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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT02981628
Other study ID # AALL1621
Secondary ID NCI-2016-01494AA
Status Recruiting
Phase Phase 2
First received
Last updated
Start date June 19, 2017
Est. completion date March 31, 2026

Study information

Verified date May 2024
Source Children's Oncology Group
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


Description:

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Study Design


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Intervention

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Sponsors (2)

Lead Sponsor Collaborator
Children's Oncology Group National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type Measure Description Time frame Safety issue
Other Changes in CD22 surface expression (Cohorts 1 and 2) 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). Baseline, post Cycle 1, and at time of relapse
Other Change in CD22 site density (Cohorts 1 and 2) 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). Baseline, post Cycle 1, and at time of relapse
Other Leukemic blast CD22 splice variants (Cohorts 1 and 2) 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. Baseline, post-Cycle 1, and at time of relapse
Other Intracellular signaling pathways in leukemic blasts treated with inotuzumab ozogamicin (Cohorts 1 and 2) 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 inotuzumab ozogamicin , as well as intracellular epitopes to assess the cellular consequences of treatment with inotuzumab ozogamicin. Exploratory analysis will be performed using Cytobank software tools (viSNE, SPADE and CITRUS) for subpopulations clustering, dimensionality reduction and hierarchical organization. Baseline up to 5 years
Other Changes in peripheral blood absolute B cell numbers and maturation of developing B cell populations with inotuzumab ozogamicin therapy (Cohorts 1 and 2) 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. Baseline up to 5 years
Other Level of MRD by next-generation high-throughput sequencing (HTS) techniques (Cohorts 1 and 2) 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. Up to 2 cycles
Other Serum levels of candidate SOS biomarkers Ang2 and L ficolin (Cohorts 1 and 2) 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 inotuzumab ozogamicin exposure will be evaluated and correlated with development of SOS. Biomarker levels will be compared using simple comparative statistics between subgroups. Up to 12 months from last dose of inotuzumab ozogamicin
Other Incidence of SOS in patients who receive prophylaxis with ursodeoxycholic acid (UDCA) during inotuzumab ozogamicin therapy (Cohorts 1 and 2) Descriptive statistics will be used to characterize clinical features of patients experiencing SOS, potential clinical risk factors, and the impact of ursodeoxycholic acid prophylaxis. Up to 12 months from last dose of inotuzumab ozogamicin
Other Interaction between CAR- T therapy and inotuzumab ozogamicin (Cohorts 1 and 2) Will be evaluated by incidence of hematologic DLT in patients with CAR-T therapy prior to inotuzumab ozogamicin, incidence of post-inotuzumab ozogamicin CAR-T therapy, time to CAR-T therapy after inotuzumab ozogamicin, and B-cell recovery prior to CAR-T therapy after inotuzumab ozogamicin. Will be summarized using descriptive statistics. Up to 5 years
Other Morphologic response (CR/CRi) (Cohort 2) Will be estimated using the proportion of eligible/evaluable patients with CR/CRi response. Analysis will be mostly descriptive. Up to 2 cycles (each cycle is 42 days)
Primary 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. Up to 28 days
Secondary 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. Up to 56 days
Secondary 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. During Cycle 1, up to 28 days
Secondary 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. Up to 2 cycles
Secondary 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. Up to 1 year from last dose of Inotuzumab ozogamicin
Secondary Event free survival (EFS) (Cohort 1) The EFS rate will be estimated using Kaplan Meier approach. 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
Secondary Overall survival (OS) (Cohort 1) The OS rate will be estimated using Kaplan Meier approach. From the time from study entry to death or date of last follow-up, assessed up to 3 years
Secondary 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. Up to 3 years
Secondary 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. Cycles 1 and 2 (each cycle is 28 days)
Secondary 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. Cycles 1 and 2
Secondary 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. Up to cycle 1 (each cycle is 42 days)
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