Ignite Creation Date:
2024-05-05 @ 7:38 PM
Last Modification Date:
2024-10-26 @ 9:51 AM
Study NCT ID:
NCT00703625
Status:
COMPLETED
Last Update Posted:
2017-03-07
First Post:
2008-06-20
Brief Title:
Phase I Study of Docetaxel and Temsirolimus in Resistant Solid Malignancies
Sponsor:
Washington University School of Medicine
Organization:
Washington University School of Medicine
Study Overview
Official Title:
Phase I Study of Docetaxel and Temsirolimus in Resistant Solid Malignancies
Status:
COMPLETED
Status Verified Date:
2017-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Rationale
The Mammalian Target of Rapamycin mTOR is a large polypeptide serinethreonine 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 001micrometers 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 mgm2 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
Docetaxel is a taxane analog which is active against many solid tumors including breast non-small cell lung prostate gastric ovarian head and neck and pancreatic cancers soft tissue sarcoma and melanoma It has been shown in several Phase III studies to have clinically significant activity in several solid tumors
We propose treating patients with resistant solid malignancies with docetaxel and temsirolimus In a study using human breast cancer cell lines mTOR inhibition with rapamycin had a synergistic cytotoxic effect with paclitaxel Given the novel mechanism of action of mTOR inhibitors and known synergistic activity of an mTOR inhibitor rapamycin with a taxane paclitaxel in vitro we envision that this regimen would be highly active in patients with solid tumor malignancies
Objectives
Primary
To define the maximum tolerated dose MTD and dose-limiting toxicities DLT of temsirolimus in combination with pegylated liposomal doxorubicin in patients with resistant solid malignancies
To determine the incidence and severity of other toxicities of temsirolimus in combination with pegylated liposomal doxorubicin in patients with resistant solid malignancies
Secondary
To assess the pharmacokinetic profile of temsirolimus in combination with pegylated liposomal doxorubicin
To determine any anti-tumor activity and response to the combination of temsirolimus and pegylated liposomal doxorubicin in treatment of patients with resistant solid malignancies
The Mammalian Target of Rapamycin mTOR is a large polypeptide serinethreonine 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 001micrometers 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 mgm2 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
Docetaxel is a taxane analog which is active against many solid tumors including breast non-small cell lung prostate gastric ovarian head and neck and pancreatic cancers soft tissue sarcoma and melanoma It has been shown in several Phase III studies to have clinically significant activity in several solid tumors
We propose treating patients with resistant solid malignancies with docetaxel and temsirolimus In a study using human breast cancer cell lines mTOR inhibition with rapamycin had a synergistic cytotoxic effect with paclitaxel Given the novel mechanism of action of mTOR inhibitors and known synergistic activity of an mTOR inhibitor rapamycin with a taxane paclitaxel in vitro we envision that this regimen would be highly active in patients with solid tumor malignancies
Objectives
Primary
To define the maximum tolerated dose MTD and dose-limiting toxicities DLT of temsirolimus in combination with pegylated liposomal doxorubicin in patients with resistant solid malignancies
To determine the incidence and severity of other toxicities of temsirolimus in combination with pegylated liposomal doxorubicin in patients with resistant solid malignancies
Secondary
To assess the pharmacokinetic profile of temsirolimus in combination with pegylated liposomal doxorubicin
To determine any anti-tumor activity and response to the combination of temsirolimus and pegylated liposomal doxorubicin in treatment of patients with resistant solid malignancies
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None