Moxetumomab Pasudotox (CAT-8015, HA22) in Children With B-lineage Acute Lymphoblastic Leukemia and Minimal Residual Disease Prior to Allogeneic Hematopoietic Stem Cell Transplantation
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|ClinicalTrials.gov Identifier: NCT02338050|
Recruitment Status : Terminated
First Posted : January 14, 2015
Last Update Posted : September 16, 2015
|Condition or disease||Intervention/treatment||Phase|
|Acute Lymphoblastic Leukemia (ALL)||Biological: Moxetumomab Pasudotox||Phase 2|
This is a Phase 2 study designed to assess safety, feasibility and clinical activity of pre-HCT moxetumomab pasudotox for patients with ALL in morphologic CR but with MRD. It is hypothesized that subjects in a morphologic complete remission with proven minimal residual disease (MRD) after chemotherapy for ALL planned for allogeneic HCT who receive a course of moxetumomab pasudotox prior to the start of conditioning will show a marked reduction or elimination of detectable MRD after moxetumomab pasudotox treatment without adverse impact on the feasibility or safety of allogeneic HCT.
The primary objective of this study is to determine if treatment with moxetumomab pasudotox in the MRD positive setting is able to lead to MRD negativity (< 0.01% by flow cytometry) or at least a 1-log10 reduction in MRD prior to allogeneic HCT.
Secondary objectives to be studied include: toxicity profile (including safety and feasibility of administration in the pre-HCT setting and ability to proceed to transplant, incidence of capillary leak syndrome, hemolytic uremic syndrome and other post-HCT toxicities), comparison of quantitative MRD assessments, progression-free survival, overall survival, pharmacokinetic profiles, immunogenicity to moxetumomab pasudotox, transplant-related mortality, acute and chronic graft-versus-host disease (GVHD), and relapse.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||1 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase II Study of the Anti-CD22 Recombinant Immunotoxin Moxetumomab Pasudotox (CAT-8015, HA22) in Children With B-lineage Acute Lymphoblastic Leukemia and Minimal Residual Disease Prior to Allogeneic Hematopoietic Stem Cell Transplantation|
|Study Start Date :||May 2015|
|Estimated Primary Completion Date :||May 2020|
Experimental: Moxetumomab Pasudotox
Moxetumomab pasudotox 32 mcg/kg/dose IV every other day for a total of 6 doses. Dexamethasone 2.5 mg/m2/dose (or corticosteroid equivalent) will be administered before and after each dose of moxetumomab pasudotox.
Biological: Moxetumomab Pasudotox
Other Name: (CAT-8015, HA22)
- MRD negativity [ Time Frame: change in MRD levels between baseline and 3-10 days post last Moxe dose ]The primary endpoint is the event of whether patients successfully achieved either MRD negativity (defined as <0.01%) or at least 1 log10 reduction in MRD levels using flow cytometry via central laboratory testing after moxetumomab treatment but prior to HCT relative to pre-moxetumomab MRD measurement (baseline). The proportion of patients who become MRD negative or who have at least a 1-log10 reduction from baseline will be summarized and 80% confidence intervals will provided. An exploratory analysis of the association between CD22 expression at eligibility and the response rate will also be conducted.
- MRD level and its log reduction from baseline [ Time Frame: baseline and 3-10 days post last Moxe dose ]will be described quantitatively at each time point using median and range. Values that go below the lower limit of detection (<0.01%) will be set to the lower limit to obtain a conservative estimate of the log reduction. A test of whether the MRD levels are significantly reduced relative to baseline will be conducted using the Wilcoxon signed rank test. Agreement between quantitative MRD assessments using flow cytometry and molecular sequencing (immunosequencing) will be assessed using reliability coefficients and Bland-Altman plots, applied to the log transformed MRD levels. The correlation between CD22 expression at eligibility and log reduction in MRD from baseline will be described using Spearman's rank correlation.
- Overall Survival (OS) [ Time Frame: from Moxe Dose 1 through date of death from any cause (assessed through 2 years post HCT or last Moxe dose) ]is defined as the time from the start of treatment with moxetumomab pasudotox until death for the treated population. The OS will be censored if the patient did not die at the end of the study. For transplant population, the start time is from the date of transplant. Kaplan-Meier estimator will be used for the median or survival rate at a particular time.
