Lymphoma
Conditions
Keywords
stage III mantle cell lymphoma, stage IV mantle cell lymphoma, contiguous stage II mantle cell lymphoma, noncontiguous stage II mantle cell lymphoma
Brief summary
RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Combining rituximab with chemotherapy may kill more cancer cells. PURPOSE: Phase II pilot study to study the effectiveness of combining chemotherapy with rituximab in treating patients who have newly diagnosed mantle cell lymphoma.
Detailed description
OBJECTIVES: * Determine the 1-year progression-free survival probability in patients with previously untreated mantle cell lymphoma treated with courses of rituximab and cyclophosphamide, doxorubicin, vincristine, and dexamethasone alternating with courses of rituximab and high-dose cytarabine and methotrexate with leucovorin calcium. * Determine the response rate (complete unconfirmed and complete and partial responses) and survival of patients treated with this regimen. * Determine the toxicity of this regimen in these patients. * Correlate chromosomal breakpoints, translocated immunoglobulin regulatory sequences, and cyclins D1, D2, and D3 with response and progression-free survival in patients treated with this regimen. * Correlate gene expression (measured by DNA microarray analysis) with response and progression-free survival in patients treated with this regimen. OUTLINE: This is a pilot, multicenter study. * Courses 1, 3, 5, and 7: Patients receive rituximab IV on day 1 (courses 1, 3, and 5 only); cyclophosphamide IV over 3 hours twice a day on days 2-4; doxorubicin IV over 24 hours on days 5-7; vincristine IV on days 5 and 12; dexamethasone orally or IV four times a day on days 2-5 and 12-15; and filgrastim (G-CSF) subcutaneously (SC) daily beginning on day 8 and continuing until blood counts recover. * Courses 2, 4, 6, and 8: Patients receive rituximab IV on day 1 (courses 2, 4, and 6 only); high-dose methotrexate IV over 24 hours on day 2; high-dose cytarabine IV over 2 hours twice a day on days 3-4; oral leucovorin calcium 4 times a day on days 3-10; and G-CSF SC daily beginning on day 5 and continuing until blood counts recover. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed within 30 days, every 3 months for 2 years, and then every 6 months for 3 years. Patients with disease progression are followed annually for up to 5 years from study entry. PROJECTED ACCRUAL: Approximately 50 patients will be accrued for this study within 25 months.
Interventions
BIOLOGICALfilgrastim
5 ug/kg
BIOLOGICALrituximab
375 mg/m\^2 on day 1 of cycles 1-6
DRUGcyclophosphamide
300 mg/m\^2 on days 2-4 of cycles 1,3,5,7
DRUGcytarabine
12 g/m\^2 over days 3-4 of cycles 2,4,6,8
DRUGdexamethasone
40 mg on days 2-5 and 12-15 of cycles 1,3,5,7
DRUGdoxorubicin
16.6 mg/m\^2/day for days 5-7 of cycles 1,3,5,7
DRUGleucovorin
170 mg over days 3-5 of cycles 2,4,6,8
DRUGmethotrexate
1000 mg/m\^2 over days 2-3 of cycles 2,4,6,8
DRUGvincristine
1.4 mg/m\^2 on days 5 and 12 of cycles 1,3,5,7
Sponsors
National Cancer Institute (NCI)
SWOG Cancer Research Network
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 69 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically proven stage III/IV or bulky stage II mantle cell lymphoma of one of the following histologic subtypes: * Nodular * Diffuse * Mantle zone * Blastic * Newly diagnosed and previously untreated disease * Bidimensionally measurable disease PATIENT CHARACTERISTICS: Age: * 18 to 69 Performance status: * Zubrod 0-2 Life expectancy: * Not specified Hematopoietic: * Absolute neutrophil count at least 1,000/mm\^3 * Platelet count at least 100,000/mm\^3 (50,000/mm\^3 if marrow involvement present) Hepatic: * Bilirubin no greater than 1.5 mg/dL (5.0 mg/dL if hepatic involvement present) Renal: * Creatinine no greater than 2.0 mg/dL * Creatinine clearance greater than 50 mL/min Cardiovascular: * Ejection fraction at least 50% by MUGA or 2-D echocardiogram * No significant abnormalities by EKG Other: * Not pregnant or nursing * Fertile patients must use effective contraception * Willing to receive blood product transfusions * No known sensitivity to E. coli-derived proteins * No known AIDS syndrome or HIV-associated complex * No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix PRIOR CONCURRENT THERAPY: Biologic therapy: * No prior monoclonal antibody therapy Chemotherapy: * No prior chemotherapy for lymphoma Endocrine therapy: * Not specified Radiotherapy: * No prior radiotherapy for lymphoma Surgery: * Not specified
