Vorinostat With or Without Bortezomib in Treating Patients With Refractory or Recurrent Stage IIB, Stage III, or Stage IV Cutaneous T-Cell Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Vorinostat and bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether vorinostat is more effective when given alone or when given together with bortezomib in treating patients with refractory or recurrent cutaneous T-cell lymphoma. PURPOSE: This randomized phase III trial is studying how well vorinostat works when given alone compared with vorinostat given together with bortezomib in treating patients with refractory or recurrent stage IIB, stage III, or stage IV cutaneous T-cell lymphoma.

Detailed Description
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OBJECTIVES: Primary To determine if the combination of bortezomib plus vorinostat (SAHA) is more effective than vorinostat alone, in terms of prolonging progression-free survival, in patients with stage IIB-IV cutaneous T-cell lymphoma who have failed prior therapy. Secondary To determine the overall survival of these patients. To determine the response rate in these patients. To determine the time to progression in these patients. To determine the duration of response in these patients. To determine the incidence of second cancers in these patients. To determine the acute and late toxicity of this regimen in these patients. To determine if translational research may provide insight into disease mechanism and identify biomarkers useful for prediction of treatment response. (Exploratory) OUTLINE: This is a multicenter study. Patients are stratified according to type of cutaneous T-cell lymphoma (mycosis fungoides vs erythrodermic mycosis fungoides/Sézary syndrome), number of prior chemotherapy regimens (1 vs ≥ 2), and country. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral vorinostat (SAHA) once daily in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive bortezomib IV on days 1, 4, 8, and 11 and oral vorinostat once daily on days 1-14. Treatment repeats every 21 days until progression or unacceptable toxicity. Blood and tissue samples are collected periodically for translational research to provide insight into disease mechanism and identify biomarkers useful for prediction of treatment response. After completion of study treatment, patients are followed up at 4 weeks and then every 3 months until disease progression.

Official Title
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Progression Free Survival (PFS) Comparison Between Suberoylanilide Hydroxamic Acid (SAHA, Vorinostat TM) in Combination With Bortezomib (Velcade TM) and SAHA Alone in Refractory or Recurrent Advanced CTCL. A Randomized Study.

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: bortezomib
* Drug: vorinostat
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed advanced cutaneous T-cell lymphoma (CTCL), including its variants mycosis fungoides and Sézary syndrome Stage IIB-IV disease Relapsed or refractory disease, including any of the following: Patients with clinical progression following EORTC-21081 protocol treatment Intolerant to ≥ 1 prior intravenous chemotherapy, including denileukin diftitox, antibodies or antibody conjugates, or any other systemic therapy No CNS involvement PATIENT CHARACTERISTICS: WHO performance status 0-2 Absolute neutrophil count > 1.5 x 10^9/L* Platelet count > 100 x 10^9/L* Hemoglobin > 9 g/dL* WBC > 3 x 10^9/L* Bilirubin ≤ 1.5 times upper limit of normal (ULN)* AST and ALT ≤ 3 times ULN (in case of liver infiltration ≤ 5 x ULN)* Serum creatinine ≤ 2.0 mg/dL* Calculated creatinine clearance ≥ 60 mL/min Electrolytes (including potassium and magnesium) ≤ 1 times ULN* Not pregnant or nursing prior to the first dose of study treatment and until 4 weeks after the last study treatment Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after completion of study therapy Able to swallow capsules and is able to take or tolerate oral medication on a continuous basis No New York Heart Association class III-IV disease None of the following known conditions: Infectious disease Autoimmune disease Immunodeficiency No known or active HIV and/or hepatitis A, B, or C infection No NCI CTC grade 1 peripheral sensory neuropathy with pain or peripheral sensory or motor neuropathy ≥ grade II No other malignancy within the past 5 years No psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule NOTE: *Patients with a buffer range from the normal values of +/- 5% for hematology and +/- 10% for biochemistry are acceptable, except for renal function. PRIOR CONCURRENT THERAPY: See Disease Characteristics Must have completely recovered from previous treatment toxicity No prior splenectomy or splenic irradiation No prior bortezomib and/or histone deacetylase inhibitors (including vorinostat [SAHA]) More than 4 weeks since prior chemotherapy, immunotherapy, radiotherapy, or surgery In case of clear progression during previous treatment, 2 weeks of wash-out is enough No concurrent chemotherapy, immunotherapy, radiotherapy, or surgery (except biopsies) No concurrent steroid (prednisone or equivalent) dose > 20 mg/day Prednisone ≤ 20 mg/day for treatment of disorders other than CTCL allowed No concomitant use of other histone deacetylase inhibitors (e.g., valproic acid)

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
Allocation: Randomized
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: bortezomib|nan|
|Drug: vorinostat|nan|
|Other: laboratory biomarker analysis|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  |  | 
| Response rate |  |  | 
| Time to progression |  |  | 
| Duration of response |  |  | 
| Second cancers |  |  | 
| Acute and late toxicity |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II mycosis fungoides/Sezary syndrome, stage III mycosis fungoides/Sezary syndrome, stage IV mycosis fungoides/Sezary syndrome, stage II cutaneous T-cell non-Hodgkin lymphoma, stage III cutaneous T-cell non-Hodgkin lymphoma, stage IV cutaneous T-cell non-Hodgkin lymphoma, recurrent mycosis fungoides/Sezary syndrome, recurrent cutaneous T-cell non-Hodgkin lymphoma