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Inotuzumab Ozogamicin in Treating Younger Patients With B-Lymphoblastic Lymphoma or Relapsed or Refractory CD22 Positive B Acute Lymphoblastic Leukemia

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ClinicalTrials.gov Identifier: NCT02981628
Recruitment Status : Recruiting
First Posted : December 5, 2016
Last Update Posted : March 1, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Brief 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 or does not respond to treatment. Immunotoxins, such as inotuzumab ozogamicin, are antibodies linked to a toxic substance and may help find cancer cells that express CD22 and kill them without harming normal cells.

Condition or disease Intervention/treatment Phase
Blasts 5 Percent or More of Bone Marrow Nucleated Cells CD22 Positive Recurrent B Acute Lymphoblastic Leukemia Recurrent B Lymphoblastic Lymphoma Refractory B Acute Lymphoblastic Leukemia Refractory B Lymphoblastic Lymphoma Biological: Inotuzumab Ozogamicin Other: Laboratory Biomarker Analysis Other: Pharmacological Study Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 53 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : June 5, 2017
Estimated Primary Completion Date : September 30, 2019
Estimated Study Completion Date : September 30, 2019


Arm Intervention/treatment
Experimental: Treatment (inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Biological: Inotuzumab Ozogamicin
Given IV
Other Names:
  • Besponsa
  • CMC-544
  • Way 207294
  • WAY-207294

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies




Primary Outcome Measures :
  1. Morphologic response (complete response [CR]+ incomplete hematologic recovery [CRi]) following one cycle of treatment with InO [ Time Frame: Up to 28 days ]
    The response rate will be estimated as the percent of eligible and evaluable responders (CR/CRi). A one-sided lower 95% Agresti-Coull confidence limit will be calculated.


Secondary Outcome Measures :
  1. Morphologic response (CR + CRi) following 2 cycles of InO therapy [ Time Frame: Up to 56 days ]
    The response rate will be estimated as the percent of eligible and evaluable responders (CR/CRi).

  2. Incidence of dose-limiting toxicities at recommended phase II dose (RP2D) evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [ Time Frame: During Cycle 1, up to 42 days ]
    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.

  3. Level of minimal residual disease (MRD) assessed in bone marrow by flow cytometry [ Time Frame: Up to 2 cycles (each cycle is 28 days) ]
    MRD negativity rates (< 0.01% detectable leukemia cells) will be estimated.

  4. Incidence of adverse events of sinusoidal obstruction syndrome (SOS) of liver evaluated according to NCI CTCAE version 5.0 [ Time Frame: Up to 1 year from last dose of Inotuzumab ozogamicin ]
    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.

  5. Event free survival (EFS) [ Time Frame: Up to 3 years ]
    EFS will be estimated using Kaplan Meier approach. EFS will be calculated from the time from study entry to first event (induction failure, induction death, relapse, second malignancy, remission death), or date of last follow-up.

  6. Overall survival [ Time Frame: Up to 3 years ]
    OS will be estimated using Kaplan Meier approach. OS will be calculated from the time from study entry to death or date of last follow-up.

  7. Duration of CR, CRi [ Time Frame: Up to 3 years ]
    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.

  8. InO trough levels [ Time Frame: Up to 28 days ]
    Concentrations of inotuzumab ozogamicin will be determined in serum by validated, high sensitivity liquid chromatography?mass spectrometry (LCMS) assays. InO trough levels measured during Cycle 1 will be compared between responders (CR/CRi) vs. non-responders after one cycle of InO treatment.

  9. Immunogenicity [ Time Frame: Up to 28 days ]
    Enhanced chemiluminescence (ECL) and cell-based assays will be used to detect anti-drug antibodies and neutralizing antibodies to inotuzumab ozogamicin in serum. InO trough levels will be compared between patients with and without antibodies.


