Trial Information

A Phase II Open-label Study of Single Agent Ofatumumab in Patients With Relapsed and/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.