Rituxan/BEAM vs Bexxar/BEAM in Autologous Hematopoietic Stem Cell Transplant for Non-Hodgkin's Lymphoma (BMTCTN0401)

Lymphoma, Non-Hodgkin Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00329030
• Other study ID #: BMTCTN0401
• Secondary ID: BMT CTN 0401U01H
• Status: Completed
• Phase: Phase 3
• Start date: December 2005
• Est. completion date: August 2013

Study information

• Verified date: August 2017
• Source: National Heart, Lung, and Blood Institute (NHLBI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Other known NCT identifiers

• NCT00415012

Recruitment information / eligibility

• Status: Completed
• Enrollment: 224
• Est. completion date: August 2013
• Est. primary completion date: August 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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 ß-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

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large-Cell, Immunoblastic
• Lymphoma, Non-Hodgkin
• Plasmablastic Lymphoma

Intervention

Drug:
• Autologous transplantation using rituxan/BEAM
Rituxan 375 mg/m2 (Day -19 and Day -12); BCNU 300 mg/m2 (Day -6); Etoposide (VP-16) 100 mg/m2 twice a day (Days -5 to -2); Cytarabine 100 mg/m2 twice a day (Days -5 to -2); Melphalan 140 mg/m2 (Day -1); Followed by autologous transplantation
• Autologous transplantation using Bexxar/BEAM
Bexxar dosimetric dose 5 mCi (Day -19); Bexxar therapy dose 75 cGy TBD (Day -12); BCNU 300 mg/m2 (Day -6); Etoposide (VP-16) 100 mg/m2 twice a day (Days -5 to -2); Cytarabine 100 mg/m2 twice a day (Days -5 to -2); Melphalan 140 mg/m2 (Day -1); Followed by autologous transplantation

Locations

Country	Name	City	State
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	Johns Hopkins/SKCCC	Baltimore	Maryland
United States	University of Maryland Medical Systems/Greenbaum Cancer Center	Baltimore	Maryland
United States	St. Lukes Mountain States Tumor Institute	Boise	Idaho
United States	Tufts-New England Medical Center	Boston	Massachusetts
United States	University of North Carolina Hospital at Chapel Hill	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University Hospitals of Cleveland/Case Western	Cleveland	Ohio
United States	Baylor University Medical Center	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Florida College of Medicine (Shands)	Gainesville	Florida
United States	Cancer Centers of the Carolinas	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	University of Miami	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Weill Cornell Medical College, The New York Presbyterian Hospital	New York	New York
United States	University of Nebraska	Omaha	Nebraska
United States	University of Pennsylvania Cancer Center	Philadelphia	Pennsylvania
United States	Columbia River Oncology Program	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Virginia Commonwealth University/MCV Hospital	Richmond	Virginia
United States	University of Rochester Medical Center	Rochester	New York
United States	Washington University/Barnes Jewish Hospital	Saint Louis	Missouri
United States	Intermountain BMT Program	Salt Lake City	Utah
United States	University of Utah Medical School, BMT	Salt Lake City	Utah
United States	Texas Transplant Institute	San Antonio	Texas
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	H. Lee Moffitt Cancer Center	Tampa	Florida

Sponsors (3)

Lead Sponsor	Collaborator
National Heart, Lung, and Blood Institute (NHLBI)	Blood and Marrow Transplant Clinical Trials Network, National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 io — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS)	Patients are considered a failure for this endpoint if they die, relapse/progress, or receive anti-lymphoma therapy, other than post-transplant consolidative localized radiation (maximum 3 sites) to sites of prior bulk disease pre-transplant (> 3cm). The time to this event is the time from randomization until death, relapse/progression, receipt of anti-lymphoma therapy, or last follow up, whichever comes first.	1 and 2 years
Secondary	Overall Survival	The event is death from any cause. The time to this event is the time from randomization to death or last follow-up. Surviving patients are censored at the time of last observation	1 and 2 years
Secondary	Incidence of Relapse/Progression	The time to this event is measured from randomization. Deaths without relapse/progression are considered as a competing risk. Surviving patients with no history of relapse/progression are censored at time of last follow-up.	1 and 2 years
Secondary	Complete Response (CR) and Partial Response (PR) Proportion		Day 100 and 2 years
Secondary	Platelet Recovery to 20,000 Cells/µL		100 and 180 days
Secondary	Hematologic Function	Hematologic function will be defined as ANC > 1,500 neutrophils/µL, hemoglobin > 10 g/dL without transfusion support, and platelet count > 100,000/µL without transfusion support.	100 days, 1 year
Secondary	Incidence of Infection		1 year
Secondary	Mucositis Severity	Mucositis severity will be scored per the modified Oral Mucositis Assessment Scale (OMAS) scoring system on a scale of 0 - 4, where 0 equals normal mucosa and 4 equals severe mucosa.	Day 21
Secondary	Immune Reconstitution	Tests to be performed on peripheral blood include CD2, CD3, CD4, CD8, CD19, CD3+/CD25+, CD45 RA/RO, CD56+/CD3-.	1 year
Secondary	Immune Reconstitution of Quantitative Immunoglobulins	Tests to be performed on peripheral blood for quantitative immunoglobulins include IgM, IgG and IgA.	1 year
Secondary	Treatment-related Mortality (TRM)	TRM is defined as death occurring in a patient from causes other than relapse or progression	1 and 2 years
Secondary	Neutrophil Recovery	Time to neutrophil recovery will be the first of two consecutive days of > 500 neutrophils/µL following the expected nadir.	Day 28 and Day 60

External Links

•   Blood and Marrow Transplant Clinical Trials Network Website