Other Outcome Measures:
  1. Changes in CD22 surface expression [ Time Frame: Baseline, post Cycle 1 (each cycle is 28 days), and at time of relapse (an average of 2 years) ]
    Exploratory analysis of CD22 will focus primarily on the comparison of paired pre-treatment and post-treatment samples at the following times, 1) End of cycle 1 and 2) at relapse to evaluate for changes in CD22 expression pre and post-inotuzumab ozogamicin. Specifically, samples will be evaluated for change in CD22 expression that occurs over time to study the role of CD22 expression as it relates to resistance to therapy or mechanism for relapse. Correlation between changes in CD22 expression and patient's clinical response to inotuzumab ozogamicin as well as cytogenetic/molecular features will be described, in particular to explore the association of CD22-negative subpopulations in patients with KMT2A-rearranged acute lymphoblastic leukemia (ALL).

  2. Change in CD22 site density [ Time Frame: Baseline, post-Cycle 1 (each cycle is 28 days), and at time of relapse (an average of 2 years) ]
    Exploratory analysis of CD22 will focus primarily on the comparison of paired pre-treatment and post-treatment samples at the following times, 1) End of cycle 1 and 2) at relapse to evaluate for changes in CD22 site density pre and post-inotuzumab ozogamicin. Samples will be evaluated for any change in CD22 site density that occurs over time and to evaluate for the emergence of a CD22 ?dim? or ?negative? population to study the role of CD22 site density as it relates to resistance to therapy or mechanism for relapse. Correlation between changes in CD22 site density and patient's clinical response to inotuzumab ozogamicin as well as cytogenetic/molecular features will be described, in particular to explore the association of CD22-negative subpopulations in patients with KMT2A-rearranged acute lymphoblastic leukemia (ALL).

  3. Leukemic blast CD22 splice variants [ Time Frame: Baseline, post-Cycle 1 (each cycle is 28 days), and at time of relapse (an average of 2 years) ]
    Will be analyzed by ribonucleic acid-sequencing (RNA-Seq). The MAJIQ and VOILA software will be used to identify splicing variations in CD22 from RNA Seq and to quantitate the percent spliced in (PSI) of the alternative exons. CD22 protein levels will be determined by immunoblotting of whole cell protein lysates using several anti-CD22 antibodies recognizing either extracellular or intracellular domains. Both protein sizes and preservation of individual epitopes will be assessed and correlated with alterations in exon inclusion.

  4. Intracellular signaling pathways in leukemic blasts treated with inotuzumab ozogamicin [ Time Frame: Baseline up to 5 years ]
    Peripheral blood samples will be evaluated by comprehensive protein profiling using CyTOF panels for the two major areas of analyses, surface immunophenotyping to assess the developmental stage of both normal and abnormal B cells and measure their responses to InO, as well as intracellular epitopes to assess the cellular consequences of treatment with InO. Exploratory analysis will be performed using Cytobank software tools (viSNE, SPADE and CITRUS) for subpopulations clustering, dimensionality reduction and hierarchical organization.

  5. Changes in peripheral blood absolute B cell numbers and maturation of developing B cell populations with inotuzumab ozogamicin therapy [ Time Frame: Baseline up to 5 years ]
    Descriptive statistics will be used to characterize patterns of B-cell development including selective loss of subsets. Changes in B cell number and subsets will be described, and exploratory analysis will be conducted to assess their correlation with clinical features including immunoglobulin levels, occurrence of infections, and need for intravenous immunoglobulin (IVIG) replacement during inotuzumab ozogamicin therapy.

  6. Level of MRD by next-generation high-throughput sequencing (HTS) techniques [ Time Frame: Up to 2 cycles (each cycle is 28 days) ]
    Compared to MRD measured by flow cytometry. MRD levels at each bone marrow evaluation time point will be measured by standard flow cytometry (MRD-negative defined as < 0.01% or 1 leukemic cell in 10-4 nucleated cells). At the end of cycles 1 and 2, MRD will also be assessed by HTS. The correlation between the measurements with each technique will be described and the sensitivity of flow-based MRD methodology in the setting of CD22-targeted therapy will be explored.

  7. Serum levels of candidate SOS biomarkers Ang2 and L ficolin [ Time Frame: Up to 12 months from last dose of InO ]
    Correlated with clinical development of SOS. Descriptive statistics will be used to characterize clinical features of patients experiencing SOS. L-ficolin and Ang2 absolute levels and change in level over time with InO exposure will be evaluated and correlated with development of SOS. Biomarker levels will be compared using simple comparative statistics between subgroups.

