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: Radiolabeled monoclonal antibodies, such as iodine I 131 tositumomab, can find cancer cells and carry cancer-killing substances to them without harming normal cells. 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, such as cyclophosphamide, doxorubicin, vincristine, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving a radiolabeled monoclonal antibody together with rituximab and combination chemotherapy may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving iodine I 131 tositumomab together with rituximab and combination chemotherapy works in treating older patients with stage II, stage III, or stage IV B-cell non-Hodgkin's lymphoma.
Detailed description
OBJECTIVES: * Determine the 2-year progression-free survival of older patients with previously untreated bulky stage II or stage III or IV diffuse large B-cell non-Hodgkin's lymphoma treated with iodine I 131 tositumomab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. * Determine the response rate (partial response, complete unconfirmed response, and complete response) in patients treated with this regimen. * Determine the 2-year progression-free survival and response rate (partial response, complete unconfirmed response, and complete response) in B-cell lymphoma 2 (BCL-2) positive patients treated with this regimen. OUTLINE: This is a multicenter study. * Rituximab and chemotherapy: Patients receive R-CHOP comprising rituximab IV over 6 hours; cyclophosphamide IV over 15-45 minutes; doxorubicin IV over 5-20 minutes; and vincristine IV over 5-15 minutes on day 1 and oral prednisone on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo a restaging evaluation. Patients without progressive disease receive CHOP chemotherapy comprising cyclophosphamide, doxorubicin, vincristine, and prednisone as outlined above. Treatment with CHOP chemotherapy repeats every 21 days for 2 courses. * Radiolabeled monoclonal antibody therapy: Approximately 4-8 weeks after completion of chemotherapy, patients receive tositumomab IV over 1 hour followed by a dosimetric dose of iodine I 131 tositumomab IV over 20 minutes. Patients then undergo gamma scans over a 1-week period in order to determine the correct treatment dose of iodine I 131 tositumomab. No more than 2 weeks after administration of the dosimetric dose, patients receive tositumomab IV over 1 hour followed by a treatment dose of iodine I 131 tositumomab IV over 20 minutes. After completion of study treatment, patients are followed periodically for up to 5 years. PROJECTED ACCRUAL: A total of 80 patients will be accrued for this study within 15 months.
Interventions
BIOLOGICALrituximab
DRUGcyclophosphamide
DRUGdoxorubicin hydrochloride
DRUGprednisone
DRUGvincristine sulfate
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 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of diffuse large B-cell non-Hodgkin's lymphoma, meeting 1 of the following stage criteria: * Bulky stage II disease * Stage III disease * Stage IV disease * Confirmed cluster of differentiation antigen 20 (CD20) antigen-positive disease * Bidimensionally measurable disease * Less than 20,000/mcL circulating lymphoid cells on white blood cell (WBC) differential count * Adequate sections AND a paraffin block OR ≥ 10 unstained sections from the original diagnostic specimen available * Needle aspiration or cytology are not considered adequate * No clinical evidence of central nervous system (CNS) involvement by lymphoma * No prior diagnosis of indolent lymphoma * No histologic transformation PATIENT CHARACTERISTICS: Performance status * Zubrod 0-2 Life expectancy * Not specified Hematopoietic * See Disease Characteristics Hepatic * Not specified Renal * Not specified Cardiovascular * Ejection fraction ≥ 45% by multiple gated acquisition scan (MUGA) OR * No significant abnormalities by echocardiogram Pulmonary * No requirement for continuous supplemental oxygen Other * Fertile patients must use effective contraception during and for 6 months after completion of study treatment * No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, stage I or II cancer in complete remission, or carcinoma in situ of the cervix * No known HIV positivity PRIOR CONCURRENT THERAPY: Biologic therapy * No prior antibody therapy for lymphoma Chemotherapy * No prior chemotherapy for lymphoma Endocrine therapy * Not specified Radiotherapy * No prior radiotherapy for lymphoma Surgery * No prior solid organ transplantation Other * Concurrent enrollment on protocol SWOG-8947 (lymphoma serum repository) or protocol SWOG-8819 (lymphoma tissue repository) is encouraged
