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

Sponsor

Children's Oncology Group (Other)

Overall Status

Recruiting

CT.gov ID

NCT03959085

Collaborator

National Cancer Institute (NCI) (NIH)

4,772

Enrollment

218

Locations

Arms

116.1

Anticipated Duration (Months)

21.9

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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 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, in order to classify patients into post-consolidation treatment groups. On the second part of this study, patients will receive the remainder of the chemotherapy cycles (interim maintenance I, delayed intensification, interim maintenance II, maintenance), with some patients randomized to receive inotuzumab. 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.

Condition or Disease	Intervention/Treatment	Phase
B Acute Lymphoblastic Leukemia B Lymphoblastic Lymphoma Central Nervous System Leukemia Mixed Phenotype Acute Leukemia Testicular Leukemia	Drug: Calaspargase Pegol-mknl 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	Phase 3

Detailed Description

PRIMARY OBJECTIVE:

To determine in a randomized manner if the addition of 2 blocks of inotuzumab ozogamicin to modified Berlin-Frankfurt-Munster (mBFM) chemotherapy will improve 5-year disease-free survival (DFS) in children and young adults with high-risk B-cell acute lymphoblastic leukemia (HR B-ALL).

SECONDARY OBJECTIVES:

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.
To determine the toxicity and tolerability of inotuzumab ozogamicin integrated into the mBFM chemotherapy backbone in HR B-ALL.
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 (MTX) without leucovorin rescue plus pegaspargase (C-MTX).
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:

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).
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.
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

Patients with MPAL are assigned to Arm IV, and patients with B-LLy are assigned to Arm

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) or IV push over 1 minute on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase intramuscularly (IM) or IV over 1-2 hours 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.

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 or IV push over 1 minute on days 15, 22, 43, and 50, and pegaspargase IV over 1-2 hours or 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.

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 or IV push over 1 minute 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 or IV push over 1 minute 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 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.

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 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 methotrexate IT on days 1 and 29 for cycles 1-4, and day 1 for subsequent cycles. Patients also receive vincristine IV or IV push over 1 minute 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 or IV push over 1 minute 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.

INTERIM MAINTENANCE II: Patients receive vincristine IV or IV push over 1 minute 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 or 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.

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 or IV push over 1 minute 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.

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 or IV push over 1 minute 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 or 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.

ARMS II AND III: HR B-ALL MAINTENANCE: Patients receive vincristine IV or IV push over 1 minute 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 or IV push over 1 minute on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase IM or IV over 1-2 hours 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.

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 or IV push over 1 minute on days 15, 22, 43, and 50, and pegaspargase IV over 1-2 hours or 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.

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 or IV push over 1 minute on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase IM or IV over 1-2 hours 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.

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 or IV push over 1 minute on days 15, 22, 43, and 50, and pegaspargase IV over 1-2 hours or 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.

ARM IV AND V: MPAL AND B-LLY (Post-Consolidation Therapy) INTERIM MAINTENANCE I: Patients receive vincristine IV or IV push over 1 minute 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.

INTERIM MAINTENANCE II: Patients receive vincristine IV or IV push over 1 minute 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 or 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 or IV push over 1 minute 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.

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 Design

Study Type:

Interventional

Anticipated Enrollment :

4772 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Oct 28, 2019

Anticipated Primary Completion Date :

Jun 30, 2029

Anticipated Study Completion Date :

