Sorafenib Tosylate in Treating Patients With Recurrent Aggressive Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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This phase II trial is studying how well sorafenib works in treating patients with recurrent diffuse large B-cell non-Hodgkin's lymphoma. Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the response rate of treatment with sorafenib (BAY43-9006) in patients with recurrent aggressive non-Hodgkin's lymphomas. SECONDARY OBJECTIVES: I. To evaluate the duration of response and progression free survival of treatment with BAY43-9006 in patients with recurrent aggressive Non-Hodgkin's Lymphomas. II. To characterize the toxicity of treatment with BAY43-9006 in patients with recurrent aggressive Non-Hodgkin's Lymphomas. III. To further characterize the pharmacokinetics properties of BAY43-9006 and assess influence of monooxygenases polymorphisms and multi-drug resistance transporter (MDR) on pharmacokinetics. OUTLINE: This is a multicenter study. Patients receive oral sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 1 year. PLANNED ACCRUAL: 41 ACTUAL ACCRUAL: 14

Official Title
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A Phase II Study of Sorafenib (BAY 43-9006) in Recurrent Aggressive Non-Hodgkin's Lymphoma

Conditions
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Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Hepatosplenic T-cell Lymphoma, Peripheral T-cell Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: sorafenib tosylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed recurrent de novo or transformed diffuse large B cell lymphoma (DLBCL) or one of its variants according to WHO classification (centroblastic, immunoblastic, T-cell/histiocyte rich and anaplastic variants) Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1 Patients must have measurable disease as defined in section 6 assessed within 4 weeks of registration Patients must have failed one or more prior Non-Hodgkin lymphoma (NHL) chemotherapy or antibody therapy with curative intent; autologous stem cell transplant is permitted Leukocytes >= 2,000/mm^3 Absolute neutrophil count >= 1,000/mm^3 Platelets >= 75,000/ mm^3 Total bilirubin =< 2.0 X normal institutional limits Aspartate Aminotransferase (AST) =< 2.5 X institutional upper limit of normal Alanine Aminotransferase (ALT) =< 2.5 X institutional upper limit of normal Creatinine within normal institutional limits; creatinine clearance calculated or measured at >= 60 ml/min/1.73m^2 if creatinine level is above institutional limits The prothrombin time (PT)/international normalized ratio (INR) within Institutional limits of normal Patients with underlying hypertension as defined by blood pressures averaging greater than 140/90 on two separate clinic visits are eligible if hypertension has been controlled by standard nonpharmacologic and pharmacologic therapy Patients must be physically able to orally ingest tablets Exclusion Criteria: Central nervous system (CNS) involvement Previously treated with Sorafenib (BAY 43-9006) or other small molecule targeted inhibitors of mitogen-activated protein kinase (MAPK) signaling intermediates or angiogenesis (e.g. bevacizumab) Progressed within 60 days of last therapy Prior allogeneic stem cell transplant Candidates for potentially curative therapy, such as hematopoietic stem cell transplantation (HSCT) Currently receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to sorafenib 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 Active HIV infection, because of possible pharmacokinetic interactions of anti-retroviral therapy with BAY43-9006 Evidence of bleeding diathesis Currently taking the cytochrome P450 enzyme-inducing anti-epileptic drugs (phenytoin, carbamazepine and phenobarbital), rifampin or St. John's Wort Pregnant or Breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception

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: Treatment (sorafenib tosylate)<br>Patients receive oral sorafenib 400 mg PO twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: sorafenib tosylate<br>* Given orally<br>* Other names: SFN;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response (OR) Rate | Response was assessed using the criteria from International Workshop to Standardize Criteria for NHL (Cheson, 1999). OR=complete response(CR)+complete response/uncertain(CRu)+partial response(PR) CR: 1)Disappearance of clinical/radiographic evidence of disease (dz) and all dz-related B-symptoms; normalization of biochemical abnormalities attributed to NHL; 2)Lymph nodes and nodal masses regress to normal size; 3)Spleen, if enlarged before therapy, has decreased in size and is not palpable; 4)Complete resolution of lymphoma in bone marrow biopsy CRu: Meet criteria 1 and 3 above but with ≥1 of the followings. Residual dominant nodal mass >1.5 cm in greatest diameter that has decreased by >75%. Indeterminate bone marrow. PR: ≥50% decrease in SPD (sum of products of diameters) of 6 largest dominant nodes or nodal masses. No increase in size of liver or spleen. No unequivocal progression in nonmeasurable or nondominant sites. Splenic/hepatic nodules regress ≥50% in SPD. No new dz sites. | Assessed at the end of Cycle 2 and Cycle 6 (1 cycle = 28 days). Then every 3 months beginning Cycle 9 if patient is < 2 years from study entry, every 6 months if patient is 2-3 years from study entry, up to 3 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the time from randomization to the first of progression, relapse or death from any cause. Per criteria from International Workshop to Standardize Criteria for NHL (Cheson, 1999), progression (for patients who have not responded) and relapse (for patients who responded) are defined as: Appearances of any new lesions/sites during or after therapy Increase of ≥50% in the SPD from nadir measurement of all involved dominant lymph nodes and liver/spleen nodules or unequivocal progression in any nonmeasurable disease or nondominant site Increase by ≥50% in greatest diameter from nadir measurement of any previously involved dominant node >1.0 cm in its short axis | Assessed after month 2 and month 6, then every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-3 years from study entry, up to 3 years | 
| Overall Survival | Overall survival is defined as the time from study entry until death from any cause. | Assessed after month 2 and month 6, then every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-3 years from study entry, up to 3 years. |