Phase I Study of DOXIL and Temsirolimus in Resistant Solid Malignancies
Status:
Completed
Trial end date:
2011-07-01
Target enrollment:
Participant gender:
Summary
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
- 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.