Jun 30, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (HR-FAV B-ALL) See detailed description for Arm I	Drug: Calaspargase Pegol-mknl Given IV Drug: Cyclophosphamide Given IV Drug: Cytarabine Given IV, IT, or SC Drug: Daunorubicin Hydrochloride Given IV Drug: Dexamethasone Given PO or IV Drug: Doxorubicin Hydrochloride Given IV Drug: Leucovorin Calcium Given PO or IV Drug: Mercaptopurine Given PO Drug: Methotrexate Given IT or IV Drug: Pegaspargase Given IV or IM Drug: Prednisolone Given PO or IV Other: Questionnaire Administration Ancillary studies Drug: Thioguanine Given PO Drug: Vincristine Sulfate Given IV or IV push
Active Comparator: Arm II (HR B-ALL CONTROL) See detailed description for Arm II.	Drug: Calaspargase Pegol-mknl Given IV Drug: Cyclophosphamide Given IV Drug: Cytarabine Given IV, IT, or SC Drug: Daunorubicin Hydrochloride Given IV Drug: Dexamethasone Given PO or IV Drug: Doxorubicin Hydrochloride Given IV Drug: Leucovorin Calcium Given PO or IV Drug: Mercaptopurine Given PO Drug: Methotrexate Given IT or IV Drug: Pegaspargase Given IV or IM Drug: Prednisolone Given PO or IV Other: Questionnaire Administration Ancillary studies Radiation: Radiation Therapy Undergo cranial radiation therapy Drug: Thioguanine Given PO Drug: Vincristine Sulfate Given IV or IV push
Experimental: Arm III (HR B-ALL EXPERIMENTAL) See detailed description for Arm III.	Drug: Calaspargase Pegol-mknl Given IV Drug: Cyclophosphamide Given IV Drug: Cytarabine Given IV, IT, or SC Drug: Daunorubicin Hydrochloride Given IV Drug: Dexamethasone Given PO or IV Drug: Doxorubicin Hydrochloride Given IV Biological: Inotuzumab Ozogamicin Given IV Drug: Leucovorin Calcium Given PO or IV Drug: Mercaptopurine Given PO Drug: Methotrexate Given IT or IV Drug: Pegaspargase Given IV or IM Other: Questionnaire Administration Ancillary studies Radiation: Radiation Therapy Undergo cranial radiation therapy Drug: Thioguanine Given PO Drug: Vincristine Sulfate Given IV or IV push
Experimental: Arm IV (MPAL) See detailed description for Arm IV.	Drug: Calaspargase Pegol-mknl Given IV Drug: Cyclophosphamide Given IV Drug: Cytarabine Given IV, IT, or SC Drug: Daunorubicin Hydrochloride Given IV Drug: Dexamethasone Given PO or IV Drug: Doxorubicin Hydrochloride Given IV Drug: Leucovorin Calcium Given PO or IV Drug: Mercaptopurine Given PO Drug: Methotrexate Given IT or IV Drug: Pegaspargase Given IV or IM Drug: Prednisolone Given PO or IV Other: Questionnaire Administration Ancillary studies Radiation: Radiation Therapy Undergo testicular radiation therapy Radiation: Radiation Therapy Undergo cranial radiation therapy Drug: Thioguanine Given PO Drug: Vincristine Sulfate Given IV or IV push
Experimental: ARM V (B-LLY) See detailed description for Arm V.	Drug: Calaspargase Pegol-mknl Given IV Drug: Cyclophosphamide Given IV Drug: Cytarabine Given IV, IT, or SC Drug: Daunorubicin Hydrochloride Given IV Drug: Dexamethasone Given PO or IV Drug: Doxorubicin Hydrochloride Given IV Drug: Leucovorin Calcium Given PO or IV Drug: Methotrexate Given IT or IV Drug: Pegaspargase Given IV or IM Drug: Prednisolone Given PO or IV Other: Questionnaire Administration Ancillary studies Radiation: Radiation Therapy Undergo testicular radiation therapy Radiation: Radiation Therapy Undergo cranial radiation therapy Drug: Thioguanine Given PO Drug: Vincristine Sulfate Given IV or IV push

Outcome Measures

Primary Outcome Measures

Improvement in 5-year disease-free survival (DFS) after adding 2 blocks of inotuzumab ozogamicin (InO) to Berlin-Frankfurt-Munster (mBFM) chemotherapy in children and young adults with High-Risk (HR) B-ALL [From end of consolidation (EOC) to first event (relapse, second malignant neoplasm, remission death) or date of last contact, assessed up to 5 years]
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

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.
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 plus pegaspargase (C-MTX) [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.
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.

