Bortezomib (Velcade) With Standard Chemotherapy for Relapsed or Refractory Follicular Lymphoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effectiveness and safety of combining bortezomib (Velcade) with rituximab, fludarabine, mitoxantrone, and dexamethasone in treating patients with follicular cell lymphoma.

Detailed Description
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This is a phase II study using the combination of bortezomib, rituximab, fludarabine, mitoxantrone and dexamethasone. The combination will given over a 28 day cycle. In addition each patient will receive Pneumocystis carinii Pneumonia (PCP) prophylaxis with Trimethoprim/sulfamethoxazole (TMP/Sulfa) or equivalent agent. On day 4 the physician has the option of starting granulocyte colony-stimulating factor (GCSF), granulocyte macrophage colony-stimulating factor (GMCSF), or pegylated GCSF. All patients who receive at least one dose of the drug will be evaluated for toxicity. Patients will be treated with the agent for at least 2 cycles to be considered eligible for evaluation of response. The chemotherapy dosing will continue until there is evidence of disease progression, a second recurrence of unacceptable toxicity, or a maximum of 8 courses of therapy.

Official Title
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A Phase II Study of Bortezomib in Combination With Rituximab, Fludarabine, Mitoxantrone, and Dexamethasone (VR-FND) for Relapsed or Refractory Follicular Lymphoma

Conditions
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Lymphoma, Follicular

Intervention / Treatment
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* Drug: Bortezomib
* Drug: Rituximab
* Drug: Fludarabine
* Drug: Mitoxantrone
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of grade 1-3 follicular lymphoma with persistent, relapsed, or refractory disease to at least one prior regimen. No prior bortezomib therapy. Voluntary written informed consent. Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control. Male subject agrees to use an acceptable method for contraception for the duration of the study therapy. 18 years of age or older. aspartate aminotransferase (AST),alanine aminotransferase (ALT), total bilirubin < 3 times the upper limit of normal unless documented by the treating physician to be secondary to underlying lymphoma. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Exclusion Criteria: Platelet count of < 50,000 within 14 days before enrollment unless documented by the treating physician to be due to the disease. Absolute neutrophil count of < 1000 within 14 days before enrollment unless documented by the treating physician to be due to disease. Estimated or measured creatinine clearance of less than 30 ml/min within 14 days before enrollment. ≥Grade 2 peripheral neuropathy within 14 days before enrollment. Myocardial infarction within 6 months prior to enrollment or has New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia. Patient has hypersensitivity to boron, mannitol or any drug included in the current protocol. Female subject is pregnant or lactating. Received other investigational drugs for this disease within 14 days of enrollment Serious medical or psychiatric illness likely to interfere with participation in this clinical study. Known HIV+ status. Cardiac ejection fraction less than 35% at study entry measured by echocardiogram, Multigated Acquisition (MUGA) or cardiac MRI.

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: VR-FND<br>Bortezomib (VELCADER) 1.6 mg/m2 IV days 1 and 8 Rituximab 375 mg/m2 IV on day 1 Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone 20 mg orally on days 1,2,3,4,5 On day 1 the sequence of drug administration will be Bortezomib followed by Fludarabine followed by Rituximab. Each cycle will be repeated every 28 days for 8 cycles maximum. | Drug: Bortezomib<br>* Bortezomib 1.6 mg/m2 on days 1 and 8 of each 28-day cycle<br>* Other names: Velcade;Drug: Rituximab<br>* Rituximab 375 mg/m2 IV on day 1<br>Drug: Fludarabine<br>* Fludarabine 25 mg/m2 IV on days 1,2,3<br>Drug: Mitoxantrone<br>* Mitoxantrone 10 mg/m2 IV on day 2<br>* Other names: Novantrone;Drug: Dexamethasone<br>* Dexamethasone 20 mg orally on days 1,2,3,4,5<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete and Partial Response | Complete Response: Complete disappearance of all detectable clinical and radiographic evidence of disease, disappearance of all disease-related symptoms and normalization of biochemical abnormalities (eg. LDH) definitely assignable to follicular lymphoma. Partial Response requires the following: greater than or equal to 50% decrease in the SPD of the 6 largest dominant nodes of nodal masses. No increase in size of other nodes, liver, or spleen. Splenic and hepatic nodes must regress by at least 50% in sum of the products (SPD). Bone marrow assessment in irrelevant for determination of Partial Response since it is not measurable disease; however, if positive the type of cell should be reported. No new lesions. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | Duration of response is measured from time of treatment to time of disease progression | up to 4 years | 
| Percentage of Subjects Experiencing Progression Free Survival | Progression free survival is measured from treatment to progression or death, whichever comes first. Progressive disease is measured as: 50% or greater increase from nadir in the sum of the products (SPD) of any previously identified abnormal node and the appearance of any new lesions during or at the end of treatment. | up to 2 years | 
| Percentage of Subjects Experiencing Overall Survival | Overall survival is from the day of enrollment to date of death from any cause. | up to 2 years | 
| Number of Participants With a Grade 3-4 Hematologic Toxicity. | Before each drug dose, the patient will be evaluated for possible toxicities that may have occurred after the previous dose(s). Toxicities are to be assessed according to the NCI Common Toxicity Criteria (CTC). | up to 1 year | 
| Number of Participants With Neuropathy, Any Grade | Before each drug dose, the patient will be evaluated for possible toxicities that may have occurred after the previous dose(s). Toxicities are to be assessed according to the NCI Common Toxicity Criteria (CTC). | up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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follicular lymphoma, Velcade, VR-FND