Bendamustine and Rituximab Followed by 90-yttrium (Y) Ibritumomab Tiuxetan for Untreated Follicular Lymphoma

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.

Inclusion Criteria:

- Previously untreated, histologically confirmed follicular lymphoma classification
grade 1, 2 or 3a

- Ann Arbor stages of II to IV with either symptomatic or bulky disease (>5 cm); or
disease progression

- 18 years of age or older

- ECOG PS <2

- Normal organ and marrow function defined as below:

Absolute neutrophil count (ANC) >= 1,000/mm3 Platelet count >=100,000/mm3 Patients with ANC
less than 1,000/mm3 and/or platelets below 100,000/mm3 are still eligible for study entry
as long as there is >50% bone marrow involvement with lymphoma

- Adequate hepatic function

- Adequate renal function

- Measureable disease with at least one lesion measuring > 2cm in its greatest
transverse diameter

- Female subjects of childbearing potential must have a negative pregnancy test (urine
or serum b-HCG) at screening and within 1 week prior to the start of treatment with
Y-90 ibritumomab tiuxetan

- Voluntary written informed consent must be given before performance of any
study-related procedure

Exclusion Criteria:

- Prior chemotherapy, immunotherapy, or monoclonal antibody therapy

- Receiving any other investigational agents

- Primary CNS lymphoma

- Known HIV

- Treatment with therapeutic doses of systemic steroids within 4 weeks of beginning
study treatment (cycle 1, day -7); topical use of corticosteroids and systemic
replacement of corticosteroids for adrenal insufficiency are allowed

- Malignant pleural, pericardial or peritoneal effusions

- Known history of myelodysplastic syndrome (MDS) or found to have MDS

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would, in the judgment of
the investigator, limit compliance with study requirements

- Pregnant or lactating female subjects

- Concurrent active malignancy other than lymphoma or history of invasive malignancy
within the past 5 years, except completely excised, non-melanoma skin cancer

- Known Hepatitis B and/or Hepatitis C Infection

- Any other condition, that in the judgment of the investigator places the patient at
unacceptable risk if he/she were to participant in the study