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Lymphoma, T-Cell

Lymphoma, T-Cell, Peripheral

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Leukemia, Large Granular Lymphocytic

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Leukemia, T-Cell

Leukemia, Lymphoid

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Aggressive NK Cell Leukemia

Injectable PEGylated peptide antagonist that binds to the common gamma chain (γc) signaling receptor for the cytokines interleukin (IL)-2, IL-9, and IL-15

BNZ132-1-40

Jonathan Brammer, MD, PhD

This study is an open-label, multi-center, dose-ranging study to characterize the safety, tolerability, preliminary efficacy, and PK/PD of up to four dose levels of BNZ-1 administered weekly by IV infusion to adults diagnosed with Large Granular Lymphocyte (LGL) Leukemia or refractory Cutaneous T-cell Lymphoma (CTCL).

This study is an open-label, multi-center, dose-ranging study to characterize the safety, tolerability, preliminary efficacy, and PK/PD of up to four dose levels of BNZ-1 administered weekly by IV infusion to adults diagnosed with LGL or CTCL. The study has 5 periods:

* Screening Period
* 4-week Treatment Period
* 3-month Treatment Extension Period
* Long-term Extension Period (open-ended)
* 6-week Follow-up Period Subjects will be screened for eligibility within 30 days of study Day 1 (first dosing day of the 4-Week Treatment Period).

A Dose-Ranging Study of IV BNZ-1 in LGL Leukemia or Refractory CTCL

A Dose-Ranging Study of Intravenous BNZ132-1-40 in Patients With Large Granular Lymphocyte Leukemia or Refractory Cutaneous T-Cell Lymphoma

ANC: \>50% improvement from baseline and \>500 cells/uL; or \>50% reduction in transfusion requirements

Flow cytometry: Change from baseline over time for Tregs, NK cells and CD8+ central memory T-cells

Plasma levels of BNZ-1 will be measured after the 1st and last doses

Plasma levels of BNZ-1 will be measured after the last dose

Bioniz Therapeutics

T-cell Large Granular Lymphocyte Leukemia

Anti-Infective Agents

Antirheumatic Agents

Dermatologic Agents

All Drugs and Chemicals

Hematinics

Central Nervous System Depressants

Other Dietary Supplements

Cyclosporine

Cyclosporins

Liver Extracts

Benzocaine

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Clotrimazole

Miconazole

Antifungal Agents

Calcineurin Inhibitors

Tannic Acid

Large Granular Lymphocyte Leukemia (LGL) is a low grade non-Hodgkins lymphoma characterized by tissue invasion of the marrow, spleen, and liver. Cyclosporine 5-10 mg/kg/day was administered as an oral preparation given every 12 hours. Doses are adjusted to maintain a therapeutic level between 200-400 ng/ml.

An oral preparation given every 12 hours, 5-10 mg/kg/day in divided doses. Doses are adjusted to maintain a therapeutic level between 200-400 ng/ml. Levels will be checked twice weekly and once the patient has achieved steady state levels they shall be monitored once every 2 weeks. These therapeutic levels shall be maintained for 3 months.

A permutation test will be performed to examine whether the overall expression profile changes due to treatment. This will be done by comparing the number of significant genes to the distribution of this number if in fact there is no difference between pre-treatment and post-treatment gene expression.

Gene expression analysis

Gene expression profiling will be carried out on Affymetrix microarrays to compare pretreatment and posttreatment samples.

Microarray analysis

Analysis of differential gene expression profiles in patients with LGL leukemia treated with cyclosporine.

Laboratory biomarker analysis

Thomas Waldmann, M.D.

Background:

* Large granular lymphocyte (LGL) leukemia is a low-grade non-Hodgkin's lymphoma.
* LGL is associated with low numbers of white blood cells (leading to recurring infections), red blood cells (causing anemia) and platelets (causing abnormal bleeding).
* Cyclosporine (CSA) is an immunosuppressive drug that improves low blood cell counts in about 50 percent of patients with LGL leukemia.

Objectives:

* To identify what factors determine why cyclosporine works in some patients and not in others.
* To identify what causes low blood counts in LGL leukemia.

