Recurrent Diffuse Large B-Cell Lymphoma, Refractory Diffuse Large B-Cell Lymphoma
Conditions
Keywords
Non-Hodgkin's lymphoma, autologous stem cell transplantation, radioimmunotherapy, Zevalin, Lymphoma, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Non-Hodgkin, Immune System Diseases, Immunoproliferative Disorders, Lymphatic Diseases, Lymphoma, B-Cell, Lymphoproliferative Disorders, Neoplasms, Neoplasms by Histologic Type, Antibodies, Monoclonal, Immunologic Factors, Pharmacologic Actions, Physiological Effects of Drugs
Brief summary
This randomized phase III trial studies 90-yttrium ibritumomab tiuxetan and combination chemotherapy compared with combination chemotherapy alone before stem cell transplant in treating patients with diffuse large b-cell non-Hodgkin lymphoma that has returned after a period of improvement. Radioactive substances linked to monoclonal antibodies, such as 90-yttrium ibritumomab tiuxetan, can bind to cancer cells and give off radiation which may help kill cancer cells. Drugs used in chemotherapy, such as carmustine, etoposide phosphate, cytarabine, and melphalan (BEAM), work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether 90-yttrium ibritumomab tiuxetan and BEAM before a stem cell transplant are more effective than BEAM alone in treating patients with diffuse large b-cell non-Hodgkin lymphoma.
Detailed description
PRIMARY OBJECTIVES: I. To compare overall survival (OS) between the two transplant arms, with at least a two year of follow-up. SECONDARY OBJECTIVES: I. To compare progression-free survival (PFS), complete response (CR) and partial response (PR) proportion at day 100, time to hematopoietic recovery, incidence of infection, grade III-IV toxicities, treatment-related mortality, incidence of myelodysplastic syndrome (MDS), and secondary acute myelogenous leukemia (AML). OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive rituximab intravenously (IV) on days -21 and -14, and 90-yttrium ibritumomab tiuxetan IV on day -14. Patients also receive BEAM comprising carmustine IV over 4 hours on day -6; cytarabine IV over 2 hours twice daily (BID) on days -5 to -2; etoposide IV over 1 hour BID or once daily (QD) on days -5 to -2; and melphalan IV on day -1. Patients then undergo peripheral blood stem cell (PBSC) transplant on day 0. ARM II: Patients receive BEAM as in Arm I and undergo PBSC transplant on day 0. After completion of study treatment, patients are followed up weekly for 30 days, 100 days, 6 months, 1 year, every 3 months for 1 year, and then annually for 3 years.
Interventions
RADIATION90-Yttrium Ibritumomab tiuxetan
0.4 mCi/kg given IV
DRUGCarmustine
Given IV
DRUGEtoposide
Given IV
DRUGCytarabine
Given IV
DRUGMelphalan
Given IV
Autologous Hematopoietic Stem Cell Transplantation (ASCT)
BIOLOGICALRituximab
Given IV
Sponsors
National Cancer Institute (NCI)
City of Hope Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Patients with CD20 positive diffuse large B-cell lymphoma as confirmed by a pathological biopsy report. 2. Patients who are candidates for autologous stem-cell transplantation due to primary refractory or first relapse of disease. 3. Patients must have chemo-sensitive disease achieving at least partial response (Cheson 2007 criteria) to last chemotherapy. 4. Patients with adequate autologous stem cell collection for transplantation (target \>= 2.5 x 10\^6 CD34+ cells/kg). 5. Patients must sign written informed consent. 6. Adequate birth control in fertile patients. 7. All prior chemotherapy completed at least three weeks before study treatment. 8. Marrow involvement less than 25% at transplantation, no limitation on blood counts (low platelet count allowed). 9. Negative HIV antibody.
