Anaplastic Large Cell Lymphoma, Cutaneous B-cell Non-Hodgkin Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Splenic Marginal Zone Lymphoma, Waldenström Macroglobulinemia
Conditions
Brief summary
This phase II trial is studying how well giving iodine I 131 tositumomab together with etoposide and cyclophosphamide followed by autologous stem cell transplant works in treating patients with relapsed or refractory non-Hodgkin's lymphoma. Radiolabeled monoclonal antibodies, such as iodine I 131 tositumomab, can find cancer cells and deliver radioactive cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as etoposide and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Combining a radiolabeled monoclonal antibody with combination chemotherapy before autologous stem cell transplant may kill more cancer cells
Detailed description
PRIMARY OBJECTIVES: I. To assess the progression-free survival of patients receiving 131 I labeled tositumomab antibody, etoposide (VP-16) and cyclophosphamide (CY) followed by autologous transplantation. II. To examine the potential efficacy of 131 I labeled tositumomab antibody, etoposide (VP-16) and cyclophosphamide (CY) followed by autologous transplantation. SECONDARY OBJECTIVES: I. To assess the overall survival of patients receiving 131 I labeled tositumomab antibody, etoposide (VP-16) and cyclophosphamide (CY) followed by autologous transplantation. II. To evaluate the toxicity and tolerability of the above therapy. OUTLINE: RADIOIMMUNOTHERAPY: Patients receive a test dose of iodine I 131 tositumomab intravenously (IV) on day -24 to determine biodistribution. Patients then receive therapeutic iodine I 131 tositumomab IV over approximately 40-60 minutes on day -14 and are entered into radiation isolation until day -4. CHEMOTHERAPY: Patients receive etoposide IV on day -4 and cyclophosphamide IV on day -2. AUTOLOGOUS STEM CELL TRANSPLANTATION: Patients undergo autologous peripheral blood stem cell transplant on day 0. After completion of study treatment, patients are followed at 1, 3, 6, and 12 months and then annually thereafter.
Interventions
DRUGcyclophosphamide
Given IV
DRUGetoposide
Given IV
RADIATIONiodine I 131 tositumomab
Given IV
PROCEDUREquality-of-life assessment
Ancillary study
PROCEDUREperipheral blood stem cell transplantation
Undergo ASCT given via central catheter
Sponsors
National Cancer Institute (NCI)
Fred Hutchinson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have a histologically confirmed diagnosis of lymphoma expressing the cluster of differentiation (CD)20 antigen and generally must have failed at least one prior standard systemic therapy; the exception will be mantle cell lymphoma (MCL) patients, who may be enrolled while in first complete remission (CR) in accordance with current transplant standard of care for these patients * Note: Patients with clinically non-transformed follicular lymphomas do not require repeat biopsies for immunophenotyping since these tumors are uniformly reactive with the tositumomab antibody * Patients must have tumor burdens \< 500cc by computed tomography (CT) or magnetic resonance (MRI) volumetric measurements and must not have splenomegaly at the time of enrollment; splenomegaly will be defined as a spleen volume \> 2 standard deviations of the mean spleen volume to body weight ratio (mean = 3.84 cc/kg, SD = 1.53 cc/kg); thus, patients with \> 6.9cc/kg will be defined as having splenomegaly; patients with splenomegaly that is thought to be due to G CSF/GM-CSF effect and not due to lymphomatous involvement of the spleen can been deemed eligible with the approval of an investigator * Patients must have normal renal function (creatinine \[Cr\] \< 2.0) * Patients must have normal hepatic function (bilirubin \< 1.5mg/dL), with the exception of patients thought to have Gilbert's syndrome, who may have a total bilirubin above 1.5mg/dL * All patients eligible for therapeutic study must have autologous hematopoietic stem cells (2 x 10\^6 CD34+ cells/kg) harvested and cryopreserved * Patients must have an expected survival of \> 60 days and must be free of major infection
Exclusion criteria
* Circulating anti-mouse antibody (HAMA) * Systemic anti-lymphoma therapy given within 30 days prior to anticipated treatment date * Inability to understand or give an informed consent * Prior radiation \> 20 Gy to any critical normal organ (e.g., lung, liver, spinal cord, or over 25% of red marrow) * Central nervous system lymphoma * Other serious medical conditions considered to represent contraindications to autologous stem cell transplant (ASCT) (e.g., active coronary artery disease, pulmonary dysfunction \[forced expiratory volume in 1 second (FEV1) \< 70% expected, Vital Capacity \< 70% expected, diffusing capacity of the lung for carbon monoxide (DLCO) \< 50%, patient on supplemental oxygen\], AIDS, etc.) * Pregnancy * Prior bone marrow or stem cell transplant * Presence of circulating lymphoma cells by morphology or flow cytometry (\>= 0.1%) at or near the time of peripheral blood stem cell (PBSC) collection if unpurged PBSC are to be used * Southwest Oncology Group (SWOG) performance status \>= 2.0 * Unable to perform self-care during radiation isolation * Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma/well differentiated lymphocytic lymphoma (ineligible because these tumors express very low surface densities of CD20)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | At year 3 | Kaplan-Meier estimate of progression-free survival at 3 years will be used as the primary determinant of potential efficacy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 5 Year Overall Survival | Up to 15 years | Survival will be estimated using the method of Kaplan and Meier. Associated confidence intervals will be provided as part of the analysis. |
