Post-Transplant Lymphoproliferative Disorder, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent B-Cell Non-Hodgkin Lymphoma, Recurrent Burkitt Lymphoma, Refractory B-Cell Non-Hodgkin Lymphoma, Refractory Burkitt Lymphoma, Refractory Diffuse Large B-Cell Lymphoma
Conditions
Brief summary
This phase II trial studies the side effects and how well high-dose yttrium-90 (Y-90)-ibritumomab tiuxetan (anti-cluster of differentiation \[CD\]20) followed by fludarabine phosphate, low-dose total body irradiation (TBI), and donor peripheral blood stem cell transplant (PBSCT) work in treating patients with aggressive B-cell lymphoma that has returned after a period of improvement (relapsed) or has not responded to previous treatment (refractory). Radiolabeled monoclonal antibodies, such as Y-90-ibritumomab tiuxetan, can find cancer cells and carry cancer-killing substances to them with less effect on normal cells. Giving chemotherapy, such as fludarabine phosphate, and TBI before a donor PBSCT helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. However, high-dose radiolabeled antibodies also destroy healthy blood cells in the patient's body. When healthy stem cells from a donor are infused into the patient (stem cell transplant), they may help the patient's body replace these blood cells. Giving high-dose Y-90-ibritumomab tiuxetan followed by fludarabine phosphate, TBI, and donor PBSCT may be an effective treatment for patients with B-cell lymphoma.
Detailed description
PRIMARY OBJECTIVES: I. To assess the safety and efficacy of 1.5 mCi/kg (max 120 mCi) 90Y-Ibritumomab tiuxetan (yttrium Y 90 ibritumomab tiuxetan) (anti-CD20) combined with fludarabine (fludarabine phosphate) (30 mg/m\^2 x 3) and 2 gray (Gy) total body irradiation followed by human leukocyte antigens (HLA) matched allogeneic hematopoietic transplantation for patients with relapsed or refractory aggressive B-cell lymphoma. OUTLINE: Beginning 24-48 hours prior to therapy infusion, patients receive rituximab intravenously (IV) over 4-6 hours and then receive a therapy-dose of high-dose yttrium Y 90 ibritumomab tiuxetan IV over 30 minutes on day -14 prior to transplant. Patients also receive fludarabine phosphate IV on days -4 to -2 and undergo TBI followed by allogeneic PBSCT on day 0. Patients also receive cyclosporine orally (PO) twice daily (BID) on days -3 to 56 with taper to day 180 (related donor) or -3 to 100 with taper over 11 weeks (unrelated donor) and mycophenolate mofetil PO BID on days 0-27 (related donor) or PO thrice daily (TID) on days 0-40 with taper to day 96 (unrelated donor). After completion of study treatment and assessments through \ day 100 following transplant, patients are followed up at 1, 3, 6, and 12 months and then annually up to 2 years thereafter.
Interventions
PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic PBSCT (infusion of donor stem cells via central catheter)
DRUGCyclosporine
Given PO
DRUGFludarabine Phosphate
Given IV
RADIATIONIndium In-111 Ibritumomab Tiuxetan
Given IV
DRUGMycophenolate Mofetil
Given PO
OTHERPharmacological Study
Correlative studies
BIOLOGICALRituximab
Given IV prior to yttrium Y 90 ibritumomab tiuxetan
RADIATIONTotal-Body Irradiation
Undergo TBI
RADIATIONYttrium Y-90 Ibritumomab Tiuxetan
Given IV
DRUGFludarabine
Given IV
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have a histologically confirmed diagnosis of aggressive B-cell lymphoma (diffuse large B-cell lymphoma \[DLBCL\], Burkitt lymphoma \[BL\], etc.) expressing the CD20 antigen and have failed at least one prior standard systemic therapy * Patients must have relapsed after high-dose therapy and autologous transplantation or be ineligible for high-dose therapy and autologous transplantation; patients that have failed autologous transplantation are those with persistent disease \> 30 days after transplant; those ineligible for autologous transplant include those with chemoresistant disease (i.e., patients who have not achieved a partial response or better with their most recent chemotherapy regimen), are expected to have a poor outcome from autologous transplant (e.g., DLBCL relapsing within one year of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone \[R-CHOP\]-like chemotherapy, double hit lymphoma, v-myc myelocytomatosis viral oncogene homolog (avian) positive \[MYC+\] lymphoma, persistent positron emission tomography \[PET\] positivity after chemotherapy), are unable to collect sufficient or tumor-free autologous stem cells per Seattle Cancer Care Alliance (SCCA) standard practice, are unable to tolerate the high-dose autologous conditioning regimens, or who refuse a high-dose autologous transplant regimen * Creatinine (Cr) \< 2.0 * Bilirubin \< 1.5 mg/dL with the exception of patients thought to have Gilbert's syndrome, who may have a total bilirubin above 1.5 mg/dL * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \< 3 x upper limit of normal (ULN) * Patients must have an expected survival without treatment of \> 60 days and must be free of major infection including human immunodeficiency virus (HIV) * Patients must have an HLA-identical related or HLA-matched unrelated donor
Exclusion criteria
