Immunotoxin Therapy and Cytarabine in Treating Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia
|ClinicalTrials.gov Identifier: NCT01408160|
Recruitment Status : Unknown
Verified January 2016 by Amit Verma, Albert Einstein College of Medicine, Inc..
Recruitment status was: Recruiting
First Posted : August 3, 2011
Last Update Posted : January 15, 2016
|Condition or disease||Intervention/treatment||Phase|
|Adult B Acute Lymphoblastic Leukemia Recurrent Adult Acute Lymphoblastic Leukemia||Drug: Cytarabine Biological: Deglycosylated Ricin A Chain-Conjugated Anti-CD19/Anti-CD22 Immunotoxins Other: Laboratory Biomarker Analysis Other: Pharmacological Study||Phase 1|
I. To define the maximum tolerated dose (MTD) of Combotox (deglycosylated ricin A chain-conjugated anti-CD19/anti-CD22 immunotoxins) when added to high-dose cytarabine during salvage therapy for adult patients with relapsed or refractory B-lineage acute lymphoblastic leukemia.
I. To evaluate the efficacy of this regimen. II. To assess for the presence of a postulated CD34+/CD38-/low/CD19+ leukemic stem cell phenotype in the bone marrow at time of relapse and to assess its association with treatment outcome.
III. To determine the development of human mouse or ricin antibodies (human anti-mouse antibodies [HAMA]/human anti-ricin antibodies [HARA]).
IV. To determine the pharmacokinetic characteristics of Combotox. V. To evaluate the value of fractional excretion of sodium (FeNa) as early marker of toxicity.
OUTLINE: This is a dose-escalation study of deglycosylated ricin A chain-conjugated anti-CD19/anti-CD22 immunotoxins.
Patients receive high-dose cytarabine intravenously (IV) over 2-3 hours every 12 hours on days 1-3 and deglycosylated ricin A chain-conjugated anti-CD19/anti-CD22 immunotoxins IV over 4 hours on days 8, 10, and 12. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 12 weeks.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||18 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1 Study of the Deglycosylated Ricin A Chain-containing Combined Anti-CD19 and Anti-CD22 Immunotoxin Combotox in Combination With High-Dose Cytarabine in Adult Relapsed or Refractory B-lineage Acute Lymphoblastic Leukemia|
|Study Start Date :||April 2013|
|Estimated Primary Completion Date :||June 2016|
Experimental: Treatment (Combotox, cytarabine)
Patients receive high-dose cytarabine IV over 2-3 hours every 12 hours on days 1-3 and deglycosylated ricin A chain-conjugated anti-CD19/anti-CD22 immunotoxins IV over 4 hours on days 8, 10, and 12. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Biological: Deglycosylated Ricin A Chain-Conjugated Anti-CD19/Anti-CD22 Immunotoxins
Other Name: Combotox
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
- Occurrence of dose-limiting toxicity, defined as grade 3 or greater non-hematological adverse event attributable to Combotox, graded per the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 28 days ]
- Clinical response rate (response defined as complete response or partial response) [ Time Frame: Up to day 42 ]Descriptive statistics and tabular representations will be used to describe and evaluate the response rates for each dose level.
- Change in expression of CD19 and CD22 on cell surface by flow cytometry [ Time Frame: Baseline to up to day 42 ]Evaluated as a percentage ranging from 0% to 100% of cells analyzed expressing the respective marker. The change in percentage expression from pre-treatment to post-treatment for cycle 1 only will be correlated with the response achieved. Response to treatment is defined as either complete or partial remission. The means of CD19 and/or 22 expression will be compared between the patients who showed response and those who didn't using a t-test if the data is normally distributed or otherwise the non-parametric alternative (Mann-Whitney U test).
- Change in fractional excretion of urinary sodium (FeNa) [ Time Frame: Day 0 to up to day 12 ]Changes in the FeNa will be correlated to the development of grade 3 or greater vascular leak syndrome (VLS). VLS will be dichotomized into absent or mild (grade 0-2) versus moderate to severe (3-5). Changes in FeNa from baseline to day 8, 10 and 12 will be calculated as percent change at each time point. Associations will be tested for in a logistic regression model using presence of moderate or severe VLS as outcome as well as in a linear regression model using the grading of VLS as an ordinal variable. Both models will be adjusted for the use of diuretics and intravenous fluids.
- Development of VLS [ Time Frame: Up to day 12 ]Changes in the FeNa will be correlated to the development of grade 3 or greater VLS. VLS will be dichotomized into absent or mild (grade 0-2) versus moderate to severe (3-5). Changes in FeNa from baseline to day 8, 10 and 12 will be calculated as percent change at each time point. Associations will be tested for in a logistic regression model using presence of moderate or severe VLS as outcome as well as in a linear regression model using the grading of VLS as an ordinal variable. Both models will be adjusted for the use of diuretics and intravenous fluids.
- Maximum Plasma Concentration [Cmaxof CD19 and CD22 immunotxins will be measured [ Time Frame: Pre-infusion; 4, 8, 12, 24 & 48 hours after start of the first and third infusion (course 1); pre-infusion and 4 hours after the start of the first and third infusions (subsequent courses) ]Maximum concentration (Cmax), t 1/2 (half-life), area under curve (AUC), and volume of distribution (Vd) will be determined. Serum concentrations of the immunotoxins will be measured and plotted against time. The association of the peak concentration (Cmax) with toxicities will be evaluated by using descriptive statistics and graphical methods.
- Presence and percentage of bone marrow cells with a CD34+/CD38-/low/CD19+ phenotype [ Time Frame: Up to day 42 ]The presence of the postulated leukemic stem cells (LSC) with the CD34+/CD38-/low/CD19+ phenotype will be determined at baseline and after each cycle. A chi-square test or the non-parametric Fisher's exact test will be used to test for an association between the presence of the postulated LSC at baseline and/or after the first treatment cycle and response as the outcome. The analysis will be exploratory.
- Presence of HAMA/HARA [ Time Frame: Up to day 28 of course 1 ]Tabulated or plotted by dose. HARA will only be determined after the first administration of Combotox (prior to course 2 and subsequent courses), whereas only HAMA will be determined prior to the first cycle.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01408160
|United States, New York|
|Albert Einstein College of Medicine||Recruiting|
|Bronx, New York, United States, 10461|
|Contact: Amit K. Verma 718-930-8761 email@example.com|
|Principal Investigator: Amit K. Verma|
|United States, Pennsylvania|
|Fox Chase Cancer Center||Recruiting|
|Philadelphia, Pennsylvania, United States, 19111|
|Contact: Stefan K. Barta 215-728-2674 Stefan.Barta@fccc.edu|
|Principal Investigator: Stefan K. Barta|
|Principal Investigator:||Amit Verma||Albert Einstein College of Medicine, Inc.|