Clinical trial NCT00329030: Rituxan/BEAM vs Bexxar/BEAM in Autologous Hematopoietic Stem Cell Transplant for Non-Hodgkin's Lymphoma (BMTCTN0401)
Official title: Phase III Rituxan/BEAM vs. Bexxar/BEAM With Autologous Hematopoietic Stem Cell Transplantation (ASCT) for Persistent or Relapsed Chemotherapy Sensitive Diffuse Large B-cell Non-Hodgkin's Lymphoma (BMTCTN0401)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lymphoma, B-Cell
Lymphoma, Large-Cell, Immunoblastic
Lymphoma, Non-Hodgkin
Keywords: Large B-Cell Lymphoma
Non-Hodgkin's Lymphoma
Lead sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Sponsor class: NIH
Collaborators: name: Blood and Marrow Transplant Clinical Trials Network
name: National Cancer Institute (NCI)
First posted: 2006-05-24
Enrollment: 224
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is designed as a Phase III, multicenter trial, comparing progression-free survival (PFS) after autologous hematopoietic stem cell transplantation using a standard Rituxan plus BEAM transplant regimen versus a regimen adding Bexxar to BEAM.

Detailed description: BACKGROUND:

Bexxar (Tositumomab and Iodine I 131 Tositumomab) is a radioimmunoconjugate with demonstrated anti-lymphoma effects. This drug is indicated for the treatment of patients with CD20 positive, relapsed or refractory, low grade, follicular, or transformed non-Hodgkin's lymphoma, including patients with Rituximab-refractory non-Hodgkin's lymphoma. Bexxar has been used in several Phase I and II transplant trials either alone or in combination with high-dose chemotherapy for the treatment of relapsed non-Hodgkin's lymphoma. The Phase I and II trials combining Bexxar with BEAM and autologous hematopoietic stem cell transplantation demonstrated promising early results with 80% event-free survival in relapsed chemosensitive diffuse large B-cell non-Hodgkin's lymphoma patients. The administration of Rituxan to the mobilization and conditioning regimen is now the standard of care at most transplant centers. Therefore, the primary endpoint of this study will be to compare progression-free survival after autologous hematopoietic stem cell transplantation for chemotherapy-sensitive diffuse large B-cell lymphoma using Rituxan/BEAM versus Bexxar/BEAM for pre-transplant conditioning.

DESIGN NARRATIVE:

All patients will receive induction or salvage chemotherapy as indicated by their clinical circumstance to achieve at least a partial response (as defined in the protocol). There must be 20% or less bone marrow involvement after their most recent salvage therapy.

Mobilization therapy may be employed per institutional guidelines, but all patients must receive one dose of rituxan (375 mg/m\^2) at least within 4 weeks of actual stem cell apheresis. Patients must have an adequate autograft (target of at least 2.0 X 10\^6 CD34+ cells/kg; minimum of more than 1.5 X 106 CD34+ cells/kg) to be eligible for the protocol. Eligible patients will be randomized to receive either: 1) Rituxan plus BEAM, with Rituxan 375 mg/m\^2 IV Days -19 and -12, Carmustine (BCNU) 300 mg/m\^2 Day -6, Etoposide 100 mg/m\^2 Days -5 to -2, Cytarabine 100 mg/m\^2 Days -5 to -2, and Melphalan 140 mg/m\^2 Day -1 followed by ASCT; or, 2) Bexxar/BEAM with the dosimetric dose of 5 mCi Bexxar on Day -19 and the therapeutic dose calculated to administer 75 cGy total body dose (TBD) on Day -12. Patients will then receive BCNU 300 mg/m\^2 Day -6, Etoposide 100 mg/m\^2 Days -5 to -2, Cytarabine 100 mg/m\^2 Days -5 to -2, and Melphalan 140 mg/m\^2 Day -1 followed by ASCT.

Patients will be followed for 2 years post-transplant. Survival data, hematopoiesis data, incidence of infection, mucositis assessment data, immune reconstitution data, and toxicity data will be recorded and reported periodically to the BMT CTN Data Coordinating Center (DCC).

Eligibility criteria: Inclusion Criteria:

