| Title |
| Phase I Dose Escalation Study of Intraperitoneal (I.P.) ONTAK Administered to Patients with Advanced Stage Ovarian Cancer |
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| Study Design |
| This will be a phase I, non-randomized, dose escalation study designed to evaluate the safety of administering ONTAK I.P. in patients with advanced refractory ovarian carcinoma. Three dose levels of ONTAK will be investigated. Subjects will be assigned to one of three cohorts defined by dose level. Subjects will be assigned to each cohort sequentially with subjects being accrued to dose level 1 (5µg/kg) first, then dose level 2 (15µg/kg), then dose level 3 (25µg/kg). A treatment cycle will consist of I.P. infusions of ONTAK for three consecutive days followed by eleven days of rest. Each subject will receive a maximum of four treatment cycles. Each cohort of patients, described in groups of 3 or 4 patients will complete four treatment cycles plus 2 weeks of follow-up before the next cohort of patients is enrolled. Thus, subsequent patients will be treated dependent on the observed rates of dose limiting toxicity (DLT). The MTD will be defined as the dose level below that at which DLT is observed. |
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| Study Contact |
| Nicole Bates | 206.543.6620 | E-Mail |
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| Rationale |
Ovarian cancer is immunogenic and associated with multiple mechanisms of tumor induced immunosuppression. Recent studies have identified a unique population of CD4+CD25+ T regulatory cells (Tregs) which function as "professional" suppressor cells and may play a role in preventing ovarian tumors from being recognized by the immune system. Tregs are potent suppressors of CD4+ and CD8+ T cells and are thought to play a key role in the maintenance of immune tolerance to self-antigens. Studies in late stage ovarian cancer patients have demonstrated increased percentages of Tregs in tumor associated lymphocytes from ascitic fluid. Tregs may inhibit attempts to induce active immunity in the peritoneum, and, thus, depletion of peritoneal associated Tregs may provide a way of restoring or inducing anti-tumor immunity.
Stimulation of peritoneal immunity by depletion of Tregs at the tumor site in the peritoneum may provide a strategy to overcome tumor-induced immunosuppression and allow intratumoral T cells to be fully functional and destroy tumor directly. Clinical studies have shown ONTAK to be a safe and effective agent in the treatment of malignancies which express CD25. Furthermore, depletion of Tregs from PBMC using ONTAK in renal cancer patients has resulted in enhanced magnitude of vaccine-induced T cell immunity against renal tumor-associated self antigens. In this phase I study we will evaluate the safety of I.P. administration of ONTAK and establish the I.P. maximum tolerated dose (MTD). In addition, we will gather data on the effect of I.P. ONTAK on Tregs in peripheral blood and peritoneum. This data will lay the foundation of the design of a Phase II study of IV vs. I.P. ONTAK for the treatment of advanced stage ovarian cancer. |
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| Study Population / Indication |
| Patients with advanced stage refractory ovarian carcinoma who are unable to achieve first complete remission (CR) with first or second line chemotherapy or who have disease relapse after achieving second CR. |
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| Number of Patients: This study will accrue a maximum of 18 patients. |
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| Start Date: April 2005 |
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| Study Location: University of Washington Medical Center | 1959 NE Pacific Street | Seattle, WA 98195 |
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| Current Enrollment: 56% |
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| Objectives |
Primary:
- To estimate the MTD of I.P. administration of ONTAK.
Secondary:
- To evaluate the change in the number of Tregs in the peritoneum with the administration of ONTAK.
- To evaluate the change in the number of Tregs in the peripheral blood with the administration of ONTAK.
- To assess the clinical impact of ONTAK on tumor burden by serial measurements of CA-125.
- To assess the level of circulating cytokines IL-2, IL-6, IL-10, TGF-ß2, and TNF-a in the peritoneum and peripheral blood before and after I.P. ONTAK.
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| Outcome Measures |
Primary endpoints:
- Safety will be assessed using Cancer Therapy Evaluation Program (CTEP), Common Terminology Criteria for Adverse Events. The MTD will be defined as the dose level below that at which DLT is observed.
Secondary endpoints:
- The efficacy of ONTAK will be defined as a 25% reduction in the number of Tregs from baseline in either the peripheral blood and/or in the peritoneal cavity. Tregs from the peripheral blood and the peritoneum will be quantitated using flow cytometry.
- Clinical response will be evaluated with serum CA-125 measurements. Clinical response will be defined using the Rustin CA-125 Response Criteria. Progression of disease will be defined on the basis of a confirmed doubling of CA-125 levels from either the upper limit of normal or the nadir CA-125 level.
- Circulating cytokines IL-2, IL-6, IL-10, TGF-ß2, and TNF-a in the peripheral blood and at the site of disease will be assessed using standard commercial ELISA kits. Changes from baseline will be tabulated and described.
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| Clinical Description |
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| ClinicalTrials.gov Identifier:
NCT00357448 |
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Page last updated 4/27/09 |
