Ofatumumab in Combination With Cyclophosphamide, Doxorubicin Hydrochloride, Vincristine Sulfate, and Dexamethasone Alternating With Ofatumumab in Combination With Cytarabine and Methotrexate in Treating Patients With Newly Diagnosed Mantle Cell Lymphoma

PRIMARY OBJECTIVES:

I. To determine the overall response rate (ORR), and in particular, the complete remission
rate (CRR) in previously untreated MCL treated with ofatumumab in combination with aggressive
chemo-immunotherapy.

SECONDARY OBJECTIVES:

I. To determine the high sensitivity flow cytometry (HSFCM) complete remission rate
(HSFCM-CRR) in previously untreated MCL treated with ofatumumab in combination with
aggressive chemo-immunotherapy +/- high dose chemotherapy and autologous stem cell transplant
(HDC-ASCT).

II. To determine the time-to-progression (TTP), progression-free survival (PFS) and overall
survival (OS) of patients with previously untreated MCL treated with ofatumumab and
aggressive chemoimmunotherapy +/- HDC-ASCT.

III. To determine the toxicity profiles of ofatumumab in combination with high dose
cytarabine chemoimmunotherapy +/- HDC-ASCT.

IV. To correlate minimal residual disease (MRD) at different time intervals with TTP, PFS,
and OS.

V. To correlate surface cluster of differentiation (CD)20 levels, Ki67, and additional
cytogenetic abnormalities in pretreatment tumor biopsies with respect to ORR, CRR, TTP, PFS,
or OS.

VI. To determine the relationship between proliferation signature and clinical outcome using
quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR).

VII. To determine changes in surface CD20 levels, Ki67, or gain of additional cytogenetic
abnormalities in relapsed/refractory tumor specimens.

VIII. To correlate serum component (C)3, C4, and hemolytic complement (CH)50 levels measured
at baseline and at the end of first ofatumumab infusion with ORR, CRR, median response rate
(MRR), TTP, PFS and OS.

IX. Evaluate the ability of the induction and consolidation therapy to get 70% of patients to
autologous stem cell transplantation.

X. Evaluate the tolerability and CD34+ cell yield following therapy with patient and
hyper-fractionated cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and
dexamethasone (HyperCVAD)/high-dose cytarabine and methotrexate (HD-MA).

XI. To compare differences in response rate in patients with MCL treated with ofatumumab +
HyperCVAD/HD-MA according Cheson and Modified Cheson Criteria.

OUTLINE:

COURSES 1, 3, and 5 (O-HyperCVAD): Patients receive ofatumumab intravenously (IV) on day 1,
cyclophosphamide IV over 2 hours every 12 hours for 6 doses on days 3-5, doxorubicin
hydrochloride IV continuously over 72 hours on days 6-8, vincristine sulfate IV on days 6 and
13, and dexamethasone IV or orally (PO) on days 3-6 and 13-16.

COURSES 2, 4, and 6 (O-HD-MA): Patients receive ofatumumab IV on day 1, methotrexate IV
continuously over 24 hours on day 3, and cytarabine IV over 2 hours every 12 hours on days
4-5.

Treatment repeats every 21 days for 6* courses in the absence of disease progression or
unacceptable toxicity.

Eligible patients then undergo standard high dose chemotherapy and autologous stem cell
transplant (HDC-ASCT). Patients achieving a high sensitivity flow cytometry complete
remission (HSFCM-CR) after 2 courses may proceed to HDC-ASCT after completing 4 courses of
treatment.

After completion of study treatment, patients are followed up every 4 months for 2 years,
every 6 months for 3 years, and then as clinically instructed.

Inclusion Criteria:

- Histologically documented mantle cell lymphoma with co-expression of CD20 and CD5 and
lack of CD23 expression by immunophenotyping and at least one of the following
confirmatory tests: 1) positive immunostaining for cyclin D1; 2) the presence of
t(11;14) on cytogenetic analysis; OR 3) molecular evidence of B-cell leukemia/lymphoma
1 (bcl-1)/immunoglobulin heavy locus (IgH) rearrangement

- Cases that are CD5-negative and/or CD23-positive will be eligible provided that
the histopathology is consistent with mantle cell lymphoma AND positive for
cyclin D1, t(11;14), or bcl-1/IgH rearrangement

- A tissue block or unstained slides (10 - 20 slides) will be submitted to the
Roswell Park Cancer Institute (RPCI) Pathology Department for central pathology
review

- A diagnosis based on peripheral blood or bone marrow aspirate is allowed; if the
diagnosis is based only on blood, in addition to the immunophenotype and
molecular confirmation above, a peripheral blood smear must be available for
central pathology review; if the diagnosis is based on a bone marrow, the bone
marrow core biopsy or aspirate clot tissue block will be submitted to the RPCI
Pathology Department: if the tissue block is not available please submit the
diagnostic smears for review

- Extent of disease: stage I - IV; patients with nodular histology mantle cell lymphoma
must have Ann Arbor stage III or IV disease to be eligible

- Patients with mantle zone type histology will not be eligible

- Patients with other mantle cell histologies are eligible regardless of stage

- Measurable or assessable disease is required; measurable tumor size (at least one node
measuring 2.25 cm^2 in bidimensional measurement)

