14  CLINICAL STUDIES
14.1  Study 1: Placebo Controlled Study in CTCL (Stage Ia to III) Patients
The safety and efficacy of Ontak were eva luated in a randomized, double-blind, placebo-controlled, 3-arm trial in patients with Stage Ia to III CD25(+) CTCL. Eligible patients were required to have expression of CD25 on≥ 20% of biopsied malignant cells by immunohistochemistry [see Warnings and Precautions ( 5.4 )]. Patients were randomized to receive 0, 9 or 18 mcg/kg/day Ontak via intravenous infusion days 1-5 of each 21-day cycle, for up to 8 cycles. Randomization was stratified by disease stage (≤IIa vs. ≥IIb). The main efficacy outcome was objective response rate (ORR), using a Weighted Skin Severity Index, in conjunction with assessment of lymph node involvement and percentage of abnormal blood lymphocytes. A total of 144 patients were randomized: 44 patients to placebo, 45 patients to 9 mcg/kg/day Ontak and 55 patients to 18 mcg/kg/day Ontak. Randomization for the study was carried out at 1:1:1 for the first 73 patients, 4:1:4 for the next 31 patients, and 1:4:4 for the remaining 40 patients. The median age of patients was 59 years (range 23 to 84 years); 34% were ≥ 65 years. Fifty-five percent were men and 86% were Caucasian. Sixty-seven percent had early stage disease (≤ IIa). Patients had received a median of 2 anti-CTCL therapies (range 0 to 6) prior to study entry. Results for objective response rate (ORR) and progression-free survival (PFS) are shown in the table below.

Table 2: Efficacy Results in Study 1 Efficacy Endpoint Ontak
18 mcg/kg/day
(N=55) Ontak
9 mcg/kg/day
(N=45) Placebo
(N=44)
a Adjusted for disease stage and changes in randomization ratios.
b Logistic regression model adjusting for disease stage and changes in randomization ratios over the course of the study; comparisons relative to placebo.
c Cox regression analysis stratified by randomization ratio and adjusted for disease stage; comparisons relative to placebo.
ORR %a
   p-valueb  46%
p=0.002 37%
p=0.03 15%
--
Median Response Duration 220 days 277 days 81 days
PFSc
   Hazard ratio
   (95% CI)
   p-value
0.27
(0.14, 0.54)
p=0.0002
0.42
(0.20, 0.86)
p=0.02
--

14.2  Study 2: Dose eva luation Study in CTCL (Stage IIb to IVa) Patients
A randomized, double-blind study was conducted to eva luate doses of 9 or 18 mcg/kg/day in 71 patients with recurrent or persistent, Stage Ib to IVa CTCL. Entry to this study required demonstration of CD25 expression on at least 20% of the cells in any relevant tumor tissue sample (skin biopsy) or circulating cells. Tumor biopsies were not eva luated for expression of other IL-2 receptor subunit components (CD122/CD132). Ontak was administered as an IV infusion daily for 5 days every 3 weeks. Patients received a median of 6 courses of Ontak therapy (range 1 to 11). The study population had received a median of 5 prior therapies (range 1 to 12) with 63% of patients entering the trial with Stage IIb or more advanced stage disease. The median age of patients was 64 years (range 26 to 91 years); 49% were ≥ 65 years. Fifty-two percent were men and 75% were Caucasian.

Overall, 30% (95% CI: 18-41%) of patients treated with Ontak experienced an objective tumor response (50% reduction in tumor burden which was sustained for ≥6 weeks; Table 3). Seven patients