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) at 2 Years | 0-2 years | Clinical responses were evaluated according to International Workshop NHL criteria (Cheson et al, 1999). Progression disease was defined as if a (CR, CRU) was not achieved at a previous assessment, a 50% increase in the SPD of target measurable lesions over the smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline. Appearance of a new lesion/site. Unequivocal progression of non-measurable disease in the opinion of the treating physician (an explanation must be provided). Death due to disease without prior documentation of progression. PFS is measured from date of registration to date of first observation of progressive disease, or death due to any cause. Patients last known to be alive and progression-free are censored at date of last contact. |
| Response Rate (Complete, Complete Unconfirmed, and Partial) | 6 months | Complete Response(CR) is a complete disappearance of all disease with the exception of nodes. No new lesions. previously enlarged organs must have regressed and not be palpable. Bone marrow(BM) must be negative if positive at baseline. Normalization of markers. CR Unconfirmed (CRU) does not qualify for CR above, due to a residual nodal mass or an indeterminate BM. Partial Response(PR) is a 50% decrease in the sum of products of greatest diameters (SPD) for up to 6 identified dominant lesions, including spleenic and hepatic nodules from baseline. No new lesions and no increase in the size of liver, spleen or other nodes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | 6 months (assessed at the end of each cycle of chemotherapy for 8 cycles (1 cycle= 21 days), at restaging, and at the end of each radiolabeled antibody treatment) | Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| R-CHOP + I-131-tositumomab Patients receive cyclophosphamide 750 mg/m\^2 IV over 15 minutes, doxorubicin 50 mg/m\^2 IV, and vincristine IV on days 1, 22, 43, 64, 85, 106, 127, and 148. Patients also receive oral prednisone 100 mg daily on days 1-5, 22-26, 43-47, 64-68, 85-89, 106-110, 127-131, and 148-152; rituximab 375 mg/m\^2 IV on days 1, 22, 43, 64, 85, and 106; unlabeled anti-B1 antibody 450 mg/m\^2 IV and dosimetric dose 35 mg IV over 20 minutes on day 170, and unlabeled anti-B1 antibody 450 mg IV and therapeutic dose 35mg IV over 20 minutes on day 177 | 84 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 7 |
| Overall Study | Death | 3 |
| Overall Study | Ineligible | 2 |
| Overall Study | Other - not protocol specified | 7 |
| Overall Study | Progression/relapse | 4 |
| Overall Study | Refusal Unrelated to Adverse Event | 7 |
Baseline characteristics
| Characteristic | R-CHOP + I-131-tositumomab |
|---|---|
| Age, Continuous | 63.8 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 65 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 16 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 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 | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 78 Participants |
| Sex: Female, Male Female | 45 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 84 / 84 |
| serious Total, serious adverse events | 8 / 84 |
Outcome results
Primary
Progression-free Survival (PFS) at 2 Years
Clinical responses were evaluated according to International Workshop NHL criteria (Cheson et al, 1999). Progression disease was defined as if a (CR, CRU) was not achieved at a previous assessment, a 50% increase in the SPD of target measurable lesions over the smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline. Appearance of a new lesion/site. Unequivocal progression of non-measurable disease in the opinion of the treating physician (an explanation must be provided). Death due to disease without prior documentation of progression. PFS is measured from date of registration to date of first observation of progressive disease, or death due to any cause. Patients last known to be alive and progression-free are censored at date of last contact.
Time frame: 0-2 years
Population: All eligible patients who started treatment were included in the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| R-CHOP + I-131-tositumomab | Progression-free Survival (PFS) at 2 Years | 69 percentage of participants |
Primary
Response Rate (Complete, Complete Unconfirmed, and Partial)
Complete Response(CR) is a complete disappearance of all disease with the exception of nodes. No new lesions. previously enlarged organs must have regressed and not be palpable. Bone marrow(BM) must be negative if positive at baseline. Normalization of markers. CR Unconfirmed (CRU) does not qualify for CR above, due to a residual nodal mass or an indeterminate BM. Partial Response(PR) is a 50% decrease in the sum of products of greatest diameters (SPD) for up to 6 identified dominant lesions, including spleenic and hepatic nodules from baseline. No new lesions and no increase in the size of liver, spleen or other nodes.