Exclusion criteria
1. Chemo-refractory disease as determined by less than partial response (Cheson 2007 Criteria) to last chemotherapy. 2. Two or more relapses after initial response to induction chemotherapy. 3. High-grade transformation from earlier diagnosis of low-grade lymphoma. Patients with De Novo Transformed DLBCL, defined as DLBCL only on lymph node biopsy and a discordant marrow with para-trabecular small cells at first diagnosis of lymphoma, are eligible if adherent to all other selection criteria. 4. Bilirubin \> 3.0 mg/dl, transaminases \> 3 times upper normal limit. 5. Creatinine \> 2.0 mg/dl. 6. KPS \< 70. 7. Uncontrolled infection. 8. Pregnancy or lactation. 9. Abnormal lung diffusion capacity (DLCO \< 40% predicted). 10. Severe cardiovascular disease; New York Heart Association (NYHA) Functional Classification ≥2. 11. Active CNS disease involvement. 12. Presence of any other malignancy or history of prior malignancy within 5 years of study entry. Within 5 years, patients treated for Stage I or II cancers are eligible provided they have a life expectancy \> 5 years in relation to this prior malignance. The 5-year exclusion rule does not apply to-non melanoma skin tumors and in situ cervical cancer. 13. Pleural effusion or ascites \> 1 liter. 14. Known hypersensitivity to rituximab. 15. Psychiatric conditions/disease that impair the ability to give informed consent or to adequately co-operate. 16. Prior radioimmunotherapy. 17. Prior autologous or allogeneic HSCT. 18. Active evidence of Hepatitis B or C infection; Hepatitis B surface antigen positive. 19. Patients who have had prior radiation to the lung will be excluded from the study, although mediastinal irradiation will be permitted if minimal lung is in the treatment volume. 20. Patients who have received \>500cGy radiation to the kidneys will be excluded from the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Measured from randomization to date of death or last follow up date, whichever occurs first, for up to 5 years post randomization | Survival estimates will be calculated using the Kaplan-Meier method |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression | Up to 5 years | Time-to-event will be measured from the date of ASCT. |
| Number of Patients With Complete or Partial Response at Day 30 | Day 0 to Day +30 post-HCT | Definition of disease status is based on the article of Revised Response Criteria for Malignant Lymphoma Response Definitions for Clinical Trials (Cheson et al, 2007). Tests used for evaluation of disease status would be physical examination, laboratory testing, bone marrow testing, bone marrow biopsy and aspirate, PET scan, and CT scans of neck, chest, abdomen and pelvis as indicated. |
| Time to Neutrophil Engraftment | Day 0 to Day 100 post-HCT | Time to neutrophil engraftment will be compared between treatment arms using a log-rank test, and the cumulative incidence curves will be estimated. |
| Incidence of Infection | Day 0 to Day +100 post-HCT | Microbiologically documented infections will be reported by site of disease, date of onset, severity, and resolution, if any. The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each patient. The proportion of patients developing infections will be compared between treatment arms. |
| Progression-free Survival | Measured from randomization until death, relapse/progression, receipt of anti-lymphoma therapy, or last follow up whichever comes first, for up to 5 years post randomization | Survival estimates will be calculated using the Kaplan-Meier method |
| Cumulative Incidence of Secondary Malignancies | Up to 5 years | Incidence of myelodysplastic syndrome (MDS), and secondary acute Myelogenous leukemia (AML) will be compared between the treatment arms using Gray's test. |
| Time to Platelet Engraftment | Day 0 to Day 100 post-HCT | Time to platelet engraftment will be compared between treatment arms using a log-rank test, and the cumulative incidence curves will be estimated. |
| Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Day -21 to Day +100 post-HCT | Observed toxicities will be summarized in terms of type and severity. In accordance with the secondary study objectives, descriptive analyses on these data will be performed. |
| Cumulative Incidence of New, Abnormal Cytogenetics | Day 0 to Year 5 post-HCT | The cumulative incidence of therapy related new, abnormal cytogenetics will be estimated for both groups taking into account the competing risk of death among patients who do not develop a second malignancy. |
| Incidence of Non-relapse Mortality (NRM) Defined as Death Occurring in a Patient From Causes Other Than Relapse or Progression | From randomization until non-disease related death, or last follow-up, whichever comes first, assessed up to 5 years | The cumulative incidence of NRM will be estimated using the method described by Gooley et al. Differences between cumulative incidence curves in the presence of a competing risk will be tested using the Gray method. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (ZBEAM) Patients receive rituximab IV on days -21 and -14, and 90-yttrium ibritumomab tiuxetan IV on day -14. Patients also receive BEAM comprising carmustine IV over 4 hours on day -6; cytarabine IV over 2 hours BID on days -5 to -2; etoposide IV over 1 hour BID or QD on days -5 to -2; and melphalan IV on day -1. Patients then undergo autologous hematopoietic stem cell transplant on day 0.