Eligibility: Patients 18 years of age and older with LGL leukemia.

Design:

* Patients have a medical history, physical examination blood tests, bone marrow biopsy and x-ray studies, including chest x-rays and computed tomography (CT) scans of the chest, abdomen and pelvis. Patients with an easily accessible enlarged lymph node have a node biopsy (removal of a small piece of tissue for microscopic examination).
* Patients take cyclosporine twice a day by mouth. Blood samples are taken at least weekly to adjust the cyclosporine dosing to maintain therapeutic serum levels.
* Patients undergo apheresis (collection of white blood cells) at a number of different time points in the study (maximum 6 times) to look at the differences in the leukemia cells before and during treatment with cyclosporine. For apheresis, blood is withdrawn through a needle in an arm vein and directed through a catheter (plastic tube) into a machine that separates it into its components. The white cells are extracted and the rest of the blood is returned through the same needle or through a second needle in the other arm.

Background:

* LGL leukemia is a low grade non-Hodgkins Lymphoma characterized by tissue invasion of the marrow, spleen and liver
* Recurrent infections due to chronic neutropenia and transfusion-dependent anemia are the principal causes for initiation of therapy
* Approximately 50% of patients treated with cyclosporine (CSA) respond to treatment. CSA appears to correct the associated cytopenia without decreasing LGL numbers, suggesting it may inhibit LGL secretion of yet unidentified mediators of neutropenia and anemia.
* Analysis of differential gene expression profiles in patients with LGL leukemia treated with cyclosporine has the potential to detect as yet unidentified, therapeutic targets and possibly provide predictors of CSA responsiveness.

Objective:

* Identify changes in gene expression patterns induced by cyclosporine therapy in patients with LGL leukemia
* Identify differences between responding and non-responding patients

Eligibility:

-Patients with Large Granular Lymphocyte leukemia

Design:

* Patients will be treated with cyclosporine at a dose of 5-10mg/kg/day in divided doses, with doses adjusted to maintain a therapeutic serum level between 200-400ng/ml. These therapeutic levels shall be maintained for 3 months.
* Tumor response will be evaluated after 3 months therapy, the dose of CsA may then be tapered to that required to sustain a response or discontinued if no evidence of response, or after relapse.
* Blood sampling or Lymphapheresis for collection of circulating malignant cells will be performed at a number of different time points. Gene expression profiling will be carried out on Affymetrix microarrays to compare pretreatment and post-treatment samples.

Effect of Cyclosporine Therapy on Gene Expression in Patients With Large Granular Lymphocyte Leukemia

Microarray Analysis of the Effect of Cyclosporine Therapy on Gene Expression Patterns in Large Granular Lymphocytic Leukemia

The goal was to examine which genes had a 2-fold gene expression between pre-treatment (baseline) and post treatment (12 weeks). Genes significant at the 0.001 level will be considered as differentially expressed due to treatment.

Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

National Cancer Institute (NCI)

Principal Investigator

LGL Patients Administered Cyclosporine

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

As there were only 5 patients treated, the primary endpoints of this protocol were not met and there is not enough data generated for statistical analysis. This protocol is being terminated due to low accrual and the investigator leaving the NIH.

This outcome measure was not performed because there were insufficient data points to provide any statistical power.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Dose-Ranging Study of IV BNZ-1 in LGL Leukemia or Refractory CTCL	NCT03239392	LGL Leukemia CTCL	BNZ132-1-40	18 Years -	Bioniz Therapeutics
A Dose-Ranging Study of IV BNZ-1 in LGL Leukemia or Refractory CTCL	NCT03239392	LGL Leukemia CTCL	BNZ132-1-40	18 Years -	Bioniz Therapeutics
Effect of Cyclosporine Therapy on Gene Expression in Patients With Large Granular Lymphocyte Leukemia	NCT00363779	Large Granular ... LGL Leukemia	Cyclosporine Gene expression... Microarray anal... Laboratory biom...	18 Years -	National Institutes of Health Clinical Center (CC)

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