PXD101 in Treating Patients With Relapsed or Refractory Aggressive B-Cell Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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This phase II trial is studying how well PXD101 works in treating patients with relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. PXD101 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. Evaluate response rate in patients with relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma treated with PXD101. SECONDARY OBJECTIVES: I. Determine the toxicity of this drug in these patients. II. Estimate the 6-month progression-free survival rate in patients treated with this drug. TERTIARY OBJECTIVES: I. Determine the major histocompatability complex of class II proteins (HLA-DR, -DP, -DQ), TUNEL, and CD8 infiltration status, by immunochemistry on paired pre- and post-treatment tumor samples, in the first 20 patients enrolled. II. Measure CIITA and HLA-DR mRNA expression using quantitative reverse transcriptase-polymerase chain reaction and determine, preliminarily, the associations of these markers with progression-free survival. III. Evaluate paired pre- and post-treatment peripheral blood mononuclear cells from patients for histone acetylation status and determine correlation with findings from duplicate experiments on pre- and post-needle core biopsies. OUTLINE: This is a multicenter study. Patients receive PXD101 IV over 30 minutes on days 1-5. Treatment repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Needle core biopsies and peripheral blood mononuclear cells are obtained from the first 20 patients pre- and post-treatment for biomarker correlative studies. After completion of study treatment, patients are followed every 3-6 months for up to 3 years.

Official Title
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Phase II Study of PXD101 (NSC-726630) in Relapsed and Refractory Aggressive B-Cell Lymphomas

Conditions
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Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma

Intervention / Treatment
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* Drug: belinostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy-proven (no needle aspirations or cytologies) aggressive B-cell non-Hodgkin's lymphoma (NHL), including 1 of the following histology subtypes: Diffuse large cell NHL Burkitt's or Burkitt-like NHL Primary mediastinal NHL Relapsed or refractory disease Bidimensionally measurable disease Transformed NHL allowed Not eligible for stem cell transplantation (for patients registered to study at first relapse) No active CNS involvement by lymphoma Zubrod performance status 0-2 No history of allergic reactions attributed to compounds of similar chemical or biologic composition to PXD101 Absolute neutrophil count >= 1,500/mm^3 Platelet count>=100,000/mm^3 WBC >= 3,000/mm^3 Creatinine < 2 times upper limit of normal (ULN) OR creatinine clearance >= 60 mL/min No significant EKG abnormalities Bilirubin normal SGOT/SGPT < 2.5 times ULN (=< 5 times ULN if liver involvement) No long QT syndrome or marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of QTc interval > 500 msec) No other significant cardiovascular disease, including any of the following: Unstable angina pectoris Uncontrolled hypertension Congestive heart failure related to primary cardiac disease Any condition requiring anti-arrhythmic therapy Ischemic or severe valvular heart disease Myocardial infarction within the past 6 months No major surgery within 28 days prior to study entry No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent medication that may cause Torsades de Pointes (i.e., prolongation of the QT interval > 500 msec) At least 14 days since prior radiotherapy At least 2 weeks since prior valproic acid or any other histone deacetylase inhibitor No clinical evidence of any of the following: Severe peripheral vascular disease Diabetic ulcers or venous stasis ulcers History of deep venous or arterial thrombosis within the past 3 months Radioimmunotherapy is considered a chemotherapy regimen Single-agent rituximab is not considered a chemotherapy regimen Standard salvage chemotherapy followed by autologous stem cell transplantation is considered 1 regimen No known AIDS or HIV-associated complex Not pregnant or nursing Fertile patients must use effective contraception No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or in situ carcinoma of the cervix At least 2 weeks since prior therapy and recovered No more than 5 prior chemotherapy regimens

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients will receive an infusion of PXD101 once a day for 5 days. Treatment may repeat every 3 weeks for up to 2 years. Some patients will also undergo core biopsy and blood collection for laboratory studies before and after treatment. After finishing treatment, patients will be evaluated every 3-6 months for up to 3 years. | Drug: belinostat<br>* Given IV<br>* Other names: PXD101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess Number of Patients Who Achieve Confirmed and Unconfirmed Complete Response (CR) or Partial Response (PR) | Complete Response(CR) is a complete disappearance of all disease with the exception of nodes. No new lesions. previously enlarged organs must have regressed and not be palpable. Bone marrow(BM) must be negative if positive at baseline. Normalization of markers. CR Unconfirmed (CRU) does not qualify for CR above, due to a residual nodal mass or an indeterminate BM. Partial Response(PR) is a 50% decrease in the SPD for up to 6 identified dominant lesions, including spleenic and hepatic nodules from baseline. No new lesions and no increase in the size of liver, spleen or other nodes. | assessed at week 8, and every 3 months for 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Measured from time of registration to death, or last contact date | assessed every 3 months for 3 years | 
| Progression-free Survival | Measured from date of registration to time of first documentation of progression or death, or last contact date. Progression is defined as a 50% increase in sum of products of greatest diameters (SPD) of target measurable lesions over the smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline; appearance of a new lesion/site; unequivocal progression of non-measurable disease in the opinion of the treating physician; death due to disease without prior documentation of progression. | assessed at week 8, then every 3 months for 3 years |