Ofatumumab in refractory CLL

[Guest guest]

Probably the easiest path to marketing approval is to prove improved

outcomes in the most difficult refractory population. ~ Karl

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Ofatumumab (HuMax-CD20), a Novel CD20 Monoclonal Antibody, Is An Active

Treatment for Patients with CLL Refractory to Both Fludarabine and

Alemtuzumab or Bulky Fludarabine-Refractory Disease: Results from the

Planned Interim Analysis of An

International Pivotal Trial

Monday, December 8, 2008: 11:45 AM

http://ash.confex.com/ash/2008/webprogram/Paper5918.html

n = 138 treated patients (Double refractory, n=59; Bulky fludarabine

refractory, n=79

Background: The prognosis for patients with CLL refractory to fludarabine

and alemtuzumab (double-refractory, DR) or refractory to fludarabine with

bulky (>5cm) lymphadenopathy (bulky fludarabine-refractory, BFR) is poor.

The overall response rate (ORR) to salvage therapy for such patients is

approximately 20% with a median survival of 9 mo (Tam et al, Leuk Lym,

2007). New effective treatments are needed for these patients.

Ofatumumab (HuMax-CD20) is a human monoclonal antibody that targets a unique

small-loop epitope on CD20 and elicits potent in vitro complement-dependent

cytotoxicity, even in malignant B cells with low CD20 expression levels. We

report on a planned interim analysis of an international, multicenter,

pivotal study of ofatumumab in patients with DR and BFR CLL.

Methods: Patients with DR or BFR CLL received 8 weekly infusions of

ofatumumab followed by 4 monthly infusions (Dose 1, 300 mg; Doses 2-12, 2000

mg). Patients were premedicated with paracetamol, antihistamine and

glucocorticoid. The primary end point was ORR (1996 NCI-WG response

criteria) assessed by an Independent end points Review Committee (IRC) over

a 24 wk period. Overall survival (OS) and safety were also evaluated.

Results: This interim analysis included all 138 treated patients (DR, n=59;

BFR, n=79: Table); 54% received all 12 infusions and 90% received ³8

infusions.

The ORR (99% CI) based upon IRC assessment was 51% (34, 68%) for the DR

group and 44% (30, 59%) for the BFR group; 1 patient had CR.

Additionally, a considerable number of patients had stable disease (Table).

Median time to next CLL therapy was 9 mo for the DR group and 8 mo for the

BFR group (Table); clinical progression was typically due to worsening

lymphadenopathy.

The median OS was about 14 mo for the DR group and 15 mo for the BFR group

(Table); based upon a landmark analysis at wk 12, response was significantly

correlated with longer survival for both groups.

Updated efficacy results will be presented at the meeting. 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

(no grade 4) in 7% and 3%, respectively (only 1 grade 3 event was considered

a serious adverse event). 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). Early death (within 8 wks

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). No patient tested

developed antibodies to ofatumumab.

Conclusions: These results demonstrate the effectiveness of ofatumumab in

patients with double-refractory CLL or bulky fludarabine-refractory disease.

Ofatumumab was well tolerated with no unexpected toxicities.

This monoclonal antibody potentially represents an active treatment option

with clinical benefit for patients with very poor prognosis who have

exhausted standard treatment options. The encouraging single-agent activity

in patients with refractory CLL warrants further investigation of ofatumumab

in earlier disease settings, in combination with other agents, as

maintenance, and in other B-cell malignancies.

Halls B and C (Moscone Center)

Anders Osterborg, MD, PhD1, J. Kipps, MD, PhD2, Jiri Mayer, MD3,

Stephan Stilgenbauer, Prof., Dr., med4, D , MBBS, MRCP,

FRCPath5*, Andrzej Hellmen, MD, PhD6*, Tadeusz Robak, MD, PhD7, R

Furman, MD8, Hillmen, MBChB, PhD9, Marek Trneny, MD, PhD10,

J.S. Dyer, MA, DPhil, FRCP11, Swaminathan Padmanabhan, MD, MBBS12, Tomas

Kozak, MD, PhD13*, Geoffrey Chan, MD14*, Randy L , DrPH15*, Nedjad

Losic, MSc16*, Charlotte A. , MD, DMSC16, Magdalena Piotrowska,

MD17*, Joris Wilms, MSc., Pharm16* and G. Wierda, MD, PhD18*

1Deptartment of Hematology, Karolinska Hospital, Stockholm, Sweden

2s UCSD Cancer Center, Univ. of California, San Diego, La Jolla, CA

3Hematology/Oncology, University Hospital Brno, Brno, Czech Republic

4Internal Medicine III, University of Ulm, Ulm, Germany

5Centre for Clinical Haematology, Nottingham University Hospitals,

Nottingham, United Kingdom

6Department of Hematology, Medical University of Gdansk, Gdansk, Poland

7Department of Hematology, Medical University of Lodz, Lodz, Poland

8Department of Hematology/Oncology, Weill Cornell Medical College, New York,

NY

9Department of Haematology, St ' Institute of Oncology, Leeds

10First Department of Medicine, University General Hosp., Prague,

Czech Republic

11MRC Toxicology Unit, Leicester University, Leicester

12Cancer Therapy and Research center, UTHSCSA, San , TX

13Department Of Clinical Hematology,, University Hospital Kralovske

Vinohrady, Prague, Czech Republic

14GlaxoKline, Collegeville, PA

15GlaxoKline, Durham, NC

16Genmab, Copenhagen, Denmark

17Department of Hematology, Klinika Hematologii CMUJ, Krakow, Poland

18MD Cancer Centre, University of Texas, Houston, TX