Phase II trial of Ontak to deplete regulatory T cells in treatment-refractory stage III/IV ovarian cancer

Proc Amer Assoc Cancer Res, Volume 47, 2006 4885 This Phase II trial tests whether Ontak (denileukin diftitox) is useful to treat epithelial ovarian cancer, stages III or IV that have failed first-line therapy with optimal surgical debulking and platinum-based chemotherapy. Ontak is a fusion toxin consisting of interleukin-2 genetically fused to diphtheria toxin. It is approved to treat cutaneous T cell leukemia/lymphoma. Our recent Phase I trial demonstrated that Ontak depletes human regulatory T cells (Tregs), associated with improved measures of T cell immunity and associated with clinical improvements in ovarian cancer. Based on Phase I results, we initiated a Phase II clinical efficacy trial in treatment-refractory epithelial ovarian cancer using Ontak 12 micrograms/kilogram 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 is antihistamines, acetaminophen and anti-emetics, but no steroids. Five patients (FIGO1,2,4-6) have been treated to date. FIGO1 experienced CA-125 stabilization and approximately 20% reduction in her pelvic mass after two cycles, but was then withdrawn for hypoalbuminemia. FIGO2 experienced CA-125 stabilization after two cycles. FIGO4 experienced a 20% drop in CA-125 after two cycles, but then progressed. FIGO5 progressed after one cycle. Immune analyzes are currently incomplete post-Katrina. Existing data confirm that Ontak treatment in the Phase II trial is associated with reductions in phenotypic CD4+CD25hi blood Tregs and increased CD3+IFN-g+ T cells consistent with our Phase I results. Studies of Treg function, T cell cytokine production and CD4+CD25+ T cell FOXP3 content will be undertaken shortly when full laboratory operations resume using saved clinical material. The trial continues to accrue patients. These data suggest that Ontak 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.