Lymphoma
Conditions
Keywords
recurrent adult Hodgkin lymphoma
Brief summary
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
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.
Interventions
DRUGbortezomib
DRUGgemcitabine hydrochloride
Sponsors
University of Rochester
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate After 2 Courses of Therapy | 21 Days/course for up to 2 courses | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Proteasome Activity Compared to Baseline (Cycle 1) | baseline to 2 hours | 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. |
| Change in Proteasome Activity Compared to Baseline (Cycle 2) | baseline and 1-2 weeks after cycle 2, day 11 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bortezomib, Gemcitabine Hydrochloride bortezomib
gemcitabine hydrochloride
Bortezomib was administered at a dose of 1 mg/m2 on days 1, 4, 8,and 11 of a 21-day schedule. Gemcitabine was administered at a dose of 800 mg/m2 on days 1 and 8 of the same 21-day schedule. | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
Baseline characteristics
| Characteristic | Bortezomib, Gemcitabine Hydrochloride |
|---|---|
| Age, Continuous | 36 years |
| Race/Ethnicity, Customized Black | 2 participants |
| Race/Ethnicity, Customized White | 16 participants |
| Region of Enrollment United States | 18 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 18 / 18 |
| serious Total, serious adverse events | 5 / 18 |
Outcome results
Primary
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).
Time frame: 21 Days/course for up to 2 courses
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bortezomib, Gemcitabine Hydrochloride | Response Rate After 2 Courses of Therapy | 4 participants |
Secondary
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.
Time frame: baseline to 2 hours
Population: Samples were not collected on one patient, so only 17 patients were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bortezomib, Gemcitabine Hydrochloride | Change in Proteasome Activity Compared to Baseline (Cycle 1) | -50 Percentage of change in proteosome activ |
Secondary
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.
Time frame: baseline and 1-2 weeks after cycle 2, day 11
Population: Samples were not collected on one patient, so only 17 patients were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bortezomib, Gemcitabine Hydrochloride | Change in Proteasome Activity Compared to Baseline (Cycle 2) | -57 percentage of change in proteosome activ |