High-Dose Y-90-Ibritumomab Tiuxetan Added to Reduced-Intensity Allogeneic Stem Cell Transplant Regimen for Relapsed or Refractory Aggressive B-Cell Lymphoma

Study Overview
=================
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.

Official Title
-----------------
A Phase II Trial of High-Dose 90Y-Ibritumomab Tiuxetan (Anti-CD20) Followed by Fludarabine and Low-Dose Total Body Irradiation and HLA-Matched Allogeneic Hematopoietic Transplantation for Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma

Conditions
-----------------
Recurrent Burkitt Lymphoma, Post-Transplant Lymphoproliferative Disorder, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent B-Cell Non-Hodgkin Lymphoma, Refractory B-Cell Non-Hodgkin Lymphoma, Refractory Burkitt Lymphoma, Refractory Diffuse Large B-Cell Lymphoma

Intervention / Treatment
-----------------
* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Drug: Cyclosporine
* Drug: Fludarabine Phosphate
* Radiation: Indium In-111 Ibritumomab Tiuxetan
* Drug: Mycophenolate Mofetil
* Other: Pharmacological Study
* Biological: Rituximab
* Radiation: Total-Body Irradiation
* Radiation: Yttrium Y-90 Ibritumomab Tiuxetan
* Drug: Fludarabine


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (radiolabeled antibody, TBI, allogeneic PBSCT)<br>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). | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic PBSCT (infusion of donor stem cells via central catheter)<br>* Other names: HSCT;Drug: Cyclosporine<br>* Given PO<br>* Other names: SangCya;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Radiation: Indium In-111 Ibritumomab Tiuxetan<br>* Given IV<br>* Other names: indium In 111 ibritumomab tiuxetan;Drug: Mycophenolate Mofetil<br>* Given PO<br>* Other names: MMF;Other: Pharmacological Study<br>* Correlative studies<br>Biological: Rituximab<br>* Given IV prior to yttrium Y 90 ibritumomab tiuxetan<br>* Other names: RTXM83;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>* Other names: Whole Body Irradiation;Radiation: Yttrium Y-90 Ibritumomab Tiuxetan<br>* Given IV<br>* Other names: yttrium Y90 ibritumomab tiuxetan;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Neutrophil Count (ANC) Engraftment | The median time in days to achieve ANC recovery defined as ANC>500uL. | Up to day 100 | 
| Overall Survival |  | Up to 2 years post transplant | 
| Response Rates | Response is defined as having achieved a Partial Response or better. | Day 100 | 
| Treatment-related Mortality | Defined as death in the absence of progressive lymphoma that can be possibly, probably, or definitely attributed to the radioimmunotherapy. | Day 100 | 
| Platelet Engraftment | The median time in days to achieve platelet recovery as defined as platelet >20,000uL. | Up to day 100 | 
| Hematopoietic Toxicity | Clinical sequelae due to hematopoietic toxicity as defined by incidences of neutropenic fever and bleeding. | Up to day 100 |