Summary

This phase II trial studies how well inotuzumab ozogamicin works in treating younger patients with B-lymphoblastic lymphoma or CD22 positive B acute lymphoblastic leukemia that has come back (relapsed) or does not respond to treatment (refractory). Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab, linked to a toxic agent called ozogamicin. Inotuzumab attaches to CD22 positive cancer cells in a targeted way and delivers ozogamicin to kill them.

Objectives

PRIMARY OBJECTIVE:
I. To determine the morphologic response rate (complete response [CR] + complete response with incomplete hematologic recovery [CRi]) following one cycle of treatment with inotuzumab ozogamicin in children with relapsed or refractory CD22+ B acute lymphoblastic leukemia (B-ALL). (Cohort 1)

SECONDARY OBJECTIVES:
I. To determine the CR/CRi rate following 2 cycles of inotuzumab ozogamicin therapy. (Cohort 1)
II. To determine the safety of single agent inotuzumab ozogamicin administered at the adult recommended phase 2 dose (RP2D) to pediatric patients with relapsed or refractory CD22+ B-ALL. (Cohort 1)
III. To determine the level of minimal residual disease (MRD) by flow cytometry in responding patients. (Cohorts 1 and 2)
IV. To determine the incidence, severity, and outcomes of sinusoidal obstruction syndrome (SOS) of the liver in patients during inotuzumab ozogamicin therapy and following subsequent treatment, including myeloablative hematopoietic stem cell transplantation (HSCT). (Cohorts 1 and 2)
V. To estimate the 3-year event-free survival (EFS), 3-year overall survival (OS), and among responders, duration of CR/CRi for pediatric patients with relapsed or refractory B-ALL treated with inotuzumab ozogamicin. (Cohort 1)
VI. To describe inotuzumab ozogamicin pharmacokinetics and immunogenicity in pediatric patients in the presence of overt leukemia and in remission. (Cohort 1)
VII. To determine the safe and tolerable dose of inotuzumab ozogamicin in combination with the augmented modified Berlin-Frankfurt-Munster (mBFM) consolidation chemotherapy backbone. (Cohort 2)

EXPLORATORY OBJECTIVES:
I. To describe the levels of leukemic blast CD22 surface expression and site density, and to explore the correlation with cytogenetics and clinical outcomes after treatment with inotuzumab ozogamicin. (Cohorts 1 and 2)
II. To explore potential mechanisms of resistance to inotuzumab ozogamicin therapy including CD22 splice variants and intracellular signaling pathways. (Cohorts 1 and 2)
III. To explore the impact of inotuzumab ozogamicin on humoral immune function and peripheral B cell populations. (Cohorts 1 and 2)
IV. To describe the level of MRD by next-generation high-throughput sequencing (HTS) techniques which may detect low level leukemic blast populations that have altered CD22 expression. (Cohorts 1 and 2)
V. To prospectively explore candidate SOS biomarkers including the endothelial marker of inflammation Angiopoietin 2 (Ang2) and the hepatic specific complement marker L-ficolin. (Cohorts 1 and 2)
VI. To explore the use of prophylactic ursodeoxycholic acid (UDCA) to prevent hepatic damage and SOS during inotuzumab ozogamicin therapy and subsequent HSCT. (Cohorts 1 and 2)
VII. To describe the interaction between inotuzumab ozogamicin and chimeric antigen receptor (CAR) T cell therapy before or after treatment with inotuzumab ozogamicin. (Cohorts 1 and 2)
VIII. To estimate the CR/CRi rate following one cycle of inotuzumab ozogamicin plus augmented mBFM consolidation chemotherapy (first 42 days) and following 2 cycles within the confines of a pilot study. (Cohort 2)

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT I: Patients receive inotuzumab ozogamicin intravenously (IV) over 60 minutes on days 1, 8, and 15 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. (COMPLETE)

COHORT II: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, and 8. Patients also receive cyclophosphamide IV over 30-60 on day 1; cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4 and 8-11; leucovorin calcium orally (PO) or IV on days 2, 9, 16, 23 and 37 of cycle 1 and days 9 and 37 of cycle 2; pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase intramuscularly (IM) on day 15; and vincristine IV on days 15 and 22. Patients receive methotrexate intrathecally (IT) on days 1, 8 and 36 of cycle 1 and day 36 of cycle 2 for CNS 1 patients, days 1, 8, 15, 22 and 36 of cycle 1, and day 36 of cycle 2 for CNS 2 patients. CNS 3 patients receive methotrexate intrathecal triple therapy (ITT) IT on days 1, 8, 15, 22 and 36 of cycle 1 and days 8 and 36 of cycle 2. There are 3 dose levels. If excessive toxicity is observed at dose level 1, the dosing of inotuzumab ozogamicin will be decreased for dose level -1 and 6-mercaptopurine omitted. If excessive toxicity is observed at this dose, then for dose level -2, the dosing of inotuzumab ozogamicin and cyclophosphamide will be decreased. Treatment repeats every 42 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration or biopsy, lumbar puncture, and blood sample collection throughout the trial. Patients also undergo imaging on screening and on study.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, and then yearly for 4 years.

