Zevalin Before Stem Cell Transplant in Treating Patients With Non-Hodgkin Lymphoma

Phase 2

Active, not recruiting

• Conditions: Refractory Non Hodgkin Lymphoma; Relapsed Non Hodgkin Lymphoma
• Interventions: Biological: rituximab; Biological: ibritumomab tiuxetan; Biological: anti-thymocyte globulin; Radiation: total nodal irradiation; Procedure: peripheral blood stem cell transplantation; Procedure: allogeneic hematopoietic stem cell transplantation; Drug: cyclosporine; Drug: mycophenolate mofetil

• Registration Number: NCT01811368
• Lead Sponsor: Joseph Tuscano

Brief Summary

This phase II trial studies how well ibritumomab tiuxetan before donor peripheral blood stem cell transplant works in treating patients with relapsed or refractory non-Hodgkin lymphoma. Giving rituximab, antithymocyte globulin, and total-lymphoid irradiation (TLI) before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. Also, radiolabeled monoclonal antibodies, such as ibritumomab tiuxetan, can find cancer cells and carry cancer-killing substances to them without harming normal cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving rituximab, antithymocyte globulin, and TLI before the transplant together with cyclosporine and mycophenolate mofetil after the transplant may stop this from happening. Giving a radiolabeled monoclonal antibody before a donor peripheral blood stem cell transplant may be an effective treatment for non-Hodgkin lymphoma.

Detailed Description

PRIMARY OBJECTIVES:

I. To measure the response conversion (progressive disease \[PD\]/stable disease \[SD\] to partial response \[PR\] and complete response \[CR\]).

SECONDARY OBJECTIVES:

I. To assess the time to engraftment/chimerism. II. To assess the rate of acute and chronic graft-versus-host disease (GVHD). III. To assess toxicity. IV. To determine the overall survival. V. To investigate immune functional and phenotypic analysis. VI. To measure two year event free survival (EFS).

OUTLINE:

CONDITIONING REGIMEN: Patients receive rituximab intravenously (IV) on days -21 and 14, ibritumomab tiuxetan IV on day -14, TLI on days -11 to -7 and -4 to -1, and antithymocyte globulin IV over 4-6 hours on days -11 to -7. Patients also undergo TLI on days -11 to -7 and -4 to -1.

TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant (PBSCT) on day 0.

GVHD PROPHYLAXIS: Patients receive cyclosporine orally (PO) twice daily (BID) or IV on days -3 to 56 with taper to 6 months and mycophenolate mofetil PO BID or IV on days 0-28.

After completion of study treatment, patients are followed up periodically.

Study Timeline

• Study First Submitted: 2013-03-11
• Study Start: 2013-03-12
• Study First Submitted QC: 2013-03-12
• Study First Posted: 2013-03-14
• Status Verified: 2022-11
• Last Update Submitted: 2022-11-28
• Last Update Posted: 2022-11-30
• Primary Completion: 2023-04
• Study Completion: 2023-12

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

• Histologically or cytologically confirmed relapsed cluster of differentiation (CD)20+ non-Hodgkin's lymphoma (NHL) (included in this category are follicular grade I, II, III, marginal zone, mantle cell, diffuse large B cell, small lymphocytic lymphoma) and CD20+ Hodgkin's disease for which standard curative therapy does not exist or is no longer effective
• Patients must have had at least one prior chemotherapeutic regimen; steroids alone and local radiation do not count as regimens; radiotherapy must have been completed at least 4 weeks prior to entry into the study; Rituxan alone does not count as a regimen; however, Bexxar or Zevalin (ibritumomab tiuxetan) do and patients must have completed radioimmunotherapy (RIT) > 12 months prior to enrollment
• Karnofsky performance status of ≥ 60%
• Life expectancy of greater than 3 months
• Total bilirubin within institutional normal limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times institutional upper limit of normal
• Creatinine within normal institutional limits OR creatinine clearance >= 60 ml/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Blood counts no restrictions
• Patients who had anything less than a CR (PR, SD or progressive disease) to their last salvage regimen
• Ability to understand and the willingness to sign a written informed consent document
• Patients fit for non-myeloablative transplantation or best treatment that have an available matched (9/10 or better) related or unrelated donor
• Patients who are considered rituximab refractory (defined as progression within 6 months of their last rituximab-containing regimen)