- No active central nervous system (CNS) disease defined as symptomatic meningeal
lymphoma or known CNS parenchymal lymphoma; a lumbar puncture demonstrating mantle
cell lymphoma at the time of registration to this study is not an exclusion for study
enrollment

- Patients must be previously untreated

- No prior radiation therapy for mantle cell lymphoma

- >= 2 weeks since major surgery

- No known hypersensitivity to murine products

- No medical condition requiring chronic use of high dose systemic corticosteroids
(i.e., doses of prednisone higher than 10 mg/day or equivalent)

- No human immunodeficiency virus (HIV) infection; patients with a history of
intravenous drug abuse or any behavior associated with an increased risk of HIV
infection should be tested for exposure to the HIV virus; patients who test positive
or who are known to be infected are not eligible; an HIV test is not required for
entry on this protocol, but is required if the patient is perceived to be at risk

- Non-pregnant and non-nursing; women and men of reproductive potential should agree to
use an effective means of birth control

- Patients who test positive for hepatitis C antibody (Ab) are eligible provided all of
the following criteria are met: 1) total bilirubin =< 2 x upper limit of normal; 2)
AND aspartate aminotransferase (AST) =< 3 x upper limit of normal; AND 3) liver biopsy
(pathology) demonstrates =< grade 2 fibrosis and no cirrhosis

- Specific guidelines will be followed regarding inclusion of MCL based on hepatitis B
serological testing as follows:

- Hepatitis B surface antigen (HBsAg) negative, hepatitis B core antibody (HBcAb)
negative, hepatitis B surface antibody (HBsAb) positive MCL patients are eligible

- Patients who test positive for HBsAg are ineligible (regardless of other
hepatitis B serologies)

- For MCL patients with HBsAg negative, but HBcAb positive (regardless of HBsAb
status), should have hepatitis B virus (HBV) deoxyribonucleic acid (DNA) testing
done and protocol eligibility determined as follows:

- If HBV DNA is positive the subject is excluded

- If HBV DNA is negative, patient may be included but must undergo at least
every 2 months HBV DNA polymerase chain reaction (PCR) testing from the
start of treatment throughout the duration the study

- Monitoring during the study is required at least every 2 months and during
follow-up at a minimum of every 2-3 months up to 6 months after the last
dose

- Prophylactic antiviral therapy with lamivudine (3TC) or investigator's
preferred antiviral regimen throughout protocol therapy and for 6-12 months
thereafter may be initiated at the discretion of the investigator

- If the patients' HBV DNA becomes positive during the study, the investigator
should manage the clinical situation as per the standard of care of
participating institution; the investigator should weigh the risks and
benefits of continuing ofatumumab or discontinuing ofatumumab before
appropriate treatment decisions are made for that individual patient

- Patients must not have a history of cardiac disease, defined as New York Heart
Association class II or greater or clinical evidence of congestive heart failure (CHF)

- No known hypersensitivity to ofatumumab, humanized antibodies or chemotherapy agents
throughout the protocol

- Left ventricular ejection fraction (LVEF) by multi gated acquisition scan (MUGA) or
echocardiogram (ECHO) >= 45%

- Neutrophils > 1000/uL

- Platelets >= 75,000/uL (unless significant bone marrow involvement with MCL)

- Creatinine =< 2.0 mg/dL

- Total bilirubin =< 2.0 mg/dL (unless MCL related or attributable to Gilbert's disease)

- Urine or serum beta-human chorionic gonadotropin (HCG) or serum HCG = negative (if
female patient of childbearing potential)

- 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 form prior to receiving any study related procedure

- Consult with a physician experience in care and management of subjects with hepatitis
B to manage/treat subjects who are anti-hepatitis B core antibody (HBc) positive

Exclusion Criteria:

- Prior history of HIV-positivity (routine HIV testing is not required pre-treatment)

- Positive serology for hepatitis B (HB) defined as a positive test for HBsAg; in
addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a
hepatitis B DNA test will be performed and if positive the patient will be excluded

- Serious non-malignant disease (e.g., active uncontrolled bacterial, viral, or fungal
infections) or other medical conditions (including psychiatric) which, in the opinion
of the Principal Investigator (PI) would compromise other protocol objectives

- Presence of symptomatic CNS lymphoma

- Pregnant or lactating females

- Prior history of radiation or chemotherapy for MCL

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ofatumumab or other agents used in study

- Patients with a "currently active" second malignancy, other than non-melanoma skin
cancer or in situ carcinoma of the cervix or breast; patients are not considered to
have a "currently active" malignancy if they have completed anti-cancer therapy, are
considered by their physician to be at less than 30% risk of relapse and at least 2-5
years have lapsed

- Major surgery, other than diagnostic surgery, within 2 weeks

- Patients with non-Hodgkin lymphoma (NHL) other than MCL

- Patients must not have a history of cardiac disease, defined as New York Heart
Association class II or greater or clinical evidence of congestive heart failure; all
patients must have a MUGA scan or 2-dimensional (D) echocardiogram indicating an
ejection fraction of >= 45% within 42 days prior to registration; the method used at
baseline must be used for later monitoring

- 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