  8. Incidence of SOS in patients who receive prophylaxis with ursodeoxycholic acid (UDCA) during inotuzumab ozogamicin therapy [ Time Frame: Up to 12 months from last dose of InO ]
    Descriptive statistics will be used to characterize clinical features of patients experiencing SOS, potential clinical risk factors, and the impact of ursodeoxycholic acid prophylaxis.



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Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

    • 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
  • 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
  • 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 1000/uL circulating blasts; alternatively, CD22 expression may be documented by immunohistochemistry of a bone marrow biopsy specimen
  • Patients with and without Down syndrome are eligible and must have 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

Patients with Down syndrome are also eligible with:

  • First relapse with no prior re-induction attempt

    • Patients with Philadelphia chromosome (Ph)+ ALL must have had two prior therapy attempts including two different tyrosine kinase inhibitors (TKIs)
    • Patients must have fully recovered from the acute non-hematologic 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
  • Myelosuppressive chemotherapy:

    • No waiting period will be required for patients receiving standard "maintenance-like" chemotherapy including oral mercaptopurine, weekly low-dose oral methotrexate, and intermittent vincristine; otherwise, at least 14 days must have elapsed since the completion of cytotoxic therapy, with the exceptions of hydroxyurea or corticosteroids used for cytoreduction
    • Intrathecal cytotoxic therapy: No waiting period is required for patients having received intrathecal cytarabine, methotrexate, and/or hydrocortisone; intrathecal chemotherapy given at the time of diagnostic lumbar puncture (LP) to evaluate for relapse prior to study enrollment is allowed
  • At least 7 days must have elapsed since the completion of therapy with a growth factor; at least 14 days must have elapsed after receiving pegfilgrastim
  • At least 7 days must have elapsed since completion of therapy with a biologic agent (including tyrosine kinase inhibitors); for agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur
  • At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody with the exception of blinatumomab; patients must have been off blinatumomab infusion 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
  • >= 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
  • 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 versus (vs.) host disease (GVHD)
  • At least 30 days must have elapsed from the last chimeric antigen receptor (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
    • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or
    • 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)

    • 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

Exclusion Criteria:

  • Patients with any prior history of SOS irrespective of severity
  • Patients with isolated central nervous system (CNS), testicular, or other extramedullary site of relapse
  • Patients who have been previously treated with inotuzumab ozogamicin
  • History of allergic reaction attributed to compounds of similar or biologic composition to inotuzumab ozogamicin or other agents in the study
  • Patients with active optic nerve and/or retinal involvement are not eligible; patients who are presenting with visual disturbances should have an ophthalmologic exam and, if indicated, a magnetic resonance imaging (MRI) to assess optic nerve or retinal involvement
  • Patients who are currently receiving another investigational drug
  • 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)
  • 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 medications (meds)
  • 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, as a premedication for InO 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 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 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
    • Active viral or protozoal infection requiring IV treatment
  • Patients known to have one of the following concomitant genetic syndromes: Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome
  • Women of childbearing potential should be advised to avoid becoming pregnant while receiving InO; women should not breast-feed during treatment with InO and for at least 2 months after the final dose

    • Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained within 7 days of starting protocol therapy
    • 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 InO
    • Men with female partners of childbearing potential should use effective contraception during treatment with InO and for at least 5 months after the last dose of InO
    • Lactating females are not eligible unless they agree not to breastfeed their infants

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02981628


  Show 129 Study Locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Maureen M O'Brien Children's Oncology Group

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Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT02981628     History of Changes
Other Study ID Numbers: AALL1621
NCI-2016-01494 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AALL1621
AALL1621 ( Other Identifier: Childrens Oncology Group )
AALL1621 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
First Posted: December 5, 2016    Key Record Dates
Last Update Posted: March 1, 2019
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Lymphoma
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Inotuzumab Ozogamicin
Antineoplastic Agents