Resistant Solid Malignancies Clinical Trial
Official title:
Phase I Study of Docetaxel and Temsirolimus in Resistant Solid Malignancies
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 0.01micrometers. 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.
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.
n/a
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT00703170 -
Phase I Study of DOXIL and Temsirolimus in Resistant Solid Malignancies
|
Phase 1 |