* Diagnosis of persistent or recurrent REAL classification diffuse large B-cell lymphoma, composite lymphoma with more than 50% diffuse large B-cell lymphoma, mediastinal B-cell lymphoma
* Demonstration of CD20+ on at least one histologic specimen
* 18-80 years old at time of first registration
* Three or fewer prior regimens of chemotherapy over the entire course of their disease treatment (including one induction chemotherapy and no more than 2 salvage chemotherapies); monoclonal antibody therapy and involved field radiation therapy will not be counted as prior therapies
* Disease status of primary induction failure, first relapse, or second complete remission; all patients must have chemosensitive disease as demonstrated by response to induction or salvage chemotherapy with at least a partial response (as defined in the protocol)
* No more than a 20% bone marrow involvement
* Patients with adequate organ function as measured by:
* Cardiac: American Heart Association Class I: Patients with cardiac disease but without resulting limitation of physical activity; ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain; additionally, patients greater than 60 years of age must have a left ventricular ejection fraction at rest of at least 40% demonstrated by Multi-Gated Acquisition Scan (MUGA)
* Hepatic: Bilirubin less than 2.0 mg/dL (except for isolated hyperbilirubinemia attributed to Gilbert syndrome) and alanine transaminase (ALT) and aspartate transaminase (AST) less than 3x the upper limit of normal
* Renal: Creatinine less than 2.0 mg/dL or creatinine clearance (calculated creatinine clearance is permitted) more than 40 mL/min; no hydronephrosis on CT scan prior to mobilization
* Pulmonary: Carbon Monoxide Diffusing Capacity (DLCO), Volume forcibly exhaled in one second (FEV1), forced vital capacity (FVC) at least 45% of predicted (corrected for hemoglobin)
* Autologous graft with a minimum of at least 1.5 X 10\^6 CD34+ cells/kg (target greater than 2.0 X 10\^6 CD34+ cells/kg. Peripheral blood stem cells (PBSC) are preferred; however, if PBSC mobilization fails, cells can be obtained by institutional practices (in cases where bone marrow will be used for transplantation, the required CD34+ dose does not apply and institutional practice for total nucleated cell dose should be used).
* Initiate conditioning therapy within 3 months of mobilization
* Signed informed consent

Exclusion Criteria:

* Karnofsky performance score less than 70%
* Transformed follicular lymphoma
* Uncontrolled bacterial, viral, or fungal infection (currently taking medication and with progression or no clinical improvement)
* Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ; cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the Medical Monitor or Protocol Chair; cancer treated with curative intent less than 5 years previously will be allowed
* Pregnant (positive β-HCG) or breastfeeding; this patient population is excluded due to the lack of data on the use of Bexxar in patients who are pregnant or breastfeeding
* Seropositivity for HIV; this patient population is excluded due to the lack of data on the use of Bexxar in HIV positive patients and because the treatment regimens are too immunosuppressive for this patient population
* Fertile men or women unwilling to use contraceptive techniques from the time of initiation of mobilization until six-months post-transplant
* Prior autologous or allogeneic hematopoietic stem cell transplantation (HSCT)
* Patients with evidence of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) or abnormal cytogenetic analysis indicative of MDS on the pre-transplant bone marrow examination
* Patients with a prior severe reaction to Rituxan or Filgrastim (G-CSF). Patients with severe reactions to G-CSF that receive pre-medication for control of the reaction are not excluded from study.
* Patients who have received prior radioimmunotherapy
* Patients with known hypersensitivity to murine proteins

Primary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: 1 and 2 years
Secondary outcomes:
measure: Overall Survival
timeFrame: 1 and 2 years
measure: Incidence of Relapse/Progression
timeFrame: 1 and 2 years
measure: Complete Response (CR) and Partial Response (PR) Proportion
timeFrame: Day 100 and 2 years
measure: Platelet Recovery to 20,000 Cells/μL
timeFrame: 100 and 180 days
measure: Hematologic Function
timeFrame: 100 days, 1 year
measure: Incidence of Infection
timeFrame: 1 year
measure: Mucositis Severity
timeFrame: Day 21
measure: Immune Reconstitution
timeFrame: 1 year
measure: Immune Reconstitution of Quantitative Immunoglobulins
timeFrame: 1 year
measure: Treatment-related Mortality (TRM)
timeFrame: 1 and 2 years
measure: Neutrophil Recovery
timeFrame: Day 28 and Day 60
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida College of Medicine (Shands)
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Boise
country: United States
facility: St. Lukes Mountain States Tumor Institute
state: Idaho
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Baltimore
country: United States
facility: University of Maryland Medical Systems/Greenbaum Cancer Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins/SKCCC
state: Maryland
city: Boston
country: United States
facility: Tufts-New England Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University/Barnes Jewish Hospital
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College, The New York Presbyterian Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Hospital at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals of Cleveland/Case Western
state: Ohio
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: Columbia River Oncology Program
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Cancer Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Greenville
country: United States
facility: Cancer Centers of the Carolinas
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: San Antonio
country: United States
facility: Texas Transplant Institute
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Medical School, BMT
state: Utah
city: Salt Lake City
country: United States
facility: Intermountain BMT Program
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University/MCV Hospital
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Center for International Blood and Marrow Transplant Research
name: Mary Horowitz, MD
role: STUDY_DIRECTOR
References:
citation: Vose JM, Carter S, Burns LJ, Ayala E, Press OW, Moskowitz CH, Stadtmauer EA, Mineshi S, Ambinder R, Fenske T, Horowitz M, Fisher R, Tomblyn M. Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and melphalan (BEAM) compared with iodine-131 tositumomab/BEAM with autologous hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the BMT CTN 0401 trial. J Clin Oncol. 2013 May 1;31(13):1662-8. doi: 10.1200/JCO.2012.45.9453. Epub 2013 Mar 11.