Patients With Relapsed or Refractory Diffuse Large B Cell Non Hodgkin Lymphomas

Ofatumumab is a fully human monoclonal IgG1κ-antibody targeting a novel CD20-epitope.
Preclinical data show that ofatumumab is active against B-cell lymphoma/chronic lymphocytic
leukemia cell-lines with low CD20-antigen density and an increased expression of complement
inhibitory molecules. Ofatumumab was superior to rituximab in its ability to induce lysis in
B-cell lines and also killed fresh B-chronic lymphocytic leukemia cells that were resistant
to rituximab. Ofatumumab has a slower off-rate and more stable CD20 binding in comparison
with rituximab and targets a different epitope of the CD20 antigen than rituximab [Teeling,
2004, Teeling, 2006]. In cynomolgus monkeys, the duration of B-cell depletion from
peripheral blood and lymph nodes induced by ofatumumab was longer than that of rituximab
[Dechant, 2003].

Ofatumumab's ability to induce complement-dependent cytotoxicity (CDC) has been specifically
studied in isolated lymphoma cells from chemotherapy refractory DLBCL patients [Cillessen,
2007]. Ofatumumab and rituximab induced CDC of all DLBCL samples tested, including the DLBCL
cell lines SUDHL-4, SUDHL-5 and HT and lymphoma cells derived from ten
chemotherapy-refractory DLBCL patients.

Ofatumumab was significantly more effective in inducing CDC in nine of the ten DLBCL tumor
samples when compared with rituximab (p=0.001). The lethal doses (LD50) for ofatumumab (0.1
± 2.8 μg/mL) were significantly lower when compared with the LD50 for rituximab (6.4 ±
4.9μg/mL, p=0.04). Sensitivity of DLBCL patient cells to ofatumumab- and rituximab-induced
CDC negatively correlated with expression of complement defense molecule CD59, but not with
expression of CD46 or CD55. Functional inhibition of CD55 and CD59 using blocking mAb
demonstrated that ofatumumab-induced CDC of DLBCL tumor cells was less sensitive to
expression of these complement defense molecules than rituximab-induced CDC.

Thus, chemotherapy-refractory DLBCL cases are sensitive to CD20 mAb-induced CDC with
ofatumumab being the most effective mAb, especially in patients expressing high levels of
CD59.

Safety and efficacy of ofatumumab, has been analyzed in multicenter dose-escalating phase
I/II studies in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). Three
cohorts of patients including 33 patients with relapsed or refractory CLL received weekly
infusions of ofatumumab for four weeks as follows: cohort A, the first infusion was 100 mg
and three subsequent infusions of 500 mg; cohort B, the first infusion was 300 mg and three
subsequent infusions of 1000 mg; cohort C, the first infusion was 500 mg and three
subsequent infusions of 2000 mg. The maximum tolerated dose was not reached. The majority of
related adverse events occurred at first infusion, and the number of adverse events
decreased at each subsequent infusion. Seventeen (51%) of 33 patients experienced
infections, 88% of them of grade 1-2. One event of interstitial pneumonia was fatal; all
other cases resolved within one month. The response rate in cohort C was 50% (13/26
patients) [Coiffier, 2008].

Interim data from a single arm study in refractory CLL was presented at ASH 2008 [Osterborg,
2008]. The activity of ofatumumab was evaluated in 138 patients with refractory CLL: 59 were
refractory to both fludarabine and alemtuzumab (double-refractory: DR) and 79 were
refractory to fludarabine and considered inappropriate candidates for alemtuzumab due to
bulky tumor in their lymph nodes (bulky fludarabine-refractory: BFR group). Patients
received 8 weekly infusions of ofatumumab followed by 4 monthly infusions. The first dose
was 300mg, doses 2-12 were 2000 mg. Median time to next CLL therapy was 9 months for the DR
group and 8 months for the BFR group. The median overall survival was about 14 months for
the DR group and 15 months for the BFR group. Response at week 12 was significantly
correlated with longer survival for both groups. Ofatumumab was associated with
infusion-related adverse events on the first infusion day in 46% of patients in the DR group
and 38% in the BFR group, which were grade 3 in 7% and 3% of events, respectively. There
were no grade 4 infusion-related events. These events generally subsided with subsequent
infusions.

The most common grade 3 or 4 toxicities were infections (25% in DR; 27% in BFR group) and
hematologic events including neutropenia (12% in DR; 10% in BFR group) and anemia (8% in DR;
4% in BFR group). Death within 8 weeks from start of treatment occurred in 2 patients (3%)
in the DR group (sepsis, n=1; fungal pneumonia, n=1) and 3 patients (4%) in the BFR group
(PD, n=1; sepsis, n=1; myocardial infarction, n=1).

