Lymphoma
Conditions
Keywords
contiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, stage III adult diffuse large cell lymphoma, stage IV adult diffuse large cell lymphoma
Brief summary
RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving rituximab together with combination chemotherapy may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving rituximab together with combination chemotherapy works in treating patients with stage II, stage III, or stage IV diffuse large B-cell non-Hodgkin's lymphoma.
Detailed description
OBJECTIVES: Primary * Determine the 2-year progression-free survival (PFS) rate after treatment with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in patients with bulky stage II or stage III or IV diffuse large B-cell non-Hodgkin's lymphoma who remain positron emission tomography (PET)-positive after 3 courses of rituximab, cyclophosphamide, vincristine, doxorubicin hydrochloride, and prednisone. Secondary * Determine the proportion of mid-treatment PET-positive patients who become PET-negative after 4 courses of R-ICE. * Determine the PFS of mid-treatment PET-negative patients treated with these regimens. * Determine the overall survival of patients treated with these regimens. * Determine the toxicity of these regimens in these patients. OUTLINE: * Rituximab and Combination Chemotherapy (R-CHOP: R= Rituximab, C= Cyclophosphamide, H= Doxorubicin Hydrochloride (Hydroxydaunomycin), O= Vincristine Sulfate (Oncovin), P= Prednisone): Patients receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine IV on day 1, and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients undergo fludeoxyglucose F18 positron emission tomography (PET) scanning and conventional restaging during course 3. Based on the PET results, patients are assigned to 1 of 2 treatment groups. * Group I (PET negative): Patients receive 2 more courses of R-CHOP as above in the absence of disease progression or unacceptable toxicity. * Group II (PET positive): Patients receive Rituximab 375 mg/m2 IV Day 1, Ifosfamide 5000 mg/m2 IV over 24 hours Day 2, Carboplatin AUC 5 (max: 800 mg) IV Day 2, Etoposide 100 mg/m2 IV Days 1, 2, 3 (R-ICE), Mesna 5000 mg/m2 IV over 24 hours Day 2, and Filgrastim 5 mcg/kg/day subcutaneous (SC) Day 4 until absolute neutrophil count (ANC) recovery every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for 10 years from the date of study entry. ACCRUAL: A total of 100 patients were accrued for this study.
Interventions
DRUGcarboplatin
Given IV
DRUGcyclophosphamide
Given IV
BIOLOGICALfilgrastim
Given subcutaneously or intravenous bolus.
BIOLOGICALrituximab
Given IV
DRUGdoxorubicin hydrochloride
Given IV
DRUGetoposide
Given IV
DRUGifosfamide
Given IV
DRUGprednisone
Taken orally
DRUGvincristine
Given IV
Sponsors
National Cancer Institute (NCI)
Eastern Cooperative Oncology Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Diffuse large B-cell non-Hodgkin's lymphoma * Bulky stage II (bulk defined as any lesion ≥ 10 cm) or stage III or IV disease * The following lymphoma types are excluded: * Primary central nervous system lymphoma * Transformed low-grade lymphoma (prior history of low-grade lymphoma or clear presence of low-grade lymphoma on histologic sections) * Primary mediastinal B-cell lymphoma or testicular lymphoma (consolidative radiotherapy is usually indicated) * Immunodeficiency-related lymphoma (i.e., after organ or bone marrow transplant) * Measurable disease * Patient must have at least one objective measurable disease site (i.e., measurable in at least 2 perpendicular parameters) * Measurable disease in the liver is required if the liver is the only site of lymphoma involvement * Abnormal positron emission tomography scans will not constitute evaluable disease, unless verified by CT scan or other appropriate imaging * Eastern Cooperative Oncology Group (ECOG) performance status 0-3 * For patients \> 50 years of age, a normal ejection fraction by ECHO or Multigated Acquisition Scan (MUGA) is required within 6 weeks prior to registration * Absolute neutrophil count ≥ 1,500/mm\^3 * Platelet count \> 100,000/mm\^3 * Creatinine \< 2.0 mg/dL * Bilirubin \< 2 mg/dL (may be up to 3.0 mg/dL if due to liver involvement by lymphoma)
Exclusion criteria
* Prior chemotherapy or radiation therapy for lymphoma * Prior anthracyclines or platinum compounds used as systemic chemotherapy * Prior radiation therapy to the mediastinum or to ≥ 25% of the bone marrow * Concurrent pentostatin or trastuzumab (Herceptin®) * Pregnant or nursing * Prior malignancy within the past 5 years unless it was in situ OR was treated with curative intent AND the patient has remained relapse-free * HIV positive
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 2-year Progression-Free Survival (PFS) | Assessed every 4 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from study entry, then every 12 months if patient is 5-10 years from study entry. | 2-year progression-free survival is defined as the probability of patients who remain alive and progression free at 2 years from study entry. The method of Kaplan and Meier (1958) was used to estimate PFS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 5-year Overall Survival | Every 4 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from study entry, then every 12 months if patient is 5-10 years from study entry. | 5-year overall survival is defined as the probability of patients who remain alive at 5 years from study entry. The method of Kaplan and Meier (1958) was used to estimate overall survival. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from Eastern Cooperative Oncology Group (ECOG) member institutions between 4/7/2006 and 8/5/2009. The first patient was accrued on 9/26/2006.
