Ofatumumab and Bortezomib in Treating Patients With Previously Untreated Waldenstrom Macroglobulinemia

PRIMARY OBJECTIVES:

I. Determine overall response rate (complete response [CR] + partial response [PR] + minor
response [MR]) of ofatumumab in combination with bortezomib.

SECONDARY OBJECTIVES:

I. Determine complete remission (CR) rate, near (n)CR rate, very good partial response
(VGPR) rate and PR rate per new criteria.

II. Determine 5 year progression free survival (PFS). III. Determine time to progression and
duration of response of ofatumumab in conjunction with bortezomib.

IV. Determine safety of ofatumumab in combination with bortezomib. V. Conduct laboratory
correlates.

OUTLINE:

INDUCTION PHASE: Patients receive ofatumumab intravenously (IV) on days 1, 8, and 15 and
bortezomib subcutaneously (SC) on days 8 and 15. Beginning on course 2, patients receive
ofatumumab IV on days 1 and 15 and bortezomib SC on days 1, 8, and 15. Treatment repeats
every 28 days for up to 4 courses in the absence of disease progression or unacceptable
toxicity.

MAINTENANCE PHASE: Beginning 8 weeks after course 4 of induction phase, patients receive
ofatumumab IV on day 1 and bortezomib SC on days 1, 8, and 15. Treatment repeats every 28
days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, and then every 3
months for 5 years.

Inclusion Criteria:

- Diagnosis of Waldenstrom Macroglobulinemia and presence of cluster of differentiation
(CD)20+ tumor cells as determined by immune-histochemistry or flow cytometric
analysis in bone marrow or representative lymphoid tissue specimen; to be deemed
eligible, patients must meet at least one of the following criteria:

- Rising immunoglobulin (Ig)M

- Hemoglobin =< 10 g/dL

- Platelet count =< 100 x 10^9/L

- Symptomatic or bulky lymphadenopathy or organomegaly

- Systemic manifestations of Waldenstrom Macroglobulinemia (WM), such as
hyperviscosity symptoms (patients with symptoms of hyperviscosity syndrome must
be treated with plasmapheresis to control the syndrome prior to enrollment),
neuropathy, amyloidosis, cryoglobulinemia, B-symptoms, or recurrent bleeding

- Must have a measurable disease as defined by the monoclonal IgM level of 1 g/dL on
serum protein electrophoresis (SPEP); if the level of IgM on SPEP is less than 1 g/dL
in patients who meet any criteria in inclusion criteria 2, then the IgM level
obtained from nephelometric measurement may be used to justify this criterion

- Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of =< 2

- Have a life expectancy of >= 3 months

- Absolute neutrophil count >= 1.0 x 10^9/L unless the result of disease infiltration
of bone marrow

- Platelet count >= 50 x 10^9/L unless the result of disease infiltration of bone
marrow

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x the
institutional upper limit of normal (ULN)

- Total bilirubin =< 3 mg/dL or 1.5 x institutional ULN, whichever is lower

- Serum creatinine =< 3 mg/dL

- Female patients are either post-menopausal or surgically sterilized otherwise they
must agree to use acceptable contraceptive methods (e.g. double barrier) during
treatment

- Male subjects, even if surgically sterilized (i.e., status post vasectomy) must agree
to one of the following:

- Practice effective barrier contraception during the entire study treatment
period and through a minimum of 30 days after the last dose of study drug

- Completely abstain from heterosexual intercourse

- Patient or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent prior to receiving any study related procedure

Exclusion Criteria:

- Pregnant and nursing female patients

- Prior anti-neoplastic therapy for WM; the use of plasmapheresis to manage the
symptoms of hyperviscosity and other IgM paraprotein mediated symptoms is allowed and
does not disqualify a patient from the study; if a patient undergoes plasmapheresis
within 8 weeks of starting the study treatment then the IgM level prior to
plasmapheresis should be used for response assessment; neoplastic use of
glucocorticoids is prohibited during the screening and treatment period; patients
with active hyperviscosity symptoms should not be enrolled in this study unless the
symptoms resolve after plasmapheresis

- Unwilling or unable to follow protocol requirements

- Any condition which in the Investigator's opinion deems the patient an unsuitable
candidate to receive study drug

- Received an investigational agent within 30 days prior to enrollment

- Known human immunodeficiency virus (HIV) positive

- Positive serology for hepatitis B (HB) defined as a positive test for hepatitis B
surface antigen (HBsAg); in addition, if HBsAg is negative and hepatitis B core
antibody (HBcAb) is positive, regardless of hepatitis B surface antibody (HBsAb)
status, a HB deoxyribonucleic acid test will be performed and if HB DNA is positive
the patient will be excluded; if a patient is HBsAg negative, HBcAb positive, and
HBsAb positive, indicating past but not active infection, the patient will be
included on the study

- Positive serology for hepatitis C (HC) defined as a positive test for Hep C by enzyme
immunoassays (EIA), in which case reflexively perform a HC recombinant immunoblot
assay (RIBA) on the same sample to confirm the result

- Diagnosis of a malignant disorder other than WM within 3 years of the study
enrollment with the exception of completely resected non-melanoma skin cancer and
successfully treated in-situ cancer

- Uncontrolled infection

- Hypersensitivity to bortezomib, boron, or mannitol

- Grade 2 or greater peripheral neuropathy; since WM is known to cause peripheral
neuropathy (PN), if, in investigator's judgement, a patient has Grade 2 PN related to
WM, then he/she can be enrolled onto the study; under no circumstances patient with
greater than Grade 2 PN can be enrolled

- Myocardial infarction within 6 months of enrollment; New York Heart Association
(NYHA) Class III or more heart failure, uncontrolled angina, severe uncontrolled
ventricular arrhythmias; arrhythmias requiring active therapy other than chronic
stable atrial fibrillation; if a patient has an implanted cardiac pacemaker and is
otherwise well can be enrolled onto this study after demonstrating normal ejection
fraction and clearance from a cardiologist; at the time of screening any
electrocardiographic abnormality has to be documented as not medically relevant by
the investigator before the patient proceeds to the enrollment phase

- Any serious medical or psychiatric illness that may interfere with participation in
the study

- Patients with symptoms of hyperviscosity syndrome will not be enrolled on the study
until they undergo plasmapheresis that results in resolution of symptoms and optimal
control of the syndrome