90-Yttrium Ibritumomab tiuxetan: 0.4 mCi/kg given IV
Carmustine: Given IV
Etoposide: Given IV
Cytarabine: Given IV
Melphalan: Given IV
Autologous Hematopoietic Stem Cell Transplant: Autologous Hematopoietic Stem Cell Transplantation (ASCT)
Rituximab: Given IV | 2 |
| Arm II (BEAM) Patients receive BEAM comprising carmustine IV over 4 hours on day -6; cytarabine IV over 2 hours BID on days -5 to -2; etoposide IV over 1 hour BID or QD on days -5 to -2; and melphalan IV on day -1. Patients then undergo autologous hematopoietic stem cell transplant on day 0.
Carmustine: Given IV
Etoposide: Given IV
Cytarabine: Given IV
Melphalan: Given IV
Autologous Hematopoietic Stem Cell Transplant: Autologous Hematopoietic Stem Cell Transplantation (ASCT) | 1 |
| Total | 3 |
Baseline characteristics
| Characteristic | Arm II (BEAM) | Arm I (ZBEAM) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Continuous | 48 years | 69 years | 66 years |
| Region of Enrollment United States | 1 participants | 2 participants | 3 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 1 |
| other Total, other adverse events | 2 / 2 | 1 / 1 |
| serious Total, serious adverse events | 0 / 2 | 0 / 1 |
Outcome results
Primary
Overall Survival
Survival estimates will be calculated using the Kaplan-Meier method
Time frame: Measured from randomization to date of death or last follow up date, whichever occurs first, for up to 5 years post randomization
Population: The study was terminated before the data are mature enough to estimate the survival outcome and conduct the test. Therefore, the overall number of participants analyzed is 0 in both groups.
Secondary
Cumulative Incidence of New, Abnormal Cytogenetics
The cumulative incidence of therapy related new, abnormal cytogenetics will be estimated for both groups taking into account the competing risk of death among patients who do not develop a second malignancy.
Time frame: Day 0 to Year 5 post-HCT
Population: The study was terminated before the data are mature enough to estimate the cumulative incidence and conduct the test. Therefore, the overall number of participants analyzed is 0 in both groups.
Secondary
Cumulative Incidence of Secondary Malignancies
Incidence of myelodysplastic syndrome (MDS), and secondary acute Myelogenous leukemia (AML) will be compared between the treatment arms using Gray's test.
Time frame: Up to 5 years
Population: The study was terminated before the data are mature enough to estimate the cumulative incidence and conduct the test. Therefore, the overall number of participants analyzed is 0 in both groups.
Secondary
Incidence of Infection
Microbiologically documented infections will be reported by site of disease, date of onset, severity, and resolution, if any. The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each patient. The proportion of patients developing infections will be compared between treatment arms.
Time frame: Day 0 to Day +100 post-HCT
Population: The study was terminated before the data are mature enough to conduct the test. Therefore, the overall number of participants analyzed is 0 in both groups.
Secondary
Incidence of Non-relapse Mortality (NRM) Defined as Death Occurring in a Patient From Causes Other Than Relapse or Progression
The cumulative incidence of NRM will be estimated using the method described by Gooley et al. Differences between cumulative incidence curves in the presence of a competing risk will be tested using the Gray method.
Time frame: From randomization until non-disease related death, or last follow-up, whichever comes first, assessed up to 5 years
Population: The study was terminated before the data are mature enough to estimate the cumulative incidence and conduct the test. Therefore, the overall number of participants analyzed is 0 in both groups.
Secondary
Number of Patients With Complete or Partial Response at Day 30
Definition of disease status is based on the article of Revised Response Criteria for Malignant Lymphoma Response Definitions for Clinical Trials (Cheson et al, 2007). Tests used for evaluation of disease status would be physical examination, laboratory testing, bone marrow testing, bone marrow biopsy and aspirate, PET scan, and CT scans of neck, chest, abdomen and pelvis as indicated.
