Trial Information

A Multicenter, Open Label, Phase II Study of Bendamustine and Rituximab Followed by 90-yttrium (Y) Ibritumomab Tiuxetan for Untreated Follicular Lymphoma (Fol-BRITe Study)

STUDY OBJECTIVES

Primary Objective

- To determine the complete response (CR) rate and overall response (OR) rate [CR + partial
response (PR) rate] to a regimen of bendamustine and rituximab (B-R), followed by
radioimmunotherapy (RIT) with 90-yttrium(Y) ibritumomab tiuxetan in subjects with untreated
follicular lymphoma.

Secondary Objectives

- To characterize the safety profile of bendamustine and rituximab followed by
90-yttrium(Y) ibritumomab tiuxetan in subjects with untreated follicular lymphoma

- To determine the CR and OR rate after B-R

- To determine the CR and OR rate after 90-yttrium(Y) ibritumomab tiuxetan specifically
the conversions from PR to CR

- To determine the progression-free survival (PFS)

- To determine time to next treatment

Exploratory Objectives

- To determine the molecular response after B-R as determined by qualitative polymerase
chain reaction (PCR) of BCL2 from blood and bone marrow examination (required after
B-R)

- To determine the molecular response after 90-yttrium(Y) ibritumomab tiuxetan
radioimmunotherapy from blood and bone marrow examination (required after RIT)

BACKGROUND

Follicular lymphoma

Non-Hodgkin's lymphomas (NHL) encompass a group of malignancies of lymphocytes that vary in
their histologic appearance, aggressiveness and response to therapy.

According to the American Cancer Society, NHL is the 6th most common cancer, with more than
50,000 new cases per year. Follicular lymphoma (FL) is the 2nd most common type of NHL
accounting for approximately 20% of newly diagnosed NHL. FL is considered an indolent, but,
incurable lymphoma. The goals of therapy are to treat symptomatic advanced stage disease to
induce a maximum response with minimal toxicity. The optimal treatment of advanced stage
follicular lymphoma (FL) remains to be determined. Combination chemotherapy is the standard
frontline treatment option for this disease and the alkylating agent cyclophosphamide has
been a common backbone in these combinations. The most common treatments for FL in the
United States are rituximab combinations with chemotherapy such as cyclophosphamide,
vincristine and prednisone (R-CVP) and cyclophosphamide, doxorubicin, vincristine and
prednisone (R-CHOP). The NCCN guidelines also include fludarabine-based regimens, and
radioimmunotherapy.

With the addition of immunotherapy (rituximab) to chemotherapy, the overall and complete
response rates have improved.1-6 Furthermore, there is suggestive evidence that overall
survival may be improved.

Radioimmunotherapy (RIT) is also effective as salvage therapy for indolent lymphoma and
transformed lymphoma.7-9 In the first-line setting, RIT following chemotherapy can increase
the CR rate and PFS.10-12

Rationale of combining bendamustine and rituximab with consolidation 90-yttrium(Y)
ibritumomab tiuxetan

As mentioned above, the combination of bendamustine plus rituximab (B-R) appears to be
non-inferior to R-CHOP as first-line treatment of indolent lymphomas including follicular
and mantle cell lymphomas, while showing a better tolerability profile such as less
alopecia, and potentially less cardiotoxicity, making it a rational choice for first line
treatment of FL.17 When given after chemotherapy radioimmunotherapy can convert partial
responses to complete responses and can prolong the PFS. The Follicular Lymphoma Ibritumomab
tiuxetan (FIT) trial of consolidation Yttrium-90-Ibritumomab tiuxetan versus no additional
therapy after first remission in advanced follicular lymphoma showed a prolongation of PFS
(36 versus 13 months) in the RIT arm.12 The PFS was prolonged regardless of PR or CR after
first-line therapy. The primary treatment included CVP, CHOP, fludarabine-based, and
chlorambucil, with the minority of patients receiving rituximab. The results also showed
that RIT converted 77% patients from PR to CR/unconfirmed CR (CRu).

An abbreviated course of CHOP-R followed by RIT has shown promise in patients with
follicular lymphoma in a phase II trial reported recently.11 Of the 60 patients entering
this trial 55 patients completed all protocol therapy. The median follow up was 19.7 months
(range, 0.26-35.9 months). For intent-to-treat analysis, the complete response (CR) rate
after CHOP-R, as assessed by CT and PET imaging, was 40% and 46%, respectively. After RIT,
the CR rate improved, as assessed by CT and PET imaging, to 82% and 89%, respectively.

In this current study, we propose a first-line regimen for untreated FL using bendamustine
and rituximab (B-R) (bendamustine 90mg/m2 on days 1 and 2 and Rituximab 375mg/m2 on Day 1 of
a 28-day [+2 days] cycle) x 4 cycles followed by RIT; Zevalin (formerly Biogen Idec/Cell
Therapeutics, now Spectrum).

The advantage of this treatment is that B-R has a better side effect profile including
significantly less alopecia and less infectious complications. Currently bendamustine is not
FDA-approved for first-line therapy for follicular lymphoma. 90-yttrium(Y) ibritumomab
tiuxetan (Zevalin) radioimmunotherapy is FDA approved for patients with previously untreated
follicular non-Hodgkin's Lymphoma (NHL), who achieve a partial or complete response to
first-line chemotherapy. Evidence suggests that consolidation with RIT leads to a longer
PFS. Since this specific combination has not been utilized in the first-line treatment of
FL, it warrants investigation in the current study.

This trial will begin to establish a standard of care for the first-line treatment of
follicular lymphoma. We hypothesize that bendamustine plus rituximab followed by RIT will
contribute to among the highest CR rates seen in follicular lymphoma with relatively low
toxicity. Based on the results of this trial, we would aim to open a larger trial for
follicular lymphoma in a cooperative group setting, i.e. CALGB.

Correlative Studies Background

The BCL2 gene-Jh rearrangement is the common abnormality in FL t(14;18). This can be
assessed by various PCR techniques.18,19

Patients can be assessed for this molecular abnormality in their bone marrow at baseline and
following therapy. For instance in a similar Southwest Oncology Group study of chemotherapy
followed by radioimmunotherapy using tositumomab/iodine I-131 tositumomab (Bexxar) for
follicular lymphoma, patients were asked to undergo serial bone marrow aspirations at study
entry, 4 weeks after the sixth cycle of CHOP (just before tositumomab/iodine I-131
tositumomab), and after tositumomab/iodine I-131 tositumomab for PCR testing.20 The
mononuclear cell fraction was isolated from marrow aspirates by Ficoll-Hypaque sedimentation
and cryopreserved for subsequent batch analysis using a double nested PCR assay to detect
the major breakpoint region and the minor cluster region of the BCL2 gene. Samples were
initially analyzed by fragment size using ethidium bromide gel electrophoresis of the PCR
product and then transferred to nitrocellulose membranes for confirmation of the identity of
the BCL2 translocation by Southern blotting. The adequacy of samples was demonstrated using
beta-globin as a positive control housekeeping gene. Patients were considered to have
attained a molecular remission if their marrow sample at study entry contained a detectable
t(14;18) translocation that became undetectable after protocol treatment.