Participants by arm
| Arm | Count |
|---|---|
| Group I (PET Positive) Initially, patients received Rituximab 375 mg/m2 IV Day 1, Cyclophosphamide 750 mg/m2 IV Day 1, Vincristine 1.4 mg/m2 (max: 2 mg) IV Day 1, Doxorubicin 50 mg/m2 IV Day 1, and Prednisone 100 mg/m2 PO Days 1-5 (R-CHOP) every 21 days for 4 cycles. PET scan and conventional restaging occurred between days 14-20 of cycle 3. Patients who were PET positive after 3 cycles of R-CHOP received Rituximab 375 mg/m2 IV Day 1, Ifosfamide 5000 mg/m2 IV over 24 hours Day 2, Carboplatin AUC 5 (max: 800 mg) IV Day 2, Etoposide 100 mg/m2 IV Days 1, 2, 3 (R-ICE), Mesna 5000 mg/m2 IV over 24 hours Day 2, and Filgrastim 5 mcg/kg/day subcutaneous (SC) Day 4 until absolute neutrophil count (ANC) recovery every 14 days for 4 cycles . | 13 |
| Group II (PET Negative) Initially, patients received Rituximab 375 mg/m2 IV Day 1, Cyclophosphamide 750 mg/m2 IV Day 1, Vincristine 1.4 mg/m2 (max: 2 mg) IV Day 1, Doxorubicin 50 mg/m2 IV Day 1, and Prednisone 100 mg/m2 PO Days 1-5 (R-CHOP) every 21 days for 4 cycles. PET scan and conventional restaging occurred between days 14-20 of cycle 3. Patients who were PET negative after 3 cycles of R-CHOP received 2 more cycles of R-CHOP (6 cycles in total). | 63 |
| No Mid-Treatment PET Initially, patients received Rituximab 375 mg/m2 IV Day 1, Cyclophosphamide 750 mg/m2 IV Day 1, Vincristine 1.4 mg/m2 (max: 2 mg) IV Day 1, Doxorubicin 50 mg/m2 IV Day 1, and Prednisone 100 mg/m2 PO Days 1-5 (R-CHOP) every 21 days for 4 cycles. PET scan and conventional restaging occurred between days 14-20 of cycle 3. Patients who did not have mid-treatment PET scan for any reasons came off study and continued to be followed up for disease progression and survival. | 4 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Step 1 (R-CHOP X 3 Cycles) | Adverse Event | 0 | 0 | 1 |
| Step 1 (R-CHOP X 3 Cycles) | Did not start treatment | 0 | 0 | 1 |
| Step 1 (R-CHOP X 3 Cycles) | Lost to Follow-up | 0 | 0 | 1 |
| Step 1 (R-CHOP X 3 Cycles) | Other complicating disease | 0 | 0 | 1 |
| Step 1 (R-CHOP X 3 Cycles) | Patient ineligible | 4 | 14 | 1 |
| Step 1 (R-CHOP X 3 Cycles) | Withdrawal by Subject | 0 | 0 | 1 |
| Step 2 (Tx Based on Mid-treatment PET) | Adverse Event | 1 | 0 | 0 |
| Step 2 (Tx Based on Mid-treatment PET) | Alternative therapy | 0 | 1 | 0 |
| Step 2 (Tx Based on Mid-treatment PET) | Death | 0 | 1 | 0 |
| Step 2 (Tx Based on Mid-treatment PET) | Lack of Efficacy | 0 | 1 | 0 |
| Step 2 (Tx Based on Mid-treatment PET) | Other complicating disease | 1 | 0 | 0 |
| Step 2 (Tx Based on Mid-treatment PET) | Patient ineligible | 4 | 15 | 0 |
| Step 2 (Tx Based on Mid-treatment PET) | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Group I (PET Positive) | Group II (PET Negative) | No Mid-Treatment PET | Total |
|---|---|---|---|---|
| Age, Continuous | 61 years | 63 years | 54 years | 62 years |
| Sex: Female, Male Female | 4 Participants | 28 Participants | 2 Participants | 34 Participants |
| Sex: Female, Male Male | 9 Participants | 35 Participants | 2 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 97 / 99 | 17 / 17 | 75 / 76 |
| serious Total, serious adverse events | 58 / 99 | 17 / 17 | 25 / 76 |
Outcome results
Primary
2-year Progression-Free Survival (PFS)
2-year progression-free survival is defined as the probability of patients who remain alive and progression free at 2 years from study entry. The method of Kaplan and Meier (1958) was used to estimate PFS.
Time frame: Assessed every 4 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from study entry, then every 12 months if patient is 5-10 years from study entry.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I (PET Negative) | 2-year Progression-Free Survival (PFS) | 0.76 probability |
| Group II (PET Positive) | 2-year Progression-Free Survival (PFS) | 0.42 probability |
Secondary
5-year Overall Survival
5-year overall survival is defined as the probability of patients who remain alive at 5 years from study entry. The method of Kaplan and Meier (1958) was used to estimate overall survival.
Time frame: Every 4 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from study entry, then every 12 months if patient is 5-10 years from study entry.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I (PET Negative) | 5-year Overall Survival | 0.77 probability |
| Group II (PET Positive) | 5-year Overall Survival | 0.69 probability |