Time frame: 6 months
Population: All eligible patients who started treatment were included in the analysis
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| R-CHOP + I-131-tositumomab | Response Rate (Complete, Complete Unconfirmed, and Partial) | Partial Response | 21 participants |
| R-CHOP + I-131-tositumomab | Response Rate (Complete, Complete Unconfirmed, and Partial) | Confirmed Response | 41 participants |
| R-CHOP + I-131-tositumomab | Response Rate (Complete, Complete Unconfirmed, and Partial) | Unconfirmed Response | 10 participants |
| R-CHOP + I-131-tositumomab | Response Rate (Complete, Complete Unconfirmed, and Partial) | No Response | 12 participants |
Secondary
Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug
Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal.
Time frame: 6 months (assessed at the end of each cycle of chemotherapy for 8 cycles (1 cycle= 21 days), at restaging, and at the end of each radiolabeled antibody treatment)
Population: Eligible patients who had received any treatment were included in the adverse event summaries. Any CTCAE 3.0 event of Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal) which deemed to be related to protocol treatment are included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Uric acid, serum-high (hyperuricemia) | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Vision-blurred vision | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Anorexia | 2 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Calcium, serum-low (hypocalcemia) | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Cardiac troponin I (cTnI) | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Cardiac-ischemia/infarction | 3 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Constipation | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Cough | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Dehydration | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Dizziness | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Dyspnea (shortness of breath) | 2 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Fatigue (asthenia, lethargy, malaise) | 12 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Febrile neutropenia | 14 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Gastrointestinal-Other (Specify: GI bleed) | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Glucose, serum-high (hyperglycemia) | 5 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Hearing: pts w/o audiogram not enroll monitor prgm | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Hemoglobin | 12 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Hemorrhage, GI - Rectum | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Hemorrhage, GU - Urinary NOS | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Hypotension | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Inf (clin/microbio) w/Gr 3-4 neuts - Blood | 2 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Inf (clin/microbio) w/Gr 3-4 neuts - Skin | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Inf (clin/microbio) w/Gr 3-4 neuts - UTI | 2 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Inf (clin/microbio) w/Gr 3-4 neuts - Upper airway | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Inf w/normal ANC or Gr 1-2 neutrophils - Blood | 2 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Inf w/normal ANC or Gr 1-2 neutrophils - Dental | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Inf w/normal ANC or Gr 1-2 neutrophils - Lung | 2 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Inf w/normal ANC or Gr 1-2 neutrophils - UTI | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Left ventricular systolic dysfunction | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Leukocytes (total WBC) | 47 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Lymphopenia | 39 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Mood alteration - anxiety | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Muscle weakness, not d/t neuropathy - body/general | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Nausea | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Neurology-Other (Specify: restless leg syndrom) | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Neuropathy: motor | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Neuropathy: sensory | 8 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Neutrophils/granulocytes (ANC/AGC) | 55 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Opportunistic inf associated w/gt=Gr 2 lymphopenia | 2 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Pain - Abdomen NOS | 2 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Pain - Back | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Pain - Esophagus | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Pain - Head/headache | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Phosphate, serum-low (hypophosphatemia) | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Platelets | 29 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Pneumonitis/pulmonary infiltrates | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Potassium, serum-low (hypokalemia) | 2 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Renal failure | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Restrictive cardiomyopathy | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | SVT and nodal arrhythmia - Atrial fibrillation | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | SVT and nodal arrhythmia - SVT tachycardia | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Secondary Malignancy-poss rel to cancer Tx | 2 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Sodium, serum-low (hyponatremia) | 1 Participants |
| R-CHOP + I-131-tositumomab | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Thrombosis/thrombus/embolism | 2 Participants |