| Title |
| A Phase II Trial of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) with Weekly Protein Bound Paclitaxel (Abraxane™) as Chemoimmunotherapy for Platinum-Resistant Epithelial Ovarian Cancer |
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| Study Design |
| This study is designed to examine the effect of GM-CSF administration during and after cytotoxic chemotherapy on the duration of tumor remission. The study has a two-stage design, with an opportunity for early closure after ten patients accrue if Abraxane and GM-CSF fail to demonstrate any clinical responses. The criteria for activity will then be the time to progression following Abraxane/GM-CSF. Unlike historical controls, where the time to progression continues to shorten with each regimen, the desired outcome would extend the time to progression following Abraxane/GM-CSF beyond the time to progression experienced by subjects during induction platinum/taxane therapy. In addition, the subjects immune responses will be measured and correlated to clinical responses. |
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| Study Contact |
| Nicole Bates | 206.543.6620 | E-Mail |
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| Rationale |
| Immune-based approaches have good rationale in the treatment of ovarian cancer. Ovarian cancer is immunogenic and a host immune response, as revealed by the presence of intratumoral T-lymphocytes, is correlated with a significantly reduced rate of recurrence and significantly prolonged survival. The stimulation of a cancer specific T cell response may potentiate eradication of micrometastatic disease and allow the development of immunologic memory which could provide long lasting protective immunity. Hopefully, therapies which enhance the host immune response to tumor antigens may be able to significantly improve the long-term survival rate in advanced ovarian neoplasms. Abraxane, a new paclitaxel formulation, avoids the need for steroid premedication at each chemotherapy dose an important property when one of the primary goals of the regimen is to enhance the immune response. The combination of immunostimulatory properties and demonstrated activity against ovarian neoplasms in the salvage setting combined with modest toxicity caused us to select the combination of weekly Abraxane and daily GM-CSF as the regimen to test for chemoimmunotherapy of platinum resistant ovarian cancer. Hypothetically, while chemotherapy causes tumor cell death and stimulates innate immunity, the macrophages and dendritic cells stimulated by GMCSF may enhance the host immune response to tumor antigens, potentially leading to a clinically observable response. In addition, by continuing with GM-CSF following cessation of cytotoxic chemotherapy, we hope to stimulate immunologic memory to provide durable, immunologically induced specific anti-cancer treatment. |
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| Study Population / Indication |
| Ovarian cancer: Platinum-resistant or platinum refractory disease with an elevated CA125 level on at least two occasions. |
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| Number of Patients: This study will accrue a maximum of 30 patients. |
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| Start Date: May 2006 |
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| Study Location: University of Washington Medical Center | 1959 NE Pacific Street | Seattle, WA 98195 |
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| Current Enrollment: 13% |
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| Objectives |
Primary:
- To determine whether chronic GM-CSF administration during and after cytotoxic chemotherapy can induce a longer secondary remission than the immediately prior remission in women with recurrent platinum resistant ovarian cancer.
Secondary:
- To determine the extent to which chronic GM-CSF administration can increase the number of activated monocytes in patients with advanced stage epithelial ovarian cancer.
- To determine the extent to which chronic GM-CSF administration can increase the number and activation state of peripheral circulating antigen presenting cells such as dendritic cells and activated monocytes in patients with advanced stage epithelial ovarian cancer.
- To determine the extent to which chronic GM-CSF administration can increase the number and functional status of T cells that recognize tumor specific antigens in patients with advanced stage epithelial ovarian cancer.
- To determine the extent to which chronic GM-CSF administration can increase the number and functional status of antigen specific T cells that recognize foreign pathogens in patients with advanced stage epithelial ovarian cancer.
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| Outcome Measures |
Primary endpoints:
- The first end point is response rate and the second is time to progression. Given that weekly paclitaxel has a response rate of 25% among recurrent platinum resistant patients (18), and given that chronic GM-CSF alone has demonstrated a response rate of 37% in heavily pre-treated breast and ovarian cancer patients (11), if the response rate is less than 30%, the regimen is judged to be not worthy of further evaluation. The criteria for activity will then be time to progression, with a desired outcome of prolonging time to progression beyond the time to progression experienced by subjects during induction platinum/taxane therapy.
- Initial time to progression will be calculated from the date of initial chemotherapy until date of first relapse (using CA125 criteria). Time to second progression will be calculated from date of first weekly Abraxane infusion until date of second relapse (again using CA125 criteria).
Secondary Endpoints:
- We will determine if circulating monocytes also correlates to time to progression.
- Circulating dendritic cells: We will measure the circulating dendritic cell count and maturation state and correlate with clinical response and response duration.
- Activated T-lymphocytes against tumor associated antigens: We will serially measure the precursor frequency of circulating activated T-lymphocytes against common ovarian cancer tumor associated antigens to measure the development of immunity to anti-tumor antigens during treatment with chemotherapy and GM-CSF.
- Activated T-lymphocytes against foreign antigens: As a control to assess overall immunity, we will serially measure the precursor frequency of circulating T-lymphocytes activated against foreign antigens (tt, Influenza)
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| Clinical Description |
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| ClinicalTrials.gov Identifier:
NCT00466960 |
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Page last updated 4/27/09 |
