Immunotoxin Therapy and Cytarabine in Treating Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Albert Einstein College of Medicine of Yeshiva University
Sponsor:
Collaborators:
Montefiore Medical Center
University of Texas Southwestern Medical Center
Information provided by (Responsible Party):
Amit Verma, Albert Einstein College of Medicine of Yeshiva University
ClinicalTrials.gov Identifier:
NCT01408160
First received: July 12, 2011
Last updated: July 24, 2014
Last verified: July 2014
  Purpose

This phase I trial studies the side effects and the best dose of deglycosylated ricin A chain-conjugated anti-cluster of differentiation (CD)19/anti-CD22 immunotoxins when given together with cytarabine in treating patients with relapsed or refractory B-cell acute lymphoblastic leukemia. Immunotoxins, such as deglycosylated ricin A chain-conjugated anti-CD19/anti-CD22 immunotoxins, can find certain cancer cells and kill them without harming normal cells. Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving deglycosylated ricin A chain-conjugated anti-CD19/anti-CD22 immunotoxins with cytarabine may kill more cancer cells.


Condition Intervention Phase
B-cell Adult Acute Lymphoblastic Leukemia
L1 Adult Acute Lymphoblastic Leukemia
L2 Adult Acute Lymphoblastic Leukemia
Recurrent Adult Acute Lymphoblastic Leukemia
Biological: deglycosylated ricin A chain-conjugated anti-CD19/anti-CD22 immunotoxins
Drug: cytarabine
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Albert Einstein College of Medicine of Yeshiva University:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Clinical response rate (response defined as complete response or partial response) [ Time Frame: Up to day 42 ] [ Designated as safety issue: No ]
    Descriptive statistics and tabular representations will be used to describe and evaluate the response rates for each dose level.


Other Outcome Measures:
  • Presence of HAMA/HARA [ Time Frame: Up to day 28 of course 1 ] [ Designated as safety issue: No ]
    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.

  • Pharmacokinetic parameters of deglycosylated ricin A chain-conjugated anti-CD19/anti-CD22 immunotoxins [ 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) ] [ Designated as safety issue: No ]
    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.

  • Change in fractional excretion of urinary sodium (FeNa) [ Time Frame: Day 0 to up to day 12 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.

  • Presence and percentage of bone marrow cells with a CD34+/CD38-/low/CD19+ phenotype [ Time Frame: Up to day 42 ] [ Designated as safety issue: No ]
    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.

  • Change in CD19 and CD22 expression [ Time Frame: Baseline to up to day 42 ] [ Designated as safety issue: No ]
    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).


Estimated Enrollment: 18
Study Start Date: July 2011
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
Given IV
Other Names:
  • Combotox
  • IgG-HD37-dgA/IgG-RFB4-dgA immunotoxins
Drug: cytarabine
Given IV
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically confirmed B-lineage acute lymphoblastic leukemia (ALL) at diagnosis and either evidence of relapse refractory disease based on a bone marrow/peripheral blood examination or evidence by cytogenetic studies or polymerase chain reaction (PCR) amplification; patients with only extramedullary disease in the absence of bone marrow or blood involvement are not eligible; patients with L3 (Burkitt's) are not eligible; for ALL in marrow or peripheral blood, immunophenotyping of the blood or marrow lymphoblasts must be performed to determine lineage (B cell, T-cell, or mixed B/T cell); NOTE: appropriate marker studies including CD19 (B cell), CD10, CD5, and CD7 (T cell) must be performed; co-expression of myeloid antigens (CD13 and CD33) will not exclude patients; if possible, the lineage specific markers cytoplasmic CD22 or CD79a (B cells), cytoplasmic CD3 (T cells) and cytoplasmic myeloperoxidase (MPO) (myeloid cells) must be determined; patients with mixed lineage ALL (ML-ALL) as defined by a lack of cytochemical markers of myeloid differentiation, and by the presence of immunophenotypic markers suggesting both lymphoid and myeloid differentiation, are allowed
  • CD19 and/or CD22 must be expressed on at least 50% of the lymphoblasts
  • Disease must be refractory to conventional induction therapy or relapsed after initial standard therapy for ALL; any number of prior therapies is permitted and including allogeneic and/or autologous stem cell transplant
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 2 months
  • Total bilirubin =<1.5 x institutional upper limit of normal, unless related to leukemic infiltration or hemolysis
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal, unless related to leukemic infiltration or hemolysis
  • Creatinine within normal institutional limits OR
  • Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Patients must have recovered from effects of prior therapy; at least 2 weeks should have elapsed since the last dose of high dose chemotherapy; hydroxyurea, steroids and vincristine are allowed to control counts until eligibility is confirmed and study treatment can be initiated
  • Adequate cardiac function defined as an ejection fraction of >= 50% by multi gated acquisition scan (MUGA) scan or echocardiogram and a corrected QT (QTc) interval of =< 450 ms for men and =< 460 ms for women
  • Adequate pulmonary function defined as no evidence of dyspnea at rest
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 2 weeks (4 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier
  • Patients may not be receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to Combotox or other agents used in study agents
  • Presence of a significant pleural effusion by chest x-ray
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic
  • Presence of active untreated central nervous system (CNS) leukemia
  • Presence of graft-versus-host disease (GVHD) more than grade 2
  • History of documented seizure disorder, presence of cerebellar dysfunction, dysphasia or altered mental status on neurological examination
  • Human anti-mouse antibody (HAMA) levels of > 100μg/ml or human ricin antibodies (HARA) > 100 μg/ml HARA after cycle 1
  • Impaired liver function defined as a total bilirubin > 1.5 x normal range and AST or ALT > 2.5 x normal range unless secondary to Gilbert's disease, hemolysis or leukemic involvement of the liver
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study; breastfeeding should be discontinued
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01408160

Locations
United States, New York
Albert Einstein College of Medicine Recruiting
Bronx, New York, United States, 10461
Contact: Amit K. Verma    718-930-8761    amit.verma@einstein.yu.edu   
Principal Investigator: Amit K. Verma         
Sponsors and Collaborators
Albert Einstein College of Medicine of Yeshiva University
Montefiore Medical Center
University of Texas Southwestern Medical Center
Investigators
Principal Investigator: Amit Verma Albert Einstein College of Medicine of Yeshiva University
  More Information

No publications provided by Albert Einstein College of Medicine of Yeshiva University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Amit Verma, Principal Investigator, Albert Einstein College of Medicine of Yeshiva University
ClinicalTrials.gov Identifier: NCT01408160     History of Changes
Other Study ID Numbers: 11-04-146, NCI-2013-01206, 11-027, 11-04-146, P30CA013330
Study First Received: July 12, 2011
Last Updated: July 24, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Burkitt Lymphoma
Leukemia
Leukemia, Lymphoid
DNA Virus Infections
Epstein-Barr Virus Infections
Herpesviridae Infections
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoma
Lymphoma, B-Cell
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Experimental
Tumor Virus Infections
Virus Diseases
Cytarabine
Immunotoxins
Anti-Infective Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antiviral Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 21, 2014