Phase I study of intraperitoneal (IP) denileukin diftitox in patients with advanced ovarian cancer (OC)

Abstract

3036 Background: CD4+CD25+Foxp3+ regulatory T cells (Tregs) which induce T cell suppression are increased in the ascites and peripheral blood (PB) of OC patients and associated with a poor prognosis. Denileukin diftitox, a diphtheria/IL-2R fusion protein, depletes PB Tregs in humans when given IV and induces an antitumor response in mice. We hypothesized that IP infusion of denileukin diftitox may reverse immune suppression in the peritoneum by depleting local Tregs. A phase I dose-escalation study was initiated to establish the MTD of IP denileukin diftitox, and assess its effect on Tregs in patients with OC. Methods: Up to 18 subjects with refractory OC are enrolled at 3 dose levels, 5, 15, and 25mcg/kg. A treatment cycle consists of IP denileukin diftitox on days 1–3 every 14 days for 4 cycles. The primary endpoint is to establish the MTD. Secondary endpoints include effect on Tregs and cytokines in PB and ascites, and clinical activity. Toxicity is evaluated days 1–3, 8, and 14 of each cycle. Tregs are assessed using RT-PCR and cytokines using LUMINEX at baseline, and after cycles 2 and 4. CA125 is checked serially during treatment. Results: 9 subjects have been enrolled, 3 to Arm 1 and 6 to Arm 2. Median age is 56 years (range, 34–73) and median salvage regimens is 3 (range, 2–7). 3 subjects in Arm 1 and 4/6 subjects in Arm 2 have completed 4 cycles without DLT. In Arm 2, 1 subject had DLT (grade 3 esophagitis) and 1 had disease progression after cycle 1. Toxicity in both Arms was primarily grade 1 and 2. Tregs (reported as relative quantitation level of Foxp3 normalized to CD4) in PB and ascites decreased in 1/3 patients in Arm 1, and 3/4 patients in Arm 2. CA125 decreased in 4/6 subjects in Arm 2 by a median value of 92 (range, 26–200). Cytokine analyses are on-going. Conclusions: Data suggests that IP denileukin diftitox at 5–15 mcg/kg is well tolerated in subjects with refractory OC; and at 15 mcg/kg results in decreased CA125 and Tregs. Accrual to dose level 3 continues. No significant financial relationships to disclose.