| Response Rate | From date of transplant through date of relapse/progression or death, assessed up to 15 years | Response rates will be estimated as the percentage of patients |
| Toxicity as Assessed by Common Terminology Criteria (CTC) v 2.0 | From date of first exposure to study drug, through date of relapse/progression or other significant medical event confounding further assessment, assessed up to 15 years | Grade 3-4 Bearman non-hematologic toxicity will be carefully monitored throughout this study. The protocol will be terminated due to safety concerns if there exists sufficient evidence suggesting that the true rate of grade 3-4 nonhematologic toxicity exceeds 25%. All patients, regardless of histology, will be evaluated together for purposes of toxicity. Sufficient evidence will be taken to be a lower limit to the appropriate 90% one-sided confidence interval in excess of 25% |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Radio Labeled Monoclonal Antibody, Chemotherapy) RADIOIMMUNOTHERAPY: Patients receive a test dose of iodine I 131 tositumomab IV on day -24 to determine biodistribution. Patients then receive therapeutic iodine I 131 tositumomab IV over approximately 40-60 minutes on day -14 and are entered into radiation isolation until day -4.
CHEMOTHERAPY: Patients receive etoposide IV on day -4 and cyclophosphamide IV on day -2.
AUTOLOGOUS STEM CELL TRANSPLANTATION: Patients undergo autologous peripheral blood stem cell transplantation on day 0.
cyclophosphamide: Given IV
etoposide: Given IV
iodine I 131 tositumomab: Given IV
quality-of-life assessment: Ancillary study
peripheral blood stem cell transplantation: Undergo ASCT given via central catheter | 111 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Eligibility requirement not met - HAMA+ | 1 |
| Overall Study | Eligibility requirement not met-low CD20 | 1 |
| Overall Study | Rapid disease progression | 2 |
Baseline characteristics
| Characteristic | Treatment (Radio Labeled Monoclonal Antibody, Chemotherapy) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 111 Participants |
| Age, Continuous | 52.3 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 103 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 6 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 | 2 Participants |
| Race (NIH/OMB) White | 101 Participants |
| Region of Enrollment United States | 111 participants |
| Sex: Female, Male Female | 35 Participants |
| Sex: Female, Male Male | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 107 |
| serious Total, serious adverse events | 9 / 107 |
Outcome results
Primary
Progression-free Survival
Kaplan-Meier estimate of progression-free survival at 3 years will be used as the primary determinant of potential efficacy.
Time frame: At year 3
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Radio Labeled Monoclonal Antibody, Chemotherapy) | Progression-free Survival | 56 percentage of participants |
Secondary
5 Year Overall Survival
Survival will be estimated using the method of Kaplan and Meier. Associated confidence intervals will be provided as part of the analysis.
Time frame: Up to 15 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Radio Labeled Monoclonal Antibody, Chemotherapy) | 5 Year Overall Survival | 72 percentage of participants |
Secondary
Response Rate
Response rates will be estimated as the percentage of patients
Time frame: From date of transplant through date of relapse/progression or death, assessed up to 15 years
Population: Percentage of patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Radio Labeled Monoclonal Antibody, Chemotherapy) | Response Rate | 41.4 percentage of participants |
Secondary
Toxicity as Assessed by Common Terminology Criteria (CTC) v 2.0
Grade 3-4 Bearman non-hematologic toxicity will be carefully monitored throughout this study. The protocol will be terminated due to safety concerns if there exists sufficient evidence suggesting that the true rate of grade 3-4 nonhematologic toxicity exceeds 25%. All patients, regardless of histology, will be evaluated together for purposes of toxicity. Sufficient evidence will be taken to be a lower limit to the appropriate 90% one-sided confidence interval in excess of 25%
Time frame: From date of first exposure to study drug, through date of relapse/progression or other significant medical event confounding further assessment, assessed up to 15 years
Population: Number of Grade 3-4 toxicities.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Radio Labeled Monoclonal Antibody, Chemotherapy) | Toxicity as Assessed by Common Terminology Criteria (CTC) v 2.0 | 9 events |