Other Outcome Measures

Therapy administered to patients with MPAL who come off protocol therapy due to poor disease response to ALL therapy [Up to 5 years]
Will be described.
Disease response in patients with MPAL who come off protocol therapy due to poor disease response to ALL therapy [Up to 5 years]
Will be described.
Survival outcomes of patients with MPAL who come off protocol therapy due to poor disease response to ALL therapy [Up to 5 years]
Will be described.
Prevalence and significance of minimal marrow disease (MMD) at diagnosis and bone marrow MRD in disseminated B-LLy [Up to 5 years]
Percentages with MMD at induction and MRD positivity at end of Induction will be described.
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 [Up to 5 years]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 24 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 7 business days after enrollment for 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.
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.
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.
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 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	USA Health Strada Patient Care Center	Mobile	Alabama	United States	36604
3	Providence Alaska Medical Center	Anchorage	Alaska	United States	99508
4	Banner Children's at Desert	Mesa	Arizona	United States	85202
5	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
6	Banner University Medical Center - Tucson	Tucson	Arizona	United States	85719
7	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202-3591
8	Kaiser Permanente Downey Medical Center	Downey	California	United States	90242
9	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
10	Loma Linda University Medical Center	Loma Linda	California	United States	92354
11	Miller Children's and Women's Hospital Long Beach	Long Beach	California	United States	90806
12	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
13	Cedars Sinai Medical Center	Los Angeles	California	United States	90048
14	Mattel Children's Hospital UCLA	Los Angeles	California	United States	90095
15	Valley Children's Hospital	Madera	California	United States	93636
16	UCSF Benioff Children's Hospital Oakland	Oakland	California	United States	94609
17	Kaiser Permanente-Oakland	Oakland	California	United States	94611
18	Children's Hospital of Orange County	Orange	California	United States	92868
19	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
20	Sutter Medical Center Sacramento	Sacramento	California	United States	95816
21	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
22	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
23	Naval Medical Center -San Diego	San Diego	California	United States	92134
24	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
25	Santa Barbara Cottage Hospital	Santa Barbara	California	United States	93102
26	Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center	Torrance	California	United States	90502
27	Children's Hospital Colorado	Aurora	Colorado	United States	80045
28	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
29	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
30	Yale University	New Haven	Connecticut	United States	06520
31	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
32	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
33	Children's National Medical Center	Washington	District of Columbia	United States	20010
34	Broward Health Medical Center	Fort Lauderdale	Florida	United States	33316
35	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida	United States	33908
36	University of Florida Health Science Center - Gainesville	Gainesville	Florida	United States	32610
37	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
38	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
39	Palms West Radiation Therapy	Loxahatchee Groves	Florida	United States	33470
40	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
41	Nicklaus Children's Hospital	Miami	Florida	United States	33155
42	Miami Cancer Institute	Miami	Florida	United States	33176
43	AdventHealth Orlando	Orlando	Florida	United States	32803
44	Arnold Palmer Hospital for Children	Orlando	Florida	United States	32806
45	Nemours Children's Hospital	Orlando	Florida	United States	32827
46	Sacred Heart Hospital	Pensacola	Florida	United States	32504
47	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
48	Tampa General Hospital	Tampa	Florida	United States	33606
49	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida	United States	33607
50	Saint Mary's Hospital	West Palm Beach	Florida	United States	33407
51	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
52	Augusta University Medical Center	Augusta	Georgia	United States	30912
53	Medical Center of Central Georgia	Macon	Georgia	United States	31201
54	Memorial Health University Medical Center	Savannah	Georgia	United States	31404
55	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii	United States	96826
56	Saint Luke's Cancer Institute - Boise	Boise	Idaho	United States	83712
57	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
58	University of Illinois	Chicago	Illinois	United States	60612
59	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
60	Loyola University Medical Center	Maywood	Illinois	United States	60153
61	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois	United States	60453
62	Advocate Children's Hospital-Park Ridge	Park Ridge	Illinois	United States	60068
63	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61637
64	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
65	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
66	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana	United States	46260
67	Blank Children's Hospital	Des Moines	Iowa	United States	50309
68	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
69	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
70	Norton Children's Hospital	Louisville	Kentucky	United States	40202
71	Children's Hospital New Orleans	New Orleans	Louisiana	United States	70118
72	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
73	Eastern Maine Medical Center	Bangor	Maine	United States	04401
74	Maine Children's Cancer Program	Scarborough	Maine	United States	04074
75	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
76	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
77	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
78	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
79	Tufts Children's Hospital	Boston	Massachusetts	United States	02111
80	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
81	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
82	Baystate Medical Center	Springfield	Massachusetts	United States	01199
83	UMass Memorial Medical Center - University Campus	Worcester	Massachusetts	United States	01655
84	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
85	Ascension Saint John Hospital	Detroit	Michigan	United States	48236
86	Michigan State University Clinical Center	East Lansing	Michigan	United States	48824-7016
87	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
88	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
89	Beaumont Children's Hospital-Royal Oak	Royal Oak	Michigan	United States	48073
90	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
91	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
92	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
93	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
94	Columbia Regional	Columbia	Missouri	United States	65201
95	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
96	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri	United States	63104
97	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
98	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
99	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska	United States	68114
100	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
