Rituxan vs Bexxar When Combined With Carmustine, Etoposide, Cytarabine and Melphalan (BEAM) With Autologous Hematopoietic Stem Cell Transplantation (BMT CTN 0401)

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).

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