- Progression-free survival (PFS) [ Time Frame: from Moxe Dose 1 through date of progression or death from any cause (assessed through 2 years post HCT or last Moxe dose) ]is defined as the time from the start of treatment with moxetumomab pasudotox until the documentation of disease progression or death due to any cause, whichever occurs first, for the treated population. PFS will be censored if the patient did not relapse by the last visit. For transplant population, the start time is from the date of transplant. Kaplan-Meier estimator will be used for the median or survival rate at a particular time.
- Proportion of patients proceeding to transplant [ Time Frame: from Moxe Dose 1 through Day 0 of transplant ]will be described, along with a breakdown of the reasons for not proceeding to transplant and their frequencies.
- Relapse [ Time Frame: from Moxe Dose 1 through date of relapse (assessed through 2 years post HCT or last Moxe dose) ]Relapse will be defined by the presence of > 5% bone marrow blasts by morphology on an aspirate sample, or by evidence of peripheral blasts or extramedullary disease. The proportion of relapse will be summarized for both the treated population (from start of treatment) and transplant population (from date of transplant), using the cumulative incidence estimator with death in the absence of relapse as the competing event.
- Transplant-related mortality (TRM) [ Time Frame: from Day 0 of transplant through date of death without evidence of disease progression or recurrence (assessed through 2 years post HCT) ]An event for this endpoint is death without evidence of disease progression or recurrence. TRM will be summarized using cumulative incidence for transplant population.
- Acute GVHD [ Time Frame: from Day 0 of transplant through first onset date of acute GVHD grades II-IV and grades III-IV (assessed through 2 years post HCT) ]The events are the incidences of grades II-IV and grades III-IV acute GVHD from day of transplant. The first day of acute GVHD onset at a certain grade will be used to calculate a cumulative incidence curve for that acute GVHD grade. Death is considered as a competing risk. Transplant population will be used.
- Chronic GVHD [ Time Frame: from Day 0 of transplant through first onset date of chronic GVHD (assessed through 2 years post HCT) ]The cumulative incidence of chronic GVHD starting at the day of transplant will be summarized, treating death as a competing risk. Transplant population will be used.
- Clinical Laboratory Values [ Time Frame: from baseline through 3-10 days post last Moxe dose ]The values and abnormalities for relevant laboratory tests will be summarized by descriptive statistics (e.g., number of subjects, mean, standard deviation, median, minimum, maximum, proportions, etc.) at each time point and also for change from baseline value. Baseline will be defined as the last non-missing value prior to treatment with moxetumomab pasudotox.
- Pre-transplant toxicities: Pre-transplant adverse events [ Time Frame: from Moxe Dose 1 through 30 days after the last dose of study drug or until start of conditioning regimen ]
Pre-transplant adverse events will be collected until 30 days after the last dose of study drug or until transplant and will be tabulated by severity and relationship to the study drug. Post-transplant adverse events will be analyzed separately as described in the next section.
Capillary Leak Syndrome, hemolytic uremic syndrome, ocular toxicities and cytokine release syndrome/infusional reactions, as well as death which is possibly, probably or definitely related to moxetumomab pasudotox are Adverse Events of Interest and will be further analyzed by examining their correlation with other clinical variables.
- Post-Transplant Toxicities: Unexpected SAEs [ Time Frame: start of conditioning regimen and continuing for 60 days from Day 0 of transplant ]Unexpected SAEs will be tabulated by severity and relationship to study drug. The cumulative incidence of thrombotic microangiopathy (TMA), and hepatic veno-occlusive disease (VOD) will be described in transplanted patients, treating death as a competing risk. Transplanted population will be used for these analyses.
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): NCT02338050
|United States, California|
|Childrens Hospital of Los Angeles|
|Los Angeles, California, United States, 90027|
|University of California San Francisco|
|San Francisco, California, United States, 94143|
|United States, Colorado|
|Children's Hospital Colorado|
|Aurora, Colorado, United States, 80045|
|United States, Illinois|
|Ann & Robert H. Lurie Children's Hospital of Chicago|
|Chicago, Illinois, United States, 60611|
|Study Chair:||Alan S Wayne, MD||Children's Hospital Los Angeles|
|Study Chair:||Nirali N Shah, MD||National Institutes of Health (NIH)|