Time frame: Day 0 to Day +30 post-HCT
Population: In Arm I (ZBEAM), one patient's disease status at Day 30 is not available. Therefore, the overall number of participants analyzed in Arm I (ZBEAM) is 1.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (ZBEAM) | Number of Patients With Complete or Partial Response at Day 30 | 1 Participants |
| Arm II (BEAM) | Number of Patients With Complete or Partial Response at Day 30 | 1 Participants |
Secondary
Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0
Observed toxicities will be summarized in terms of type and severity. In accordance with the secondary study objectives, descriptive analyses on these data will be performed.
Time frame: Day -21 to Day +100 post-HCT
Population: Number of patients with grade 3, 4 or 5 toxicities in each arm, are reported below.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (ZBEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Anemia | 2 Participants |
| Arm I (ZBEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Febrile neutropenia | 2 Participants |
| Arm I (ZBEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Hyperglycemia | 1 Participants |
| Arm I (ZBEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Hyponatremia | 1 Participants |
| Arm I (ZBEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | INR increased | 1 Participants |
| Arm I (ZBEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Lymphocyte count decreased | 2 Participants |
| Arm I (ZBEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Mucositis oral | 2 Participants |
| Arm I (ZBEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Neutrophil count decreased | 2 Participants |
| Arm I (ZBEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Obesity | 1 Participants |
| Arm I (ZBEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Oral pain | 0 Participants |
| Arm I (ZBEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Pharyngeal mucositis | 0 Participants |
| Arm I (ZBEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Platelet count decreased | 2 Participants |
| Arm I (ZBEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Sore Throat | 0 Participants |
| Arm I (ZBEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | White blood cell decreased | 2 Participants |
| Arm II (BEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Pharyngeal mucositis | 1 Participants |
| Arm II (BEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Anemia | 1 Participants |
| Arm II (BEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Neutrophil count decreased | 1 Participants |
| Arm II (BEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Febrile neutropenia | 1 Participants |
| Arm II (BEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Platelet count decreased | 1 Participants |
| Arm II (BEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Hyperglycemia | 0 Participants |
| Arm II (BEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Obesity | 1 Participants |
| Arm II (BEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Hyponatremia | 0 Participants |
| Arm II (BEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | White blood cell decreased | 1 Participants |
| Arm II (BEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | INR increased | 0 Participants |
| Arm II (BEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Oral pain | 1 Participants |
| Arm II (BEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Lymphocyte count decreased | 1 Participants |
| Arm II (BEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Sore Throat | 1 Participants |
| Arm II (BEAM) | Number of Patients With Grade 3-5 Toxicities Graded by the NCI CTCAE Version 4.0 | Mucositis oral | 1 Participants |
Secondary
Progression-free Survival
Survival estimates will be calculated using the Kaplan-Meier method
Time frame: Measured from randomization until death, relapse/progression, receipt of anti-lymphoma therapy, or last follow up whichever comes first, for up to 5 years post randomization
Population: The study was terminated before the data are mature enough to estimate the survival outcome and conduct the test. Therefore, the overall number of participants analyzed is 0 in both groups.
Secondary
Time to Neutrophil Engraftment
Time to neutrophil engraftment will be compared between treatment arms using a log-rank test, and the cumulative incidence curves will be estimated.
Time frame: Day 0 to Day 100 post-HCT
Population: The study was terminated before the data are mature enough to estimate the cumulative incidence and conduct the test. Therefore, the descriptive analysis was performed. The median time to ANC engraftment and range are reported below.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (ZBEAM) | Time to Neutrophil Engraftment | 11 days |
| Arm II (BEAM) | Time to Neutrophil Engraftment | 10 days |
Secondary
Time to Platelet Engraftment
Time to platelet engraftment will be compared between treatment arms using a log-rank test, and the cumulative incidence curves will be estimated.
Time frame: Day 0 to Day 100 post-HCT
Population: The study was terminated before the data are mature enough to estimate the cumulative incidence and conduct the test. Therefore, the descriptive analysis was performed. The median time to platelet engraftment and range are reported below.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (ZBEAM) | Time to Platelet Engraftment | 22.5 days |
| Arm II (BEAM) | Time to Platelet Engraftment | 26 days |
Secondary
Time to Progression
Time-to-event will be measured from the date of ASCT.
Time frame: Up to 5 years
Population: The study was terminated before the data are mature enough to estimate the cumulative incidence and conduct the test. Therefore, the overall number of participants analyzed is 0 in both groups.