Exclusion Criteria

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study, rituximab within three months (unless there is evidence of progression), or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier are excluded; this does not include the use of steroids which may continue until two days prior to enrollment

• Patients may not be receiving any other investigational agents

• Failure to obtain insurance/payment authorization for Zevalin, unless the subject agrees to cover the cost

• Patients with known active brain metastases, other neurological disorders/dysfunction or a history of seizure disorder, or other neurological dysfunction should be excluded from this clinical trial because of their poor prognosis

• Patients who have an uncontrolled infection (presumed or documented) with progression after appropriate therapy for greater than one month

• Patients with symptomatic coronary artery disease, uncontrolled congestive heart failure; left ventricular ejection fraction is not required to be measured, however if it is measured, patient is excluded if ejection fraction is < 30%

• Patients requiring supplementary continuous oxygen; diffusion capacity of the lung of carbon monoxide (DLCO) is not required to be measured, however if it is measured, patient is excluded if DLCO < 35%

• Patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function and histology, and for the degree of portal hypertension

• Patients with any of the following liver function abnormalities will be excluded:

  • Fulminant liver failure
  • Cirrhosis with evidence of portal hypertension or bridging fibrosis
  • Alcoholic hepatitis
  • Esophageal varices
  • A history of bleeding esophageal varices
  • Hepatic encephalopathy
  • Uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time
  • Ascites related to portal hypertension
  • Chronic viral hepatitis with total serum bilirubin > 3 mg/dL
  • Symptomatic biliary disease

