that does not resolve by the end of induction will and continued evidence of testicular disease at end of induction undergo testicular radiation over 12 once-daily fractions. Calaspargase pegol can only be given to patients less than 22 years of age.

ARM V: B-LLY INDUCTION: Patients receive cytarabine IT on day 1 and CNS2 patients also receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive 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 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.

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 8 weeks in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis that does not resolve by the end of induction will and continued evidence of testicular disease at end of induction undergo testicular radiation therapy over 12 once-daily fractions. Calaspargase pegol can only be given to patients less than 22 years of age.

ARM IV AND V: MPAL AND B-LLY (Post-Consolidation Therapy) INTERIM MAINTENANCE I: 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 9 weeks in the absence of disease progression or unacceptable toxicity.

DELAYED INTENSIFICATION (PART I): 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 1-15 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 I and II of Delayed Intensification) continues for 9 weeks 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 II): 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 I and II of Delayed Intensification) continues for 9 weeks 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 II: 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 8 weeks 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, 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.

Study Timeline

• Study First Submitted: 2019-05-20
• Study First Submitted QC: 2019-05-20
• Study First Posted: 2019-05-22
• Study Start: 2019-10-31
• Status Verified: 2025-06
• Last Update Submitted: 2025-07-09
• Last Update Posted: 2025-07-10
• Primary Completion: 2030-03-31
• Study Completion: 2030-03-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 4997

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

• 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:

    • Testicular leukemia
    • CNS leukemia (CNS3)
    • Steroid pretreatment.

• 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. 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.

• 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 (patients with Down syndrome and B-ALL are eligible for AALL1731, regardless of NCI risk group).

• 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II (HR B-ALL CONTROL)	Thioguanine	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Vincristine Sulfate	See detailed description for Arm II.
Arm III (HR B-ALL EXPERIMENTAL)	Biospecimen Collection	See detailed description for Arm III.
Arm III (HR B-ALL EXPERIMENTAL)	Bone Marrow Aspiration	See detailed description for Arm III.
Arm III (HR B-ALL EXPERIMENTAL)	Bone Marrow Biopsy	See detailed description for Arm III.
Arm III (HR B-ALL EXPERIMENTAL)	Calaspargase Pegol	See detailed description for Arm III.
Arm III (HR B-ALL EXPERIMENTAL)	Cyclophosphamide	See detailed description for Arm III.
Arm III (HR B-ALL EXPERIMENTAL)	Thioguanine	See detailed description for Arm III.
Arm III (HR B-ALL EXPERIMENTAL)	Vincristine Sulfate	See detailed description for Arm III.
Arm IV (MPAL)	Biospecimen Collection	See detailed description for Arm IV.
Arm IV (MPAL)	Bone Marrow Aspiration	See detailed description for Arm IV.
Arm IV (MPAL)	Bone Marrow Biopsy	See detailed description for Arm IV.
Arm IV (MPAL)	Calaspargase Pegol	See detailed description for Arm IV.
Arm III (HR B-ALL EXPERIMENTAL)	Questionnaire Administration	See detailed description for Arm III.
Arm III (HR B-ALL EXPERIMENTAL)	Radiation Therapy	See detailed description for Arm III.
Arm IV (MPAL)	Pegaspargase	See detailed description for Arm IV.
Arm I (HR-FAV B-ALL)	Biospecimen Collection	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Bone Marrow Aspiration	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Bone Marrow Biopsy	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Calaspargase Pegol	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Cyclophosphamide	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Cytarabine	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Daunorubicin Hydrochloride	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Dexamethasone	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Doxorubicin Hydrochloride	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Leucovorin Calcium	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Mercaptopurine	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Methotrexate	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Pegaspargase	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Prednisolone	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Questionnaire Administration	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Thioguanine	See detailed description for Arm I
Arm I (HR-FAV B-ALL)	Vincristine Sulfate	See detailed description for Arm I
Arm II (HR B-ALL CONTROL)	Biospecimen Collection	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Bone Marrow Aspiration	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Bone Marrow Biopsy	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Calaspargase Pegol	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Cyclophosphamide	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Cytarabine	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Daunorubicin Hydrochloride	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Dexamethasone	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Doxorubicin Hydrochloride	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Leucovorin Calcium	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Mercaptopurine	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Methotrexate	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Pegaspargase	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Prednisolone	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Questionnaire Administration	See detailed description for Arm II.
Arm II (HR B-ALL CONTROL)	Radiation Therapy	See detailed description for Arm II.
Arm III (HR B-ALL EXPERIMENTAL)	Cytarabine	See detailed description for Arm III.
Arm III (HR B-ALL EXPERIMENTAL)	Daunorubicin Hydrochloride	See detailed description for Arm III.
Arm III (HR B-ALL EXPERIMENTAL)	Dexamethasone	See detailed description for Arm III.
Arm III (HR B-ALL EXPERIMENTAL)	Doxorubicin Hydrochloride	See detailed description for Arm III.
Arm III (HR B-ALL EXPERIMENTAL)	Inotuzumab Ozogamicin	See detailed description for Arm III.
Arm III (HR B-ALL EXPERIMENTAL)	Leucovorin Calcium	See detailed description for Arm III.
Arm III (HR B-ALL EXPERIMENTAL)	Mercaptopurine	See detailed description for Arm III.
Arm III (HR B-ALL EXPERIMENTAL)	Methotrexate	See detailed description for Arm III.
Arm III (HR B-ALL EXPERIMENTAL)	Pegaspargase	See detailed description for Arm III.
Arm IV (MPAL)	Cyclophosphamide	See detailed description for Arm IV.
Arm IV (MPAL)	Cytarabine	See detailed description for Arm IV.
Arm IV (MPAL)	Daunorubicin Hydrochloride	See detailed description for Arm IV.
Arm IV (MPAL)	Dexamethasone	See detailed description for Arm IV.
Arm IV (MPAL)	Doxorubicin Hydrochloride	See detailed description for Arm IV.
Arm IV (MPAL)	Leucovorin Calcium	See detailed description for Arm IV.
Arm IV (MPAL)	Mercaptopurine	See detailed description for Arm IV.
Arm IV (MPAL)	Methotrexate	See detailed description for Arm IV.
Arm IV (MPAL)	Prednisolone	See detailed description for Arm IV.
Arm IV (MPAL)	Questionnaire Administration	See detailed description for Arm IV.
Arm IV (MPAL)	Radiation Therapy	See detailed description for Arm IV.
Arm IV (MPAL)	Thioguanine	See detailed description for Arm IV.
Arm IV (MPAL)	Vincristine Sulfate	See detailed description for Arm IV.
ARM V (B-LLY)	Biospecimen Collection	See detailed description for Arm V.
ARM V (B-LLY)	Bone Marrow Aspiration	See detailed description for Arm V.
ARM V (B-LLY)	Bone Marrow Biopsy	See detailed description for Arm V.
ARM V (B-LLY)	Bone Scan	See detailed description for Arm V.
ARM V (B-LLY)	Calaspargase Pegol	See detailed description for Arm V.
ARM V (B-LLY)	Computed Tomography	See detailed description for Arm V.
ARM V (B-LLY)	Cyclophosphamide	See detailed description for Arm V.
ARM V (B-LLY)	Cytarabine	See detailed description for Arm V.
ARM V (B-LLY)	Daunorubicin Hydrochloride	See detailed description for Arm V.
ARM V (B-LLY)	Dexamethasone	See detailed description for Arm V.
ARM V (B-LLY)	Doxorubicin Hydrochloride	See detailed description for Arm V.
ARM V (B-LLY)	Leucovorin Calcium	See detailed description for Arm V.
ARM V (B-LLY)	Magnetic Resonance Imaging	See detailed description for Arm V.
ARM V (B-LLY)	Methotrexate	See detailed description for Arm V.
ARM V (B-LLY)	Pegaspargase	See detailed description for Arm V.
ARM V (B-LLY)	Positron Emission Tomography	See detailed description for Arm V.
ARM V (B-LLY)	Prednisolone	See detailed description for Arm V.
ARM V (B-LLY)	Questionnaire Administration	See detailed description for Arm V.
ARM V (B-LLY)	Radiation Therapy	See detailed description for Arm V.
ARM V (B-LLY)	Thioguanine	See detailed description for Arm V.
ARM V (B-LLY)	Vincristine Sulfate	See detailed description for Arm V.

