A Phase 2 Study of Inotuzumab Ozogamicin (NSC# 772518) in Children and Young Adults With Relapsed or Refractory CD22+ B-Acute Lymphoblastic Leukemia (B-ALL)

  • End date
    Dec 31, 2024
  • participants needed
  • sponsor
    Children's Oncology Group
Updated on 13 October 2022


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.



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)


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)


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 36 days) and following 2 cycles (72 days) 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, 8, and 15. 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 IV over 1-2 hours or intramuscularly (IM) on day 22; and vincristine IV on days 22 and 29. 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 will be 3 dose levels. If excessive toxicity is observed at dose level 1, the dosing of inotuzumab ozogamicin will be decreased for dose level -1. If excessive toxicity is observed at this dose, then for dose level -2, pegaspargase will be omitted. Treatment repeats every 36 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.

Condition Recurrent B Acute Lymphoblastic Leukemia, Recurrent B Lymphoblastic Lymphoma, Refractory B Acute Lymphoblastic Leukemia, Refractory B Lymphoblastic Lymphoma
Treatment cyclophosphamide, methotrexate, Leucovorin calcium, cytarabine, diagnostic imaging, vincristine, Pegaspargase, Mercaptopurine, biospecimen collection, Inotuzumab Ozogamicin, Lumbar puncture, Bone Marrow Aspiration and Biopsy
Clinical Study IdentifierNCT02981628
SponsorChildren's Oncology Group
Last Modified on13 October 2022


Yes No Not Sure

Inclusion Criteria

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
Patients must be >= 1 year and < 22 years of age at the time of enrollment
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
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)
Patients with ALL or B-LL who have M2 morphology must have local confirmatory testing
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
showing >= 5% blasts by flow cytometry, fluorescence in situ hybridization
Patients with one of the following
(FISH) testing or other molecular method
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
Patients with Philadelphia chromosome (Ph)+ ALL must have had two prior therapy attempts including two different tyrosine kinase inhibitors (TKIs)

Exclusion Criteria

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. 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
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
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
Patients with any prior history of SOS irrespective of severity
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or
Patients with isolated central nervous system (CNS), testicular, or any other extramedullary site of relapse
A serum creatinine based on age/gender as follows
Patients who have been previously treated with inotuzumab ozogamicin
to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)
Patients who have previously received HSCT (Cohort 2 only)
to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)
Patients with Down syndrome (Cohort 2 only)
to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)
History of allergic reaction attributed to compounds of similar or biologic composition to inotuzumab ozogamicin or other agents in the study
to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)
Note: Patients with history of allergy to pegaspargase are eligible for enrollment on Cohort 2 (dose levels 1 and -1) if asparaginase Erwinia can be obtained
to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
If Cohort 2 is enrolling at dose level -2, then patients who cannot receive asparaginase due to prior allergy, toxicity, or lack of access may enroll
>= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)
NOTE: patients on AALL1621 are not eligible to co-enroll on AALL1931
Direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
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
Patients who are currently receiving another investigational drug
Exclusion Criteria
Patients who are currently receiving or plan to receive corticosteroids except as described below
Systemic corticosteroids may be administered for cytoreduction up to 24 hours prior to the start of protocol therapy, (Cohort 1 only) for all patients, corticosteroids may be administered as a premedication for inotuzumab ozogamicin and as treatment for allergic reactions or for physiologic replacement/stress dosing of hydrocortisone for documented adrenal insufficiency; corticosteroids are not allowed for other indications
Patients who have an active uncontrolled infection defined as
Positive bacterial blood culture within 48 hours of study enrollment
Fever above 38.2 degree Celsius (C) within 48 hours of study enrollment with clinical signs of infection; fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability
A positive fungal culture within 30 days of study enrollment or active therapy for presumed invasive fungal infection
Patients may be receiving IV or oral antibiotics to complete a course of therapy for a prior documented infection as long as cultures have been negative for at least 48 hours and signs or symptoms of active infection have resolved; for patients with clostridium (C.) difficile diarrhea, at least 72 hours of antibacterial therapy must have elapsed and stools must have normalized to baseline
Patients with active optic nerve and/or retinal involvement are not eligible; patients
Active viral or protozoal infection requiring IV treatment
who are presenting with visual disturbances should have an ophthalmologic exam
and, if indicated, a magnetic resonance imaging (MRI) to assess optic nerve or
There have been no human studies of inotuzumab ozogamicin in pregnant women and no reports of exposure in utero; based on nonclinical safety studies, inotuzumab ozogamicin has the potential to impair human male and female fertility and to adversely affect human embryo fetal development; women of childbearing potential should be advised to avoid becoming pregnant while receiving inotuzumab ozogamicin; there is no information regarding the presence of inotuzumab ozogamicin in human milk, the effects on the breast-fed infant, or the effects on milk production; because of the potential for adverse reactions in breast-fed infants, women should not breast-feed during treatment with inotuzumab ozogamicin and for at least 2 months after the final dose
retinal involvement
Female patients who are sexually active and of reproductive potential are not eligible unless they agree to use an effective contraceptive method for the duration of their study participation and for 8 months after the last dose of inotuzumab ozogamicin
Patients who are currently receiving or plan to receive other anti-cancer agents (except hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy, and intrathecal chemotherapy)
Men with female partners of childbearing potential should use effective contraception during treatment with inotuzumab ozogamicin and for at least 5 months after the last dose of inotuzumab ozogamicin
Anti-GVHD or agents to prevent organ rejection post-transplant; patients who are receiving cyclosporine, tacrolimus, or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial; at least 3 half-lives must have elapsed after the last dose of GVHD or anti-rejection medications
Lactating females are not eligible unless they agree not to breastfeed their infants
Patients with known human immunodeficiency virus (HIV), hepatitis B or C infections
testing to prove negative status is not required for enrollment unless it is
deemed necessary for usual medical care of the patient
Patients known to have one of the following concomitant genetic syndromes: Bloom
syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Schwachman
(Schwachman-Diamond-Blackfan) syndrome or any other known bone marrow failure
Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained within 7 days prior to enrollment
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