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | assessed after cycle 4, after completion of treatment, then every 3 months until 1 year after registration | Progression-Free Survival (PFS) rate at 1 year. PFS measured from date of registration to date of first observation of progressive disease or death due to any cause. Progressive disease is a 50% increase in the sum of products of greatest diameters (SPD) of target measurable lesions over the smallest sum observed if a complete response (confirmed, or unconfirmed) was not previously achieved; appearance of a new lesion/site; unequivocal progression of non-measurable disease; or death due to disease without prior documentation of progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response | assessed after cycle 4 and after completion of treatment (168 days) | Complete (CR), complete unconfirmed (CRU) and partial responses (PR). CR is complete disappearance of all measurable and non-measurable disease with the exception of nodes; no new lesions; previously enlarged organs must have regressed in size; and if bone marrow positive at baseline, it must be negative. CRU is complete disappearance of all measurable and non-measurable disease; regressed, non-palpable organs; and one or more exceptions not qualifying for CR (see protocol section 10). PR applies to patients with at least one measurable lesion who do not qualify for CR or CRU. PR is a 50% decrease in sum of products of greatest diameters (SPD) for up to six identified dominant lesions identified at baseline; no new lesions; no increase in the size of liver, spleen or other nodes; and splenic and hepatic nodules must have regressed in size by at least 50% in SPD. |
| Overall Survival | assessed after cycle 4, after completion of treatment, then every 3 months for 2 years, then every 6 months thereafter until 5 years | Overall Survival rate at 1 year. Time to death is from date of registration to date of death due to any cause. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Hyper-CVAD + MTX/Ara-C + Rituximab 21-day cycles of Hyper-CVAD and high-dose methotrexate/Ara-C are alternated beginning with Hyper-CVAD for a maximum of 8 cycles. Rituximab is given for cycles 1-6.
Hyper-CVAD (cycles 1,3,5,7): rituximab 375 mg/m\^2 on day 1, mesna 600 mg/m\^2 on days 2-4, cyclophosphamide 300 mg/m\^2 on days 2-4, doxorubicin 16.6 mg/m\^2/day on days 5-7, vincristine 1.4 mg/m\^2 on days 5 and 12, dexamethasone 40 mg on days 2-5 and 12-15, and G-CSF 5 ug/kg on days 8-21.
Methotrexate/Ara-C (cycles 2,4,6,8): rituximab 375 mg/m\^2 on day 1, methotrexate 1000 mg/m\^2 over days 2-3, Ara-C 12 g/m\^2 over days 3-4, leucovorin 170 mg over days 3-5, and G-CSF 5 ug/kg on days 5-21. | 49 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 19 |
| Overall Study | Death | 1 |
| Overall Study | Not Eligible | 7 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Hyper-CVAD + MTX/Ara-C + Rituximab |
|---|---|
| Age Continuous | 57.4 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 48 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 48 / 49 |
| serious Total, serious adverse events | 4 / 49 |
Outcome results
Primary
Progression-free Survival
Progression-Free Survival (PFS) rate at 1 year. PFS measured from date of registration to date of first observation of progressive disease or death due to any cause. Progressive disease is a 50% increase in the sum of products of greatest diameters (SPD) of target measurable lesions over the smallest sum observed if a complete response (confirmed, or unconfirmed) was not previously achieved; appearance of a new lesion/site; unequivocal progression of non-measurable disease; or death due to disease without prior documentation of progression.
Time frame: assessed after cycle 4, after completion of treatment, then every 3 months until 1 year after registration
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hyper-CVAD + MTX/Ara-C + Rituximab | Progression-free Survival | 90 percentage of participants |
Secondary
Overall Survival
Overall Survival rate at 1 year. Time to death is from date of registration to date of death due to any cause.
Time frame: assessed after cycle 4, after completion of treatment, then every 3 months for 2 years, then every 6 months thereafter until 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hyper-CVAD + MTX/Ara-C + Rituximab | Overall Survival | 92 percentage of participants |
Secondary
Response
Complete (CR), complete unconfirmed (CRU) and partial responses (PR). CR is complete disappearance of all measurable and non-measurable disease with the exception of nodes; no new lesions; previously enlarged organs must have regressed in size; and if bone marrow positive at baseline, it must be negative. CRU is complete disappearance of all measurable and non-measurable disease; regressed, non-palpable organs; and one or more exceptions not qualifying for CR (see protocol section 10). PR applies to patients with at least one measurable lesion who do not qualify for CR or CRU. PR is a 50% decrease in sum of products of greatest diameters (SPD) for up to six identified dominant lesions identified at baseline; no new lesions; no increase in the size of liver, spleen or other nodes; and splenic and hepatic nodules must have regressed in size by at least 50% in SPD.
Time frame: assessed after cycle 4 and after completion of treatment (168 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hyper-CVAD + MTX/Ara-C + Rituximab | Response | 42 participants |