Primary Outcome Measures

Name	Time	Method
Improvement in 5-year disease-free survival (DFS)	From end of consolidation (EOC) to first event (relapse, second malignant neoplasm, remission death) or date of last contact, assessed up to 5 years	Improvement in 5-year disease-free survival (DFS) with modified Berlin-Frankfurt-Münster (mBFM) chemotherapy without delayed intensification (DI) part 2 but with inotuzumab ozogamicin, versus full mBFM chemotherapy backbone including DI Part 2 without the addition of inotuzumab ozogamicin. Power calculations are based on detecting an improvement in post consolidation DFS with the addition of InO to standard therapy for high risk (HR) B-acute lymphoblastic leukemia (ALL). All survival time analyses assume a Weibull distribution with shape parameter of 0.6 (based on historical data). 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 intent-to-treat (ITT) analysis based on randomized group.

Secondary Outcome Measures

Name	Time	Method
Incidence of adverse events for the integration of inotuzumab ozogamicin into the mBFM chemotherapy backbone in HR B-ALL	Up to 5 years	Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Will be monitored and reported.
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 calapargase pegol	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	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.
Overall survival (OS)	Time from study entry to death or date of last contact for those alive at last contact, assessed up to 5 years	OS rates will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto.
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	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	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.
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	From EOC to first event (relapse, second malignant neoplasm, remission death) or date of last contact, assessed up to 5 years	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.

Trial Locations

Locations (230)

Children's Hospital of Alabama; 🇺🇸 Birmingham, Alabama, United States

USA Health Strada Patient Care Center; 🇺🇸 Mobile, Alabama, United States

Providence Alaska Medical Center; 🇺🇸 Anchorage, Alaska, United States

Banner Children's at Desert; 🇺🇸 Mesa, Arizona, United States

Phoenix Childrens Hospital; 🇺🇸 Phoenix, Arizona, United States

Banner University Medical Center - Tucson; 🇺🇸 Tucson, Arizona, United States

Arkansas Children's Hospital; 🇺🇸 Little Rock, Arkansas, United States

Kaiser Permanente Downey Medical Center; 🇺🇸 Downey, California, United States

City of Hope Comprehensive Cancer Center; 🇺🇸 Duarte, California, United States

Loma Linda University Medical Center; 🇺🇸 Loma Linda, California, United States

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