Eligibility

1. Patients must be >= 1 year and < 22 years of age at the time of enrollment
2. Patients must have B-ALL, or previously diagnosed B lymphoblastic lymphoma (B-LL), with >= 5% (M2 or M3) bone marrow blasts with or without extramedullary disease * NOTE: Relapsed patients previously diagnosed with B-lymphoblastic lymphoma (B-LL) are eligible if they have an M2 or M3 marrow at the time of enrollment on this study
3. Patients with ALL or B-LL who have M2 morphology must have local confirmatory testing showing >= 5% blasts by flow cytometry, fluorescence in situ hybridization (FISH) testing or other molecular method
4. Leukemic blasts must demonstrate surface expression of CD22 at the time of relapse by local/institutional flow cytometry of a bone marrow aspirate sample; (assessment of CD22 using a bright fluorophore such as phycoerythrin [PE] is strongly recommended) * In the case of an inadequate aspirate sample (dry tap) or if bone marrow aspirate is unable to be performed due to patient clinical status, flow cytometry of peripheral blood specimen may be substituted if the patient has at least 1,000/uL circulating blasts; alternatively, CD22 expression may be documented by immunohistochemistry of a bone marrow biopsy specimen
5. Patients with one of the following: * Second or greater relapse; * Primary refractory disease with at least 2 prior induction attempts; * First relapse refractory to at least one prior re-induction attempt * Any relapse after HSCT (Cohort 1 ONLY) Patients with Down syndrome are eligible ONLY for Cohort 1 with: * Any of above disease status, OR * First relapse with no prior re-induction attempt NOTE: Patients with Down syndrome or prior HSCT are NOT eligible for Cohort 2 combination therapy
6. Patients with Philadelphia chromosome (Ph)+ ALL must have had two prior therapy attempts including two different tyrosine kinase inhibitors (TKIs)
7. Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy, defined as resolution of all such toxicities to =< grade 2 or lower per the inclusion/exclusion criteria prior to entering this study. Apply to Cohort 2: * Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator prior to enrollment. ** A waiting period prior to enrollment is not required for patients receiving standard cytotoxic maintenance chemotherapy (i.e., corticosteroid, vincristine, 6MP, and/or methotrexate). ** A waiting period is not required for patients receiving a single dose of intrathecal methotrexate, hydrocortisone, and/or cytarabine within 7 days prior to enrollment ** >= 14 days must have elapsed after the completion of other cytotoxic therapy, with the exception of hydroxyurea, for patients not receiving standard maintenance therapy. For patients who previously received calaspargase pegol, >= 21 days must have elapsed after the last dose. Additionally, patients must have fully recovered from all acute toxic effects of prior therapy. *** Note: Cytoreduction with hydroxyurea must be discontinued >= 24 hours prior to the start of protocol therapy. * Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment. * Anti-cancer agents that are antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1. There is an exception for blinatumomab infusions, for which patients must have been off for at least 3 days and all drug related toxicity must have resolved to grade 2 or lower as outlined in the inclusion/exclusion criteria. * Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid. A waiting period prior to enrollment is not required for patients receiving corticosteroid for leukemia therapy/cytoreduction. * Radiotherapy: >= 2 weeks must have elapsed since local palliative radiation therapy (XRT) (small port); >= 3 months must have elapsed if prior cranial or craniospinal XRT was received, if >= 50% of the pelvis was irradiated, or if total body irradiation (TBI) was received; >= 6 weeks must have elapsed if other substantial bone marrow irradiation was given. * Stem cell transplant or rescue without TBI: For Cohort 1, at least 90 days must have elapsed since stem cell transplant and at least 30 days from donor lymphocyte infusion. Patient must have had no more than one previous HSCT and currently have no evidence of active graft vs. host disease (GVHD). For Cohort 2, no prior HSCT is allowed. * Chimeric antigen receptor (CAR) T cell therapy: At least 30 days must have elapsed from the last CAR-T cell infusion
8. Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
9. Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or
10. A serum creatinine based on age/gender as follows: * 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female) * 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female) * 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female) * 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female) * 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female) * >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)
11. Direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
12. Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5 x ULN for age; for the purpose of this study, the ULN for ALT will be 45 U/L

Treatment Sites in Georgia