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.
- 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
- To assess the pharmacokinetic profile of temsirolimus in combination with pegylated
- To determine any anti-tumor activity and response to the combination of temsirolimus
and pegylated liposomal doxorubicin in treatment of patients with resistant solid
Inclusion and Exclusion Criteria:
- Patients must have a histologically or cytologically proven solid malignancy which is
resistant to conventional therapy or for which no effective therapy is known.
- Patients with measurable or non-measurable disease are eligible for entry to this
study. In addition, patients without measurable or non-measurable disease are also
- Patients must have recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy prior to entering this study. Neuropathy must have
recovered to grade 1. No chemotherapy or radiotherapy may be given within 4 weeks
prior to the start of protocol treatment.
- Patients must be ≥18 years old.
- ECOG 0-2 at study entry.
- Patients must have a life expectancy of greater than 8 weeks.
- Required Laboratory Values:
- absolute neutrophil count ≥1,500/mm3
- platelets ≥100,000/mm3
- hemoglobin ≥9.0 g/dL
- total bilirubin ≤1.5 x ULN
- AST(SGOT)/ALT(SGPT) ≤1.5 x ULN (≤2.5 x ULN for patients with liver metastases
- alkaline phosphatase ≤2.5 x ULN
- creatinine ≤1.5 x ULN OR
- creatinine clearance ≥60 mL/min/1.732 for patients with creatinine levels above 2.0
- serum cholesterol ≤350 mg/dL /9.0 mmol/L (fasting)
- triglycerides ≤400 mg/dL (fasting)*
- albumin ≥3.0 mg/dL
- PT/INR ≤1.5, unless the patient is on full dose warfarin or stable dose of LMW
heparin with a therapeutic INR of >1.5 - ≤3
- Patients cannot be receiving enzyme-inducing antiepileptic drugs (EIAEDs; e.g.,
phenytoin, carbamazepine, phenobarbital) nor any other CYP3A4 inducer such as
rifampin or St. John's wort, as these may decrease temsirolimus levels.
- Patients with known hypersensitivity reactions to macrolide antibiotics (such as
erythromycin, clarithromycin, and azithromycin) are not eligible for this trial.
- For all sexually active patients, the use of adequate contraception (hormonal or
barrier method of birth control) will be required prior to study entry and for the
duration of study participation. Non-pregnant status will be determined in all women
of childbearing potential. Pregnant and nursing women are not eligible.
- Patients must not have active CNS disease.
- Patients must have recovered from uncontrolled intercurrent illness including, but
not limited to, ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris or cardiac arrhythmia.
- Patients must have signed a Washington University, Human Research Protection Office
(HRPO) approved informed consent. The patient should not have any serious medical or
psychiatric illness that would prevent either the giving of informed consent or the
receipt of treatment.