101	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
102	Sunrise Hospital and Medical Center	Las Vegas	Nevada	United States	89109
103	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada	United States	89135
104	Summerlin Hospital Medical Center	Las Vegas	Nevada	United States	89144
105	Renown Regional Medical Center	Reno	Nevada	United States	89502
106	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
107	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
108	Morristown Medical Center	Morristown	New Jersey	United States	07960
109	Jersey Shore Medical Center	Neptune	New Jersey	United States	07753
110	Saint Peter's University Hospital	New Brunswick	New Jersey	United States	08901
111	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
112	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
113	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
114	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
115	Presbyterian Hospital	Albuquerque	New Mexico	United States	87106
116	Albany Medical Center	Albany	New York	United States	12208
117	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
118	Maimonides Medical Center	Brooklyn	New York	United States	11219
119	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
120	NYU Winthrop Hospital	Mineola	New York	United States	11501
121	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York	United States	11040
122	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York	United States	10016
123	Mount Sinai Hospital	New York	New York	United States	10029
124	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
125	NYP/Weill Cornell Medical Center	New York	New York	United States	10065
126	University of Rochester	Rochester	New York	United States	14642
127	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
128	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
129	New York Medical College	Valhalla	New York	United States	10595
130	Mission Hospital	Asheville	North Carolina	United States	28801
131	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
132	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
133	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
134	Duke University Medical Center	Durham	North Carolina	United States	27710
135	East Carolina University	Greenville	North Carolina	United States	27834
136	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
137	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
138	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
139	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
140	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
141	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
142	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
143	Dayton Children's Hospital	Dayton	Ohio	United States	45404
144	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio	United States	43606
145	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
146	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma	United States	74136
147	Legacy Emanuel Children's Hospital	Portland	Oregon	United States	97227
148	Oregon Health and Science University	Portland	Oregon	United States	97239
149	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania	United States	18103
150	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
151	Penn State Children's Hospital	Hershey	Pennsylvania	United States	17033
152	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
153	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134
154	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
155	Medical University of South Carolina	Charleston	South Carolina	United States	29425
156	Prisma Health Richland Hospital	Columbia	South Carolina	United States	29203
157	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
158	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
159	T C Thompson Children's Hospital	Chattanooga	Tennessee	United States	37403
160	East Tennessee Childrens Hospital	Knoxville	Tennessee	United States	37916
161	The Children's Hospital at TriStar Centennial	Nashville	Tennessee	United States	37203
162	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
163	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
164	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
165	Medical City Dallas Hospital	Dallas	Texas	United States	75230
166	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
167	El Paso Children's Hospital	El Paso	Texas	United States	79905
168	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
169	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
170	M D Anderson Cancer Center	Houston	Texas	United States	77030
171	Covenant Children's Hospital	Lubbock	Texas	United States	79410
172	UMC Cancer Center / UMC Health System	Lubbock	Texas	United States	79415
173	Vannie Cook Children's Clinic	McAllen	Texas	United States	78503
174	Children's Hospital of San Antonio	San Antonio	Texas	United States	78207
175	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
176	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
177	Scott and White Memorial Hospital	Temple	Texas	United States	76508
178	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
179	University of Vermont and State Agricultural College	Burlington	Vermont	United States	05405
180	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
181	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042
182	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507
183	Naval Medical Center - Portsmouth	Portsmouth	Virginia	United States	23708-2197
184	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
185	Carilion Children's	Roanoke	Virginia	United States	24014
186	Seattle Children's Hospital	Seattle	Washington	United States	98105
187	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
188	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington	United States	98405
189	Madigan Army Medical Center	Tacoma	Washington	United States	98431
190	West Virginia University Charleston Division	Charleston	West Virginia	United States	25304
191	West Virginia University Healthcare	Morgantown	West Virginia	United States	26506
192	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
193	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53792
194	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin	United States	54449
195	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
196	John Hunter Children's Hospital	Hunter Regional Mail Centre	New South Wales	Australia	2310
197	Queensland Children's Hospital	South Brisbane	Queensland	Australia	4101
198	Women's and Children's Hospital-Adelaide	North Adelaide	South Australia	Australia	5006
199	Monash Medical Center-Clayton Campus	Clayton	Victoria	Australia	3168
200	Perth Children's Hospital	Perth	Western Australia	Australia	6009
201	Alberta Children's Hospital	Calgary	Alberta	Canada	T3B 6A8
202	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
203	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
204	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
205	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador	Canada	A1B 3V6
206	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
207	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
208	Kingston Health Sciences Centre	Kingston	Ontario	Canada	K7L 2V7
209	Children's Hospital	London	Ontario	Canada	N6A 5W9
210	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
211	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
212	The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Canada	H3H 1P3
213	Centre Hospitalier Universitaire de Sherbrooke-Fleurimont	Sherbrooke	Quebec	Canada	J1H 5N4
214	Jim Pattison Children's Hospital	Saskatoon	Saskatchewan	Canada	S7N 0W8
215	Saskatoon Cancer Centre	Saskatoon	Saskatchewan	Canada	S7N 4H4
216	Starship Children's Hospital	Grafton	Auckland	New Zealand	1145
217	Christchurch Hospital	Christchurch		New Zealand	8011
218	University Pediatric Hospital	San Juan		Puerto Rico	00926