Bortezomib and Gemcitabine Hydrochloride in Treating Patients With Relapsed or Refractory Hodgkin's Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with gemcitabine hydrochloride may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving bortezomib together with gemcitabine hydrochloride works in treating patients with relapsed or refractory Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Primary Determine the overall response rate (partial and complete response) in patients with relapsed or refractory Hodgkin's lymphoma treated with bortezomib and gemcitabine hydrochloride. Secondary Determine the safety and toxic effects of this regimen in these patients. Determine the time to progression in patients treated with this regimen. Correlate NF-kB inhibition and proteasome activity with response in patients treated with this regimen. OUTLINE: This is a multicenter, pilot study. Patients receive bortezomib IV on days 1, 4, 8, and 11 and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for 2 years and then annually thereafter. PROJECTED ACCRUAL: A total of 24 patients will be accrued for this study.

Official Title
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Phase II Pilot Study of Bortezomib (VELCADE®) and Gemcitabine for Patients With Relapsed or Refractory 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: Histologically confirmed Hodgkin's lymphoma Recurrent or refractory disease after prior standard combination chemotherapy Measurable disease, defined as ≥ 1 unidimensionally measurable lesion > 1 cm by physical exam or imaging studies No history of non-Hodgkin's lymphoma No history of other hematological malignancy PATIENT CHARACTERISTICS: Performance status ECOG 0-2 Life expectancy Not specified Hematopoietic Platelet count ≥ 100,000/mm^3 Absolute neutrophil count ≥ 1,000/mm^3 Hepatic Bilirubin ≤ 2 times upper limit of normal (ULN) (unless due to Gilbert's disease or involvement by Hodgkin's lymphoma) AST ≤ 3 times ULN (unless due to involvement by Hodgkin's lymphoma) Renal Creatinine clearance ≥ 30 mL/min Cardiovascular Ejection fraction ≥ 40% by MUGA or echocardiogram (in patients with a history of cardiac disease) Pulmonary Must not require supplemental oxygen therapy Immunologic No known HIV infection No uncontrolled bacterial, viral, or fungal infection Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other malignancy requiring therapy No peripheral neuropathy ≥ grade 2 within the past 14 days No hypersensitivity to boron No hypersensitivity to mannitol PRIOR CONCURRENT THERAPY: Biologic therapy More than 30 days since prior monoclonal antibody therapy for Hodgkin's lymphoma More than 6 months since prior autologous stem cell transplantation No prior allogeneic stem cell transplantation No concurrent sargramostim (GM-CSF) No concurrent pegfilgrastim or filgrastim (G-CSF) No concurrent interleukin-11(oprelvekin) Chemotherapy See Disease Characteristics More than 30 days since prior chemotherapy for Hodgkin's lymphoma No prior treatment with gemcitabine hydrochloride Endocrine therapy More than 30 days since prior corticosteroid therapy for Hodgkin's lymphoma No concurrent corticosteroid therapy Radiotherapy More than 30 days since prior radiotherapy for Hodgkin's lymphoma Other No prior treatment with bortezomib More than 14 days since prior investigational drugs No other concurrent investigational agents

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Bortezomib, Gemcitabine Hdrochloride<br> | Drug: bortezomib<br> <br> Drug: gemcitabine hydrochloride<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate After 2 Courses of Therapy | Response was evaluated after two cycles of therapy using the 1999 Cheson response criteria. All responses were based on CT scans. The criteria that were developed include anatomic definitions of response, with normal lymph node size after treatment of 1.5 cm in the longest transverse diameter by computer-assisted tomography scan. A designation of complete response/unconfirmed was adopted to include patients with a greater than 75% reduction in tumor size after therapy but with a residual mass, to include patients-especially those with large-cell NHL-who may not have residual disease. For patients who had FDG-PET imaging, metabolic response was defined as a decrease in the standardized uptake value in target lesions (regions of abnormal FDG uptake on pretreatment FDG-PET images) to below three on posttreatment FDG-PET imaging). All PET scans were reviewed and interpreted by a single radiologist (SV). | 21 Days/course for up to 2 courses | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Proteasome Activity Compared to Baseline (Cycle 1) | Peripheral blood (40 ml) was collected on cycle 1, day 1 of prebortezomib at baseline and 2 hrs post-bortezomib treatment. The samples were refrigerated at 4C and processed within 36 h of collection. Frozen cell lysates were thawed and the proteasome activity in 10 microliters was determined using a spectroflourometric 20S proteasome assay kit. Samples were run in triplicate on two separate days. The percent change between baseline and 2 hrs (day1, cycle 1) was calculated. | baseline to 2 hours | 
| Change in Proteasome Activity Compared to Baseline (Cycle 2) | Peripheral blood (40 ml) was collected at baseline and 1-2 weeks after cycle 2, day 11 post-bortezomib treatment. The samples were refrigerated at 4C and processed within 36 h of collection. Frozen cell lysates were thawed and the proteasome activity in 10 microliters was determined using a spectroflourometric 20S proteasome assay kit. Samples were run in triplicate on two separate days. The percent change between baseline and 2 hrs (day1, cycle 1) was calculated. | baseline and 1-2 weeks after cycle 2, day 11 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult Hodgkin lymphoma