Lymphoma
Conditions
Keywords
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
Brief summary
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
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.
Interventions
DRUGbortezomib
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.
DRUGgemcitabine hydrochloride
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.
Sponsors
Eli Lilly and Company
Millennium Pharmaceuticals, Inc.
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate in Patients With Relapsed or Refractory B- and T-cell NHL With Gemcitabine and Bortezomib Combination Treatment. | At screening and after completing cycle 3, cycle 6 and 30 days after Cycle 8 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Treatment Failure and Duration of Response | At screening and after completing cycle 3, cycle 6 and 30 days after cycle 8, then every 6 months for 3 years | 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 |
| Overall Survival | Every 6 months while on treatment and then every 6 months while off of treatment for up to 3 years | 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 |
| Evaluate Safety and Tolerability of Bortezomib and Gemcitabine Therapy | During treatment through a maximum of 8 Cycles (1 Cycle = 28 Days) and 30 days post last treatment | 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 |
Countries
United States
Participant flow
Recruitment details
The study opened for accrual to phase I on September 26, 2005 with first patient treated April 7 2006.The study was closed on October 17 2007 to phase I and opened to phase II on December 18 2007. The study closed permanently March 9 2011 with a total accrual of 32 patients treated on the study before reaching the total accrual goal.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 -Gemcitabine 800 mg/m2 + Bortezomib 1.3 mg/m2 Patients are treated with Gemcitabine 800mg/m2 IV over 30 minutes and Bortezomib 1.3 mg/m2 IVP over 3-5 seconds on Day 1 and Day 8 of a 28 day Cycle for up to 8 cycles of treatment. | 5 |
| Cohort 1 -Gemcitabine 800 mg/m2 + Bortezomib 1.6 mg/m2 Patients are treated with Gemcitabine 800mg/m2 IV over 30 minutes and Bortezomib 1.6 mg/m2 IVP over 3-5 seconds on Day 1 and Day 8 of a 28 day Cycle for up to 8 cycles of treatment. | 6 |
| Phase II Gemcitabine 800 mg/m2 + Bortezomib 1.6 mg/m2 D1+D8 Patients are treated with Gemcitabine 800mg/m2 IV over 30 minutes and Bortezomib 1.6 mg/m2 IVP over 3-5 seconds on Day 1 and Day 8 of a 28 day Cycle for up to 8 cycles of treatment. | 7 |
| Phase II Gemcitabine 800 mg/m2 + Bortezomib 1.6 mg/m2 D1+D15 Patients are treated with Gemcitabine 800mg/m2 IV over 30 minutes and Bortezomib 1.6 mg/m2 IVP over 3-5 seconds on Day 1 and Day 15 of a 28 day Cycle for up to 8 cycles of treatment. | 14 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 2 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 |
| Overall Study | Progressive Disease | 3 | 5 | 4 | 10 |
| Overall Study | Receive auto transplant or radiation | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase II Gemcitabine 800 mg/m2 + Bortezomib 1.6 mg/m2 D1+D8 | Cohort 1 -Gemcitabine 800 mg/m2 + Bortezomib 1.3 mg/m2 | Cohort 1 -Gemcitabine 800 mg/m2 + Bortezomib 1.6 mg/m2 | Phase II Gemcitabine 800 mg/m2 + Bortezomib 1.6 mg/m2 D1+D15 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 1 Participants | 5 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 3 Participants | 5 Participants | 9 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 5 Participants | 6 Participants | 12 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 5 Participants | 4 Participants | 11 Participants | 25 Participants |
| Region of Enrollment United States | 7 Participants | 5 Participants | 6 Participants | 14 Participants | 32 Participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 4 Participants | 5 Participants | 14 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 2 Participants | 9 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 5 | 6 / 6 | 7 / 7 | 11 / 14 |
| other Total, other adverse events | 5 / 5 | 6 / 6 | 7 / 7 | 14 / 14 |
| serious Total, serious adverse events | 4 / 5 | 2 / 6 | 3 / 7 | 6 / 14 |
Outcome results
Primary
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
Time frame: At screening and after completing cycle 3, cycle 6 and 30 days after Cycle 8
Population: Patients must complete 3 cycles of treatment to be evaluable for this outcome measure. Only 3 patients reached Cycle 3 and the study closed before accrual was met due to lack of efficacy. Below shows response of patients that reached Cycle 3 and is not a reflection of response rate.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II Gemcitabine 800 mg/m2 + Bortezomib 1.6 mg/m2 D1+D8 | Response Rate in Patients With Relapsed or Refractory B- and T-cell NHL With Gemcitabine and Bortezomib Combination Treatment. | 1 participants |
| Phase II Gemcitabine 800 mg/m2 + Bortezomib 1.6 mg/m2 D1+D15 | Response Rate in Patients With Relapsed or Refractory B- and T-cell NHL With Gemcitabine and Bortezomib Combination Treatment. | 2 participants |
Secondary
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
Time frame: During treatment through a maximum of 8 Cycles (1 Cycle = 28 Days) and 30 days post last treatment
Population: The study was terminated before total accrual was met due to lack of efficacy. Data was not collected for analysis for this outcome measure
Secondary
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
Time frame: Every 6 months while on treatment and then every 6 months while off of treatment for up to 3 years
Population: The study was terminated early due to lack of efficacy. Data not collect for analysis of this outcome measure.
Secondary
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
Time frame: At screening and after completing cycle 3, cycle 6 and 30 days after cycle 8, then every 6 months for 3 years
Population: Study was terminated due to lack of efficacy. Data not collected for analysis of outcome measure.