Inotuzumab Ozogamicin in Treating Younger Patients With B-Lymphoblastic Lymphoma or Relapsed or Refractory CD22 Positive B Acute Lymphoblastic Leukemia
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02981628|
Recruitment Status : Recruiting
First Posted : December 5, 2016
Last Update Posted : March 1, 2019
|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|
Show Detailed Description
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||53 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
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
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
- 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.
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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
|Principal Investigator:||Maureen M O'Brien||Children's Oncology Group|