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


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Trial ID: NCT03959085


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.

Official Title

A Phase 3 Randomized Trial of Inotuzumab Ozogamicin (NSC#: 772518) for Newly Diagnosed High-Risk B-ALL; Risk-Adapted Post-Induction Therapy for High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and Disseminated B-LLy

Stanford Investigator(s)


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

   - 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

      - 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

   - 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

   - 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

   - 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.


drug: Cyclophosphamide

drug: Cytarabine

drug: Daunorubicin Hydrochloride

drug: Dexamethasone

drug: Doxorubicin Hydrochloride

biological: Inotuzumab Ozogamicin

drug: Leucovorin Calcium

drug: Mercaptopurine

drug: Methotrexate

drug: Pegaspargase

drug: Prednisolone

other: Questionnaire Administration

radiation: Radiation Therapy

radiation: Radiation Therapy

drug: Thioguanine

drug: Vincristine Sulfate

procedure: Biospecimen Collection

procedure: Bone Marrow Aspiration

procedure: Bone Marrow Biopsy

procedure: Bone Scan

procedure: Computed Tomography

procedure: Magnetic Resonance Imaging

procedure: Positron Emission Tomography

drug: Calaspargase Pegol


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Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Stefania Ursu Chirita

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