A Trial of Intravenous Denileukin Diftitox Plus Subcutaneous Pegylated IFNα-2A in Stage III or IV Ovarian Cancer

A Phase II Trial of Intravenous Denileukin Diftitox Plus Subcutaneous Pegylated IFNα-2a to Treat Epithelial Ovarian Cancer FIGO Stage III or Stage IV, Extraovarian Peritoneal or Fallopian Tube Carcinoma or Ineligible for First-Line Therapy

This study will test the hypothesis that adding pegylated IFN (IFN)a-2b to denileukin diftitox improves the potential of denileukin diftitox alone to deplete regulatory T cells (Tregs) and will thereby boost tumor immunity in patients with advanced-stage epithelial ovarian cancers, enhancing treatment efficacy.

The aims of this study are to:

• Assess the efficacy of adding pegylated IFN-α2b to denileukin diftitox to treat selected advanced-stage epithelial ovarian cancers
• Test the immune-modulating effects of adding pegylated IFN-α2b to denileukin diftitox in ovarian cancer patients and relate them to clinical efficacy
• Identify any toxicity associated with pegylated IFN-α2b plus denileukin diftitox treatment in these patients
• Identify practical means to dose the immunomodulating agents denileukin diftitox and pegylated IFN-α2b based on immunopharmacodynamic metrics

Inclusion Criteria:

• Able to provide informed consent
• Not on immune-modulating drugs, except those used as denileukin diftitox premedication, unless the principal investigator grants an exception (which exception must be documented in writing)
• Histologically proven epithelial (non-germ cell, non-stromal cell) cancer of the ovaries, fallopian tubes or extraovarian peritoneal carcinoma. Clinical recurrence without documented pathology is acceptable
• FIGO stage III or IV with failed prior first-line therapy, or ineligible for or intolerant of such therapy
• Measurable disease as defined in section 6 within 30 days of study enrollment
• Blood hemoglobin ≥ 8.5 gm/dl within 7 days of study enrollment
• Absolute neutrophil count ≥ 750/mm3 within 7 days of study enrollment
• Platelet count ≥ 40,000/mm3 within 7 days of study enrollment
• SGOT (serum glutamic oxaloacetic transaminase) ≤10 x upper limit of normal within 7 days of study enrollment
• Normal TSH (thyroid-stimulating hormone ) within 30 days of study enrollment
• No chemotherapy in the 14 days prior or radiation therapy in the thirty days prior to initiation of treatment on this study
• No other concurrent chemotherapy, surgery or radiation therapy during this protocol except surgery or radiation therapy to control symptoms with concurrence of the principal investigator
• No contraindication to any study treatment
• No active major medical problems, including untreated or uncontrolled infections
• Beck Depression Index ≥15 within 30 days of study enrollment
• If of reproductive potential, a negative urine pregnancy test within 3 days of study enrollment, and agreement to use adequate contraception. Pregnancy testing will continue monthly while on treatment unless the subject is no longer able to become pregnant or there is sufficient justification otherwise
• Not breast feeding
• Life expectancy ≥ six months
• ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2
• Serum albumin ≥ 1.8 gm/dl
• Age ≥ 18 years
• Acceptable baseline retinal examination within 30 days of study enrollment
• No active substance abuse in the prior 6 months
• Patients failing single agent denileukin diftitox in the ongoing trial "A Phase II Trial of Intravenous Ontak to Treat Epithelial Ovarian Cancer FIGO Stage III or Stage IV, or Extraovarian Peritoneal Carcinoma, Failing or Ineligible for First-Line Therapy" are eligible for this trial provided that three or more weeks have elapsed since their last denileukin diftitox infusion and they meet all eligibility criteria and successfully undergo all screening examinations for this trial.

Exclusion Criteria:

• Unable to tolerate phlebotomy
• Germ cell or stromal cell cancers of the ovaries, or other currently uncured cancer
• Active autoimmune disease including systemic lupus erythematosus, psoriasis, or inflammatory bowel disease that is not medically controlled
• Autoimmune hepatitis, whether medically controlled or not
• Contraindication to any study drug
• Known hypersensitivity to denileukin diftitox, pegylated IFN-α2a or any of their components or excipients
• Current pregnancy or breast feeding
• Inability to document adequate contraception if a female of reproductive potential
• On other immune-modulating drugs, except denileukin diftitox premedications or those approved by the principal investigator
• Chemotherapy within 14 days or radiation therapy within the thirty days prior to initiation of study treatment
• Life expectancy less than six months
• Serum albumin < 1.8 gm/dl
• Blood hemoglobin < 8.5 gm/dl
• ECOG performance status> 2
• Symptomatic coronary artery disease (including uncontrolled angina, congestive heart failure, and the like)
• Uncontrolled hypertension (diastolic BP consistently >100 mm Hg or systolic BP consistently >160 mm Hg on a regular basis)
• Uncontrolled, symptomatic cardiac arrhythmia
• Retinopathy associated with significant visual impairment
• Beck Depression Index >15
• Active substance abuse in the prior 6 months