on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after four weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area.
14 CLINICAL STUDIES
ISTODAX was eva luated in 2 multicenter, single-arm clinical studies in patients with CTCL. Overall, 167 patients with CTCL were treated in the US, Europe, and Australia. Study 1 included 96 patients with confirmed CTCL after failure of at least 1 prior systemic therapy. Study 2 included 71 patients with a primary diagnosis of CTCL who received at least 2 prior skin directed therapies or one or more systemic therapies. Patients were treated with ISTODAX at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days.
In both studies, patients could be treated until disease progression at the discretion of the investigator and local regulators. Objective disease response was eva luated according to a composite endpoint that included assessments of skin involvement, lymph node and visceral involvement, and abnormal circulating T-cells ("Sézary cells.").
The primary efficacy endpoint for both studies was overall objective disease response rate (ORR) based on the investigator assessments, and defined as the proportion of patients with confirmed complete response (CR) or partial response (PR). CR was defined as no evidence of disease and PR as ≥50% improvement in disease. Secondary endpoints in both studies included duration of response and time to response.
14.1 Baseline Patient Characteristics
Demographic and disease characteristics of the patients in Study 1 and Study 2 are provided in Table 2.
Table 2. Baseline Patient Characteristics Characteristic Study 1
(N=96) Study 2
(N=71)
Age
N 96 71
Mean (SD) 57 (12) 56 (13)
Median (Range) 57 (21, 89) 57 (28, 84)
Sex, n (%)
Men 59 (61) 48 (68)
Women 37 (39) 23 (32)
Race, n (%)
White 90 (94) 55 (77)
Black 5 ( 5) 15 (21)
Other/Not Reported 1 ( 1) 1 ( 1)
Stage of Disease at Study Entry, n (%)
IA 0 ( 0) 1 ( 1)
IB 15 (16) 6 ( 9)
IIA 13 (14) 2 ( 3)
IIB 21 (22) 14 (20)
III 23 (24) 9 (13)
IVA 24 (25) 27 (38)
IVB 0 ( 0) 12 (17)
Number of Prior Skin-Directed Therapies
Median (Range) 2 (0,6) 1 (0,3)
Number of Prior Systemic Therapies
Median (Range) 2 (1, 8) 2 (0, 7)
14.2 Clinical Results
Efficacy outcomes are provided in Table 3. Median time to first response was 2 months (range 1 to 6) in both studies. Median time to CR was 6 months in Study 1 and 4 months in Study 2 (range 2 to 9).
Table 3. Clinical Results Response Rate Study 1
(N=96) Study 2
(N=71)
ORR (CR + PR), n (%)
[95% Confidence Interval] 33 (34)
[25, 45] 25 (35)
[25, 49]
CR, n (%)
[95% Confidence Interval] 6 (6)
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