A phase II trial of denileukin diftitox to treat refractory advanced-stage ovarian cancer

Abstract

2506 Background: Denileukin diftitox is a fusion toxin consisting of interleukin-2 genetically fused to diphtheria toxin. It is approved to treat cutaneous T cell lymphoma. Our recent Phase I trial demonstrated that denileukin diftitox depletes human regulatory T cells (Tregs), and is associated with improved measures of T cell immunity and clinical improvements in ovarian cancer. This Phase II trial tests whether denileukin diftitox has clinical activity in the treatment of relapsed epithelial ovarian cancer. Methods: Patients with Stage III or IV ovarian cancer who have failed first-line therapy with optimal surgical debulking and platinum-based chemotherapy were eligible. Denileukin diftitox was given at 12 mcg/kg once monthly. In the Phase II design, patients received no chemotherapy for at least two weeks and no immune or radiation therapy for at least four weeks prior to enrollment. Infusion pretreatment includes antihistamines, acetaminophen and anti-emetics, but no corticosteroid. Results: Six patients (F1,2,4–7) have been treated to date. F1 experienced CA-125 stabilization and approximately 20% reduction in her pelvic mass after two cycles, but was then withdrawn for hypoalbuminemia. F2 experienced CA-125 stabilization after two cycles and remains stable through four cycles. F4 experienced a 20% drop in CA-125 after two cycles, but then progressed. F5 progressed after one cycle. Treatment was recently initiated for F6–7. Existing immune data to date confirm that denileukin diftitox treatment in the Phase II trial is associated with reductions in phenotypic CD4+CD25hi blood Tregs and increased CD3+IFN-γ+ T cells consistent with our Phase I results. Studies of Treg function, T cell cytokine production and CD4+CD25+ T cell FOXP3 content using saved clinical material will be undertaken when full laboratory operations resume. The trial continues to accrue patients. Conclusions: These data suggest that denileukin diftitox depletes Tregs in ovarian cancer. The link between Treg depletion and any observed immune changes or clinical effects is under active investigation, and remains to be determined. No significant financial relationships to disclose.