• Pregnant women are excluded from this study

• Human immunodeficiency virus (HIV)-positive patients

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (ibritumomab tiuxetan, allogeneic PBSCT)	allogeneic hematopoietic stem cell transplantation	CONDITIONING REGIMEN: Patients receive rituximab IV on days -21 and 14, ibritumomab tiuxetan IV on day -14, TLI on days -11 to -7 and -4 to -1, and antithymocyte globulin IV over 4-6 hours on days -11 to -7. Patients also undergo TLI on days -11 to -7 and -4 to -1. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. GVHD PROPHYLAXIS: Patients receive cyclosporine PO BID or IV on days -3 to 56 with taper to 6 months and mycophenolate mofetil PO BID or IV on days 0-28.
Treatment (ibritumomab tiuxetan, allogeneic PBSCT)	anti-thymocyte globulin	CONDITIONING REGIMEN: Patients receive rituximab IV on days -21 and 14, ibritumomab tiuxetan IV on day -14, TLI on days -11 to -7 and -4 to -1, and antithymocyte globulin IV over 4-6 hours on days -11 to -7. Patients also undergo TLI on days -11 to -7 and -4 to -1. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. GVHD PROPHYLAXIS: Patients receive cyclosporine PO BID or IV on days -3 to 56 with taper to 6 months and mycophenolate mofetil PO BID or IV on days 0-28.
Treatment (ibritumomab tiuxetan, allogeneic PBSCT)	ibritumomab tiuxetan	CONDITIONING REGIMEN: Patients receive rituximab IV on days -21 and 14, ibritumomab tiuxetan IV on day -14, TLI on days -11 to -7 and -4 to -1, and antithymocyte globulin IV over 4-6 hours on days -11 to -7. Patients also undergo TLI on days -11 to -7 and -4 to -1. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. GVHD PROPHYLAXIS: Patients receive cyclosporine PO BID or IV on days -3 to 56 with taper to 6 months and mycophenolate mofetil PO BID or IV on days 0-28.
Treatment (ibritumomab tiuxetan, allogeneic PBSCT)	rituximab	CONDITIONING REGIMEN: Patients receive rituximab IV on days -21 and 14, ibritumomab tiuxetan IV on day -14, TLI on days -11 to -7 and -4 to -1, and antithymocyte globulin IV over 4-6 hours on days -11 to -7. Patients also undergo TLI on days -11 to -7 and -4 to -1. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. GVHD PROPHYLAXIS: Patients receive cyclosporine PO BID or IV on days -3 to 56 with taper to 6 months and mycophenolate mofetil PO BID or IV on days 0-28.
Treatment (ibritumomab tiuxetan, allogeneic PBSCT)	total nodal irradiation	CONDITIONING REGIMEN: Patients receive rituximab IV on days -21 and 14, ibritumomab tiuxetan IV on day -14, TLI on days -11 to -7 and -4 to -1, and antithymocyte globulin IV over 4-6 hours on days -11 to -7. Patients also undergo TLI on days -11 to -7 and -4 to -1. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. GVHD PROPHYLAXIS: Patients receive cyclosporine PO BID or IV on days -3 to 56 with taper to 6 months and mycophenolate mofetil PO BID or IV on days 0-28.
Treatment (ibritumomab tiuxetan, allogeneic PBSCT)	peripheral blood stem cell transplantation	CONDITIONING REGIMEN: Patients receive rituximab IV on days -21 and 14, ibritumomab tiuxetan IV on day -14, TLI on days -11 to -7 and -4 to -1, and antithymocyte globulin IV over 4-6 hours on days -11 to -7. Patients also undergo TLI on days -11 to -7 and -4 to -1. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. GVHD PROPHYLAXIS: Patients receive cyclosporine PO BID or IV on days -3 to 56 with taper to 6 months and mycophenolate mofetil PO BID or IV on days 0-28.
Treatment (ibritumomab tiuxetan, allogeneic PBSCT)	cyclosporine	CONDITIONING REGIMEN: Patients receive rituximab IV on days -21 and 14, ibritumomab tiuxetan IV on day -14, TLI on days -11 to -7 and -4 to -1, and antithymocyte globulin IV over 4-6 hours on days -11 to -7. Patients also undergo TLI on days -11 to -7 and -4 to -1. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. GVHD PROPHYLAXIS: Patients receive cyclosporine PO BID or IV on days -3 to 56 with taper to 6 months and mycophenolate mofetil PO BID or IV on days 0-28.
Treatment (ibritumomab tiuxetan, allogeneic PBSCT)	mycophenolate mofetil	CONDITIONING REGIMEN: Patients receive rituximab IV on days -21 and 14, ibritumomab tiuxetan IV on day -14, TLI on days -11 to -7 and -4 to -1, and antithymocyte globulin IV over 4-6 hours on days -11 to -7. Patients also undergo TLI on days -11 to -7 and -4 to -1. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. GVHD PROPHYLAXIS: Patients receive cyclosporine PO BID or IV on days -3 to 56 with taper to 6 months and mycophenolate mofetil PO BID or IV on days 0-28.

Primary Outcome Measures

Name	Time	Method
Response conversion rate (PD/SD to PR and CR)	Up to 60 days post-transplant	Calculated along with 95% confidence intervals (CI). Logistic regression will be used to assess the impact of patient characteristics (e.g., low/high lactate dehydrogenase isoenzyme-3 \[LDH\] or immunologic correlates) on the response conversion rate.

Secondary Outcome Measures

Name	Time	Method
Time to engraftment/chimerism	Up to 3 years	Estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups of patients will be made using the logrank test. Cox (proportional hazards) regression will be used to evaluate multivariable predictive models of time-to-event outcomes when proper.
Toxicities	Up to day 730	Toxicities as measured by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v4.0
Rate of acute GVHD	Up to day 730
Rate of chronic GVHD	Up to day 730
EFS	2 years	Comparison of time-to-event endpoints by important subgroups of patients will be made using the logrank test. Cox (proportional hazards) regression will be used to evaluate multivariable predictive models of time-to-event outcomes when proper.
Overall survival	Up to day 730	Estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups of patients will be made using the logrank test. Cox (proportional hazards) regression will be used to evaluate multivariable predictive models of time-to-event outcomes when proper.

Trial Locations

Locations (1)

University of California Davis; 🇺🇸 Sacramento, California, United States