* Receipt of systemic anti-lymphoma therapy withinthe following intervals prior to the therapeutic 90Y-ibritumomab tiuxetan dose: * \< 30 days for intravenously-administered cytotoxic chemotherapy and/or monoclonal antibodies * \< 5 half-lives for all other anti-cancer agents (e.g., targeted therapies, corticosteroids, immunomodulatory agents, etc.) * Inability to understand or give an informed consent * Active central nervous system lymphoma * Pregnancy * Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment * Southwest Oncology Group (SWOG)/Eastern Cooperative Oncology Group (ECOG) performance score \>= 2 * High-dose chemotherapy or external beam radiation therapy to lung, liver, or kidneys \> 20 Gy within the previous 100 days prior to therapeutic 90Y-ibritumomab tiuxetan dose * Medical condition that would contraindicate allogeneic transplantation as per standard practice guidelines (e.g., impaired cardiopulmonary function, hepatitis, etc)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 1 year | Based on a one-sample chi-square test with one-sided significance level of five percent. This study will be deemed successful if the 1 year progression-free survival of this highest-risk group of patients is 54% or greater. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 2 years post transplant | — |
| Response Rates | Day 100 | Response is defined as having achieved a Partial Response or better. |
| Absolute Neutrophil Count (ANC) Engraftment | Up to day 100 | The median time in days to achieve ANC recovery defined as ANC\>500uL. |
| Platelet Engraftment | Up to day 100 | The median time in days to achieve platelet recovery as defined as platelet \>20,000uL. |
| Hematopoietic Toxicity | Up to day 100 | Clinical sequelae due to hematopoietic toxicity as defined by incidences of neutropenic fever and bleeding. |
| Treatment-related Mortality | Day 100 | Defined as death in the absence of progressive lymphoma that can be possibly, probably, or definitely attributed to the radioimmunotherapy. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Radiolabeled Antibody, TBI, Allogeneic PBSCT) Beginning 24-48 hours prior to therapy infusion, patients receive rituximab IV over 4-6 hours and then receive a therapy-dose of high-dose yttrium Y 90 ibritumomab tiuxetan IV over 30 minutes on day -14 prior to transplant. Patients also receive fludarabine phosphate IV on days -4 to -2 and undergo TBI followed by allogeneic PBSCT on day 0. Patients also receive cyclosporine PO BID on days -3 to 56 with taper to day 180 (related donor) or -3 to 100 with taper over 11 weeks (unrelated donor) and mycophenolate mofetil PO BID on days 0-27 (related donor) or PO TID on days 0-40 with taper to day 96 (unrelated donor).
Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic PBSCT (infusion of donor stem cells via central catheter)
Cyclosporine: Given PO
Fludarabine Phosphate: Given IV
Indium In-111 Ibritumomab Tiuxetan: Given IV
Mycophenolate Mofetil: Given PO
Pharmacological Study: Correlative studies
Rituximab: Given IV prior to yttrium Y 90 ibritumomab tiuxetan
Total-Body Irradiation: Undergo TBI
Yttrium Y-90 Ibritumomab Tiuxetan: Given IV
Fludarabine: Given IV | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Treatment (Radiolabeled Antibody, TBI, Allogeneic PBSCT) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants |
| Age, Continuous | 52.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 16 Participants |
| Region of Enrollment United States | 20 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 20 |
| other Total, other adverse events | 11 / 20 |
| serious Total, serious adverse events | 11 / 20 |
Outcome results
Primary
Progression-free Survival
Based on a one-sample chi-square test with one-sided significance level of five percent. This study will be deemed successful if the 1 year progression-free survival of this highest-risk group of patients is 54% or greater.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Radiolabeled Antibody, TBI, Allogeneic PBSCT) | Progression-free Survival | 11 Participants |
Secondary
Absolute Neutrophil Count (ANC) Engraftment
The median time in days to achieve ANC recovery defined as ANC\>500uL.
Time frame: Up to day 100
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Radiolabeled Antibody, TBI, Allogeneic PBSCT) | Absolute Neutrophil Count (ANC) Engraftment | 16 Days |
Secondary
Hematopoietic Toxicity
Clinical sequelae due to hematopoietic toxicity as defined by incidences of neutropenic fever and bleeding.
Time frame: Up to day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Radiolabeled Antibody, TBI, Allogeneic PBSCT) | Hematopoietic Toxicity | 5 Incidences |
Secondary
Overall Survival
Time frame: Up to 2 years post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Radiolabeled Antibody, TBI, Allogeneic PBSCT) | Overall Survival | 14 Participants |
Secondary
Platelet Engraftment
The median time in days to achieve platelet recovery as defined as platelet \>20,000uL.
Time frame: Up to day 100
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Radiolabeled Antibody, TBI, Allogeneic PBSCT) | Platelet Engraftment | 9 Days |
Secondary
Response Rates
Response is defined as having achieved a Partial Response or better.
Time frame: Day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Radiolabeled Antibody, TBI, Allogeneic PBSCT) | Response Rates | 16 Participants |
Secondary
Treatment-related Mortality
Defined as death in the absence of progressive lymphoma that can be possibly, probably, or definitely attributed to the radioimmunotherapy.
Time frame: Day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Radiolabeled Antibody, TBI, Allogeneic PBSCT) | Treatment-related Mortality | 1 Participants |