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

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

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.

Study Overview

• Status: Terminated
• Conditions: Recurrent Adult Diffuse Large Cell Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Recurrent B-Cell Non-Hodgkin Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Post-Transplant Lymphoproliferative Disorder; Recurrent Burkitt Lymphoma; Refractory Burkitt Lymphoma
• Intervention / Treatment: Other: Pharmacological Study; Drug: Fludarabine; Drug: Mycophenolate Mofetil; Radiation: Total-Body Irradiation; Drug: Fludarabine Phosphate; Drug: Cyclosporine; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Radiation: Indium In-111 Ibritumomab Tiuxetan; Biological: Rituximab; Radiation: Yttrium Y-90 Ibritumomab Tiuxetan

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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).

Other: Pharmacological Study; Correlative studies; Drug: Fludarabine; Given IV; Other Names: Fluradosa; 2-Fluorovidarabine; 9-Beta-D-arabinofuranosyl-2-fluoro-9H-purin-6-amine; 118218; 2-Fluoro-9-beta-arabinofuranosyladenine; Drug: Mycophenolate Mofetil; Given PO; Other Names: Cellcept; MMF; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: TBI; Whole Body Irradiation; Whole-Body Irradiation; TOTAL BODY IRRADIATION; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Cyclosporine; Given PO; Other Names: 27-400; Sandimmune; Ciclosporin; CsA; Neoral; Gengraf; Sandimmun; Cyclosporin; Cyclosporin A; OL 27-400; SangCya; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic PBSCT (infusion of donor stem cells via central catheter); Other Names: HSC; HSCT; allogeneic stem cell transplantation; Radiation: Indium In-111 Ibritumomab Tiuxetan; Given IV; Other Names: IDEC In2B8; IDEC-In2B8; In 111 Ibritumomab Tiuxetan; In 111 Zevalin; indium In 111 ibritumomab tiuxetan; Biological: Rituximab; Given IV prior to yttrium Y 90 ibritumomab tiuxetan; Other Names: Rituxan; MabThera; ABP 798; BI 695500; C2B8 Monoclonal Antibody; Chimeric Anti-CD20 Antibody; CT-P10; IDEC-102; IDEC-C2B8; IDEC-C2B8 Monoclonal Antibody; Monoclonal Antibody IDEC-C2B8; PF-05280586; Rituximab Biosimilar ABP 798; Rituximab Biosimilar BI 695500; Rituximab Biosimilar CT-P10; Rituximab Biosimilar PF-05280586; Rituximab Biosimilar RTXM83; Rituximab Biosimilar SAIT101; RTXM83; Radiation: Yttrium Y-90 Ibritumomab Tiuxetan; Given IV; Other Names: IDEC-Y2B8; IDEC-Y2B8 monoclonal antibody; Y 90 Ibritumomab Tiuxetan; Y 90 Zevalin; Yttrium Y 90 Ibritumomab Tiuxetan; yttrium Y90 ibritumomab tiuxetan

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

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2011
• Primary Completion (Actual): May 6, 2020
• Study Completion (Actual): May 6, 2020

Study Registration Dates

• First Submitted: July 26, 2011
• First Submitted That Met QC Criteria: September 14, 2011
• First Posted (Estimate): September 15, 2011

Study Record Updates

• Last Update Posted (Actual): July 20, 2021
• Last Update Submitted That Met QC Criteria: July 16, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Infections; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; DNA Virus Infections; Tumor Virus Infections; Epstein-Barr Virus Infections; Herpesviridae Infections; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Recurrence; Lymphoma, Non-Hodgkin; Burkitt Lymphoma; Lymphoproliferative Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Antibodies; Immunoglobulins; Rituximab; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Fludarabine; Fludarabine phosphate; Mycophenolic Acid; Cyclosporine; Cyclosporins; Vidarabine
• Other Study ID Numbers: 2398.00 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); P01CA044991 (U.S. NIH Grant/Contract); P30CA015704 (U.S. NIH Grant/Contract); NCI-2011-01189 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); RG9213033 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)