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| Sponsor: | Washington University School of Medicine |
|---|---|
| Information provided by: | Washington University School of Medicine |
| ClinicalTrials.gov Identifier: | NCT00703170 |
Purpose
Rationale:
The Mammalian Target of Rapamycin (mTOR) is a large polypeptide serine/threonine kinase of 289 kDa; kinases have been shown to be important regulators of cancer cell cycle, proliferation, invasion, and angiogenesis, and mTOR has been shown to have a key role in the signaling of malignant cell growth, proliferation, differentiation, migration, and survival. Inhibition of mTOR would result in arrest of cell growth in the G1 phase of the cell cycle.
Temsirolimus (CCI-779) is a soluble ester analogue of rapamycin (sirolimus) which has shown impressive in vitro and in vivo cytostatic activity in selectively inhibiting mTOR. In animal models, temsirolimus has demonstrated an impressive cytostatic effect on a wide variety of cancer cells. In vitro, it inhibited the growth of human T-cell leukemia, glioblastoma, melanoma, prostate, breast, renal cell, and pancreatic cells, all of which showed particular sensitivity to temsirolimus, with significant growth inhibition at concentrations of less that 0.01micrometer. In Phase I trials, temsirolimus has been investigated as a single agent on a weekly schedule as well as daily for 5 days every other week, and evidence of activity was observed over the entire dose range (15 - 220 mg/m2) in patients with both breast and renal cancer. There was no apparent relationship between exposure and clinical benefit, suggesting that the inhibition of mTOR may be achieved at doses well below dose levels that result in dose limiting toxicities. Major tumor responses were noted in Phase I trials in patients previously treated with lung, breast, renal as well as neuroendocrine tumors. Minor responses were noted in soft tissue sarcoma, endometrial, and cervical carcinoma.
Pegylated liposomal doxorubicin has been FDA approved for use in refractory metastatic ovarian cancer and AIDS-related Kaposi's Sarcoma. It has also been shown to be effective in previously treated metastatic breast cancer.
Combination studies in preclinical models suggest that rapamycin and its analogues are at least additive in effect with standard chemotherapy and radiation. In addition, studies in breast cancer cell lines suggest that the mTOR inhibitors may reverse resistance to anti-estrogen agents. Thus, we are proposing that the combination of temsirolimus and liposomal doxorubicin will be highly effective in metastatic solid tumor malignancies.
Objectives:
Primary
Secondary
| Condition | Intervention | Phase |
|---|---|---|
|
Resistant Solid Malignancies |
Drug: temsirolimus & pegylated liposomal doxorubicin |
Phase I |
| Study Type: | Interventional |
| Study Design: | Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Phase I Study of Pegylated Liposomal Doxorubicin and Temsirolimus in Resistant Solid Malignancies |
| Estimated Enrollment: | 25 |
| Study Start Date: | March 2008 |
| Estimated Primary Completion Date: | July 2011 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: A
The patient will receive pegylated liposomal doxorubicin into the vein on day 1 of each cycle and will receive temsirolimus into the vein on days 1, 8, and 15 of each cycle. Each cycle is 28 days long.
|
Drug: temsirolimus & pegylated liposomal doxorubicin
dose level 1: 30mg/m2 pegylated liposomal doxorubicin, 20mg temsirolimus dose level 2: 30mg/m2 pegylated liposomal doxorubicin, 25mg temsirolimus dose level 3: 40mg/m2 pegylated liposomal doxorubicin, 20mg temsirolimus dose level 4: 40mg/m2 pegylated liposomal doxorubicin, 25mg temsirolimus
Other Names:
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Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion and Exclusion Criteria:
Contacts and Locations| United States, Missouri | |
| Washington University School of Medicine | |
| St. Louis, Missouri, United States, 63110 | |
| Principal Investigator: | Joel Picus, MD | Washington University School of Medicine |
More Information
| Responsible Party: | Joel Picus, M.D., Washington University School of Medicine |
| ClinicalTrials.gov Identifier: | NCT00703170 History of Changes |
| Other Study ID Numbers: | 07-0447 |
| Study First Received: | June 20, 2008 |
| Last Updated: | May 18, 2011 |
| Health Authority: | United States: Food and Drug Administration |
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Neoplasms Doxorubicin Sirolimus Everolimus Antibiotics, Antineoplastic Antineoplastic Agents Therapeutic Uses |
Pharmacologic Actions Antifungal Agents Anti-Infective Agents Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Anti-Bacterial Agents |