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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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

Official Title
-----------------
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

Conditions
-----------------
Epithelial Ovarian Cancer, Extraovarian Peritoneal Cancer, Fallopian Tube Carcinoma

Intervention / Treatment
-----------------
* Drug: Denileukin Diftitox/SC Pegylated IFNα-2a


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Denileukin Diftitox/SC Pegylated IFNα-2A<br>Administration of Denileukin Diftitox Plus Subcutaneous Pegylated IFNα-2A | Drug: Denileukin Diftitox/SC Pegylated IFNα-2a<br> <br> * Other names: Ontak plus Pegylated IFNα-2a;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Response = CR + PR. Failure to respond criteria are not based on RECIST criteria, which have unclear application to immune-based clinical trials. Instead, novel lack-of-failure criteria, rather than failure-of-success criteria have been written to avoid stopping therapy prematurely without compromising patient safety, to accommodate the uncertainties of assessing failure in this setting. The criteria as written are based on sound medical, scientific and ethical principles. The trial is further designed to help establish the utility of these novel criteria. | every 3 months until the date of first documented progression or date of death from any cause, assessed up to 2 years when study terminated early | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Epithelial Ovarian Cancer, FIGO (Int Federation of Gyn and Ob )Stage III or Stage IV, Extraovarian Peritoneal Cancer, Fallopian Tube Carcinoma Failing