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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
80
Given Asparaginase Erwinia chrysanthemi
Undergo blood sample collection
Undergo a bone marrow aspiration and biopsy
Given IV
Given IV
Given IV or SC
Undergo imaging
Given IV
Given PO or IV
Undergo lumbar puncture
Given IT
Given IV or IM
Given IV
Children's Hospital of Alabama
Birmingham, Alabama, United States
RECRUITINGProvidence Alaska Medical Center
Anchorage, Alaska, United States
RECRUITINGBanner Children's at Desert
Mesa, Arizona, United States
RECRUITINGPhoenix Childrens Hospital
Phoenix, Arizona, United States
Morphologic response (complete response [CR]+ incomplete hematologic recovery [CRi]) following one cycle of treatment with inotuzumab ozogamicin (Cohort 1)
The response rate will be estimated using the proportion of eligible/evaluable patients with CR/CRi response. A one-sided lower 95% Agresti-Coull confidence limit will be calculated.
Time frame: Up to 28 days
Morphologic response (CR + CRi) following 2 cycles of inotuzumab ozogamicin therapy (Cohort1)
The response rate will be estimated using the proportion of eligible/evaluable patients with CR/CRi response.
Time frame: Up to 56 days
Incidence of dose-limiting toxicities at recommended phase II dose (RP2D) (Cohort 1)
Evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. For a given reporting period, a patient will be counted only once for a given toxicity for the worst grade of that toxicity reported for that patient.
Time frame: During Cycle 1, up to 28 days
Level of minimal residual disease (MRD) assessed in bone marrow by flow cytometry (Cohort 1 and 2)
MRD negativity rates (\< 0.01% detectable leukemia cells) will be estimated.
Time frame: Up to 2 cycles
Incidence of adverse events of sinusoidal obstruction syndrome (SOS) of liver (Cohort 1 and 2)
Evaluated according to NCI CTCAE version 5.0. The incidence of SOS of the liver in patients during inotuzumab ozogamicin therapy and following subsequent treatment including myeloablative hematopoietic cell transplantation (HSCT) will be described.
Time frame: Up to 1 year from last dose of Inotuzumab ozogamicin
Event free survival (EFS) (Cohort 1)
The EFS rate will be estimated using Kaplan Meier approach.
Time frame: From study entry to first event (induction failure, induction death, relapse, second malignancy, remission death), or date of last follow-up for event free subjects, assessed up to 3 years
Overall survival (OS) (Cohort 1)
The OS rate will be estimated using Kaplan Meier approach.
Time frame: From the time from study entry to death or date of last follow-up, assessed up to 3 years
Duration of CR, CRi (Cohort 1)
Among responding patients, three-year complete continuous response will also be estimated using duration of CR/CRi for the overall responding group and stratified by whether or not the patients proceed to HSCT.
Time frame: Up to 3 years
Pharmacokinetic (PK) parameters, i.e., inotuzumab ozogamicin trough levels (Cohort 1)
Inotuzumab ozogamicin trough levels (ng/mL) will be determined in serum by validated, high sensitivity liquid chromatography-mass spectrometry (LCMS) assays. Descriptive summary statistics will be provided for the trough levels at scheduled visits for Cycles 1 and 2.
Time frame: Cycles 1 and 2 (each cycle is 28 days)
Immunogenicity (Cohort 1)
Enhanced chemiluminescence (ECL) and cell-based assays will be used to detect anti-drug antibodies and neutralizing antibodies to inotuzumab ozogamicin in serum. Inotuzumab ozogamicin trough levels will be compared between patients with and without antibodies.
Time frame: Cycles 1 and 2
Incidence of dose-limiting toxicities at the selected dose level of inotuzumab ozogamicin in combination with the augmented modified Berlin-Frankfurt-Munster (mBFM) consolidation chemotherapy (Cohort 2)
Evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. For a given reporting period, a patient will be counted only once for a given toxicity for the worst grade of that toxicity reported for that patient.
Time frame: Up to cycle 1 (each cycle is 42 days)
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Banner University Medical Center - Tucson
Tucson, Arizona, United States
ACTIVE_NOT_RECRUITINGArkansas Children's Hospital
Little Rock, Arkansas, United States
RECRUITINGKaiser Permanente Downey Medical Center
Downey, California, United States
RECRUITINGCity of Hope Comprehensive Cancer Center
Duarte, California, United States
ACTIVE_NOT_RECRUITINGLoma Linda University Medical Center
Loma Linda, California, United States
RECRUITINGChildren's Hospital Los Angeles
Los Angeles, California, United States
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