Safety data are available for 3clinical studies in which 234patients received Ontak at 9mcg/kg (n=80) or 18mcg/kg (n=154) at the recommended schedule. Of these studies, 1 was placebo-controlled and dose-ranging (Study1, 100Ontak-treated patients), one was a dose-comparison of 9 and 18mcg/kg (Study2, n=71), and the third was a single-arm study using 18mcg/kg (n=63); all studies were limited to adult patients with CTCL. The median age of patients across the clinical studies was 60years (range 23-91years) and 36% (n=85) were 65years of age or older; 55% were men and 85% were Caucasian.

Across all 3studies, the most common adverse reactions in Ontak-treated patients (≥20%) were pyrexia, nausea, fatigue, rigors, vomiting, diarrhea, headache, peripheral edema, cough, dyspnea and pruritus. The most common serious adverse reactions were capillary leak syndrome (11.1%), infusion reactions (8.1%), and visual changes including loss of visual acuity (4%). Ontak was discontinued in 28.2% (66/234) of patients due to adverse reactions.

The data described in Table1 reflect exposure to Ontak in 100patients administered as a single agent at the recommended dosing schedule in the randomized placebo-controlled trial (Study1). The median number of Ontak cycles was 7 (range 1-10) for the 9mcg/kg cohort and 6 (range 1-11) for the 18mcg/kg cohort. The median age of patients was 59years (range 23-84years) and 34% (n=34) were 65years of age or older; 55% were men and 86% were Caucasian.

Table 1: Incidence of Adverse Reactions Occurring in ≥10% of Ontak-treated patients (18mcg/kg group) and at a higher rate than Placebo in Study1 MedDRAversion6.1
PreferredTerm Placebo
N=44
n (%) Ontak
9 mcg/kg
N=45
n (%) Ontak
18 mcg/kg
N=55
n (%)
Pyrexia 7 (15.9) 22 (48.9) 35 (63.6)
Nausea 10 (22.7) 21 (46.7) 33 (60.0)
Rigors 9 (20.5) 19 (42.2) 26 (47.3)
Fatigue 14 (31.8) 21 (46.7) 24 (43.6)
Vomiting 3 (6.8) 6 (13.3) 19 (34.5)
Headache 8 (18.2) 13 (28.9) 14 (25.5)
Edema peripheral 10 (22.7) 9 (20.0) 14 (25.5)
Diarrhea 4 (9.1) 10 (22.2) 12 (21.8)
Anorexia 2 (4.5) 4 (8.9) 11 (20.0)
Rash 2 (4.5) 11 (24.4) 11 (20.0)
Myalgia 2 (4.5) 8 (17.8) 11 (20.0)
Cough 3 (6.8) 9 (20.0) 10 (18.2)
Pruritus 4 (9.1) 7 (15.6) 10 (18.2)
Back pain 1 (2.3) 7 (15.6) 10 (18.2)
Asthenia 2 (4.5) 8 (17.8) 10 (18.2)
Hypotension 1 (2.3) 3 (6.7) 9 (16.4)
Upper respiratory tract infection 5 (11.4) 6 (13.3) 7 (12.7)
Dizziness 5 (11.4) 5 (11.1) 7 (12.7)
Arthralgia 5 (11.4) 7 (15.6) 7 (12.7)
Pain 3 (6.8) 5 (11.1) 7 (12.7)
Chest pain 1 (2.3) 2 (4.4) 7 (12.7)
Dysgeusia 1 (2.3) 0 (0) 6 (10.9)
Dyspnea 2 (4.5) 6 (13.3) 6 (10.9)

Hepatobiliary Disorders: Increase in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) from baseline occurred in 84% of subjects treated with Ontak (197/234). In the majority of subjects, these enzyme elevations occurred during either the first or the second cycle; enzyme elevation resolved without medical intervention and did not require discontinuation of Ontak.

6.2 Immunogenicity
An immune response to denileukin diftitox was assessed using 2enzyme-linked immunoassays (ELISA). The first assay measured reactivity directed against intact denileukin diftitox calibrated against anti-diphtheria toxin, and the second assay measured reactivity against the IL-2 portion of the protein. An additional invitro cell-based assay that measured the ability of antibodies in