In a phase I/II study evaluating safety and efficacy of ofatumumab in relapsed or refractory
FL grade 1-2, 4 dose-groups of 10 patients received 4 weekly infusions of 300, 500, 700, or
1000 mg [Hagenbeek, 2008]. Patients had a median of two prior FL therapies and 13% had
elevated LDH. No safety concerns or maximum tolerated dose were identified. Most adverse
events occurred on the first infusion day and were CTC grade 1-2. Eight related events were
grade 3. Treatment caused immediate and profound B-cell depletion. The response rate was not
dose dependent (dose expressed as mg/patient, mg/kg body weight or body surface area
(mg/m2)) with responses obtained in all 4 dose groups (300 mg: 5 of 8 subjects (63%); 500
mg: 3 of 10 subjects (30%); 700 mg: 2 of 10 subjects (20%); and 1000 mg: 5 of 10 subjects
(50%). Median time to progression (TTP) for all patients was 8.8 months. Median TTP for
responders, duration of response, and time to next anti-FL therapy has not been reached at a
median follow-up of 9.2 months. Ofatumumab was able to induce responses in 8 of 14 patients
relapsing following rituximab, including 3 of 4 rituximab refractory patients.

Ofatumumab is currently being evaluated in patients with rituximab-refractory FL
(Hx-CD20-405), relapsed DLBCL (GEN-415), rituximab-relapsed/refractory DLBCL in combination
with salvage chemotherapy (OMB110927) and in a phase III trial in relapsed/refractory DLBCL
(OMB110928) at a dose of 1000mg, and in combination with chemotherapy in FL (Hx-CD20-409) at
doses of 500mg and 1000mg.

Inclusion Criteria:

- Relapsed and/or refractory DLBCL,not HSCT candidates. Pts must have failed SOC
therapy w/rituximab plus CHOP or its equivalent & not considered HSCT candidates
based on investigator's discretion

- Pts must have measurable disease radiographically on CT and/or PET scans and/or bone
marrow biopsy.

- ECOG performance status of 0, 1, or 2

- Age ≥18 years. No upper limit of age

- Life expectancy of 6 months or more based on investigator's best estimate.

- Pts able to read, understand, & sign informed consent

- Evidence of CD20 positivity in treated pts, using flow or immunohistochemistry.

- Pts will be stratified based on bulk of disease (bulk defined as any area w/ more
than 5cm in greatest dimension)

- Pts must agree to an acceptable form of birth control

Exclusion Criteria:

- Other histologies of NHL

- Known CNS involvement with NHL

- Known HIV positive status

- Chronic or current active infectious disease requiring systemic antibiotics,
antifungal, or antiviral treatment.

- Corticosteroid use is allowed as long as it is for non-lymphoma related causes such
as rheumatoid arthritis and COPD.

- Pts w/prior malignancies are allowed as long as they are in remission & their last
treatment for such malignancy is 2 years prior to enrollment or more. Pts
w/non-melanoma skin cancers that have received adequate therapy prior to enrollment &
women w/history of cervical cancers are allowed.

- Significant concurrent uncontrolled medical condition including, but not limited to,
renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurologic,
cerebral, or psychiatric disease.

- Current active liver or biliary disease (with the exception of Gilbert's syndrome or
asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease
per the investigator's assessment).

- Adequate bone marrow function by virtue of having Platelets >50,000/ul & ANC >1000/ul
is required unless low counts are attributed to diffuse bone marrow infiltration with
NHL as documented with a bone marrow biopsy exam.

- Pts with creatinine >2.0 times the upper limit of normal will be excluded unless they
have a normal creatinine clearance-estimated or measure 12 or 24 hour creatinine
clearance of <60 mL/min

- Pts w/total bilirubin >1.5 times upper limit of normal will be excluded, unless due
to DLBCL involvement of liver or a known history of Gilbert's disease.

- Pts with AST/ALT/AlkPhos >2.5 times upper limit of normal

- Previous tx with Ofatumumab

- Prior exposure to an investigational agent within 4-weeks from starting Ofatumumab

- History of significant cerebrovascular disease or event w/significant symptoms or
sequelae

- Clinically significant cardiac disease including unstable angina, acute myocardial
infarction within 6 months prior to randomization, congestive heart failure (NYHA
III-IV), & arrhythmia unless controlled by therapy, w/exception of extra systoles or
minor conduction abnormalities.

- 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 HB
DNA test will be performed and if positive the subject to be excluded. Note: If HBcAb
positive and HBsAb positive, which is indicative of a past infection, subject can be
included

- Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which
case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the
result.

- Pregnant or lactating women. Women of childbearing potential must have a negative
pregnancy test at screening, including women whose last menstrual period was less
than 1 year prior to screening, unable or unwilling to use adequate contraception
from study start to 1 year after the last dose of protocol therapy. Adequate
contraception is defined as hormonal birth control, intrauterine device, double
barrier method or total abstinence.