A Phase I/II Trial of VELCADE & Gemcitabine for Patients With Relapsed or Refractory Aggressive B- and T-cell Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving gemcitabine together with bortezomib may kill more cancer cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of bortezomib when given together with gemcitabine and to see how well they work in treating patients with relapsed or refractory B-cell or T-cell non-Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Primary Determine the response rate (complete and partial remission) in patients with relapsed or refractory aggressive B- or T-cell non-Hodgkin's lymphoma treated with gemcitabine hydrochloride and bortezomib. Determine the maximum tolerated dose of bortezomib when administered with gemcitabine hydrochloride in these patients. Secondary Determine the time to treatment failure, duration of response, and overall survival of patients treated with this regimen. Determine the safety and tolerability of this regimen in these patients. OUTLINE: This is a phase I, dose-escalation study of bortezomib followed by a phase II, open-label study. Phase I: Patients receive gemcitabine hydrochloride IV over 30 minutes and bortezomib IV over 3-5 seconds on days 1 and 8. Treatment repeats every 21 days for up to 9 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 3 of 6 patients experience dose-limiting toxicity (DLT) OR the dose that at which 2 of 6 patients experience DLT. Phase II: Patients receive gemcitabine hydrochloride and bortezomib as in phase I at the MTD. After completion of study therapy, patients are followed periodically for 3 years. PROJECTED ACCRUAL: A total of 37 patients will be accrued for this study.

Official Title
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A Phase I/II Trial of Combination Bortezomib (VELCADE) and Gemcitabine Therapy for Patients With Relapsed or Refractory Aggressive B- and T-cell Non-Hodgkin's Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: bortezomib
* Drug: gemcitabine hydrochloride


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of B- or T-cell non-Hodgkin's lymphoma (NHL) Intermediate histology B-cell NHL, including any of the following: Diffuse large B-cell lymphoma Transformed large cell lymphoma Any T-cell NHL histology Cutaneous T-cell lymphoma (CTCL) or mycosis fungoides (MF) allowed Relapsed or refractory disease, defined as disease progressed after prior complete remission (CR), partial remission (PR), or stable disease (SD) to last therapy OR failure to achieve CR, PR, or SD after completion of last therapy Must have received 1-3 prior therapeutic regimens Cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (CHOP) AND cyclophosphamide, vincristine, and prednisone (CVP) OR CHOP with rituximab (CHOP-R) AND CVP with rituximab (CVP-R) is considered 1 regimen Monoclonal antibody (e.g., rituximab) given as maintenance therapy is considered 1 regimen Salvage chemotherapy followed by an autologous stem cell transplant is considered 1 regimen No more than 7 prior therapeutic regimens for patients with CTCL or MF No mantle cell lymphoma PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy > 3 months Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 At least 50,000/mm^3 if documented bone marrow involvement Hemoglobin ≥ 8.0 g/dL AST and ALT ≤ 3 times upper limit of normal (ULN) Alkaline phosphatase ≤ 3 times ULN Bilirubin ≤ 2 times ULN Creatinine ≤ 2.0 mg/dL No known history of HIV infection No other active infection No uncontrolled hypertension No peripheral neuropathy ≥ grade 2 within the past 2 weeks No myocardial infarction within the past 6 months No New York Heart Association class III or IV heart failure No uncontrolled angina No severe uncontrolled ventricular arrhythmias No acute ischemia or active conduction system abnormalities by ECG No hypersensitivity to bortezomib, boron, or mannitol Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier-method contraception No serious medical or psychiatric illness that would preclude study participation PRIOR CONCURRENT THERAPY: Prior autologous and/or allogeneic stem cell transplantation allowed More than 3 weeks since prior chemotherapy, radiotherapy, or immunotherapy More than 3 weeks since prior systemic biologic anticancer therapy More than 3 weeks since prior systemic corticosteroids (e.g., oral prednisone > 10 mg per day) More than 2 weeks since prior investigational drug No prior bortezomib or gemcitabine hydrochloride No other concurrent systemic cytotoxic chemotherapy or investigational agents

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: Gemcitabine 800 mg/m2 + Bortezomib IVP over 3-5 seconds<br>Gemcitabine dose of 800 mg/m2 over 30 minutes followed by Bortezomib IVP given over 3-5 seconds on day 1 and day 15 of each cycle every 28 days for up to 8 cycles. | Drug: bortezomib<br>* Bortezomib 1.6mg/m2 on days 1 and 15 of each cycle, given over 3-5 seconds on day 1 and day 15 of each cycle every 28 days for up to 8 cycles.<br>* Other names: PS-341;Drug: gemcitabine hydrochloride<br>* Gemcitabine dose of 800 mg/m2 over 30 minutes on day 1 and day 15 of each cycle every 28 days for up to 8 cycles.<br>* Other names: Gemzar®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate in Patients With Relapsed or Refractory B- and T-cell NHL With Gemcitabine and Bortezomib Combination Treatment. | Response rate in patients with relapsed or refractory B- and T-cell NHL with Gemcitabine and Bortezomib combination treatment will be defined as the number of patients with Complete Remission [CR] and Partial Remission [PR]. CT scans at screening and after completing cycle 3, cycle 6 and 30 days after Cycle 8 assessed by the Response Criteria for Non-hodgkins Lymphoma will be used to determine response where: CR=Complete disappearance of all detectable clinical and radiographic evidence of disease PR=> 50% decrease in SPD of the six largest dominant nodes or nodal masses | At screening and after completing cycle 3, cycle 6 and 30 days after Cycle 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Treatment Failure and Duration of Response | Time to treatment failure and duration of response will be measured by CT Scan at screening and after completing cycle 3, cycle 6 and 30 days after cycle 8, then every 6 months for 3 years | At screening and after completing cycle 3, cycle 6 and 30 days after cycle 8, then every 6 months for 3 years | 
| Overall Survival | Overall survival will be evaluated every 6 months while on treatment and then every 6 months while off of treatment for up to 3 years | Every 6 months while on treatment and then every 6 months while off of treatment for up to 3 years | 
| Evaluate Safety and Tolerability of Bortezomib and Gemcitabine Therapy | Safety and tolerability of the study drugs will be assessed on Day 1 and on either Day 8 or Day 15 of each treatment cycle (1 Cycle - 28 days) while on active treatment; and 30 days post last treatment. Adverse Events that are experienced by patients, determined to be either grade 3 or grade 4 and at least possibly related to at least one of the study drugs as assessed according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0) will be collected. In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE | During treatment through a maximum of 8 Cycles (1 Cycle = 28 Days) and 30 days post last treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent grade 3 follicular lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma, recurrent mycosis fungoides/Sezary syndrome