Phase I Study of DOXIL and Temsirolimus in Resistant Solid Malignancies

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 eligible.
• Patients must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. 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 mg/dl
• 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 with triglyceride levels >400 mg/dL can be started on lipid lowering agents and reevaluated within 1 week. If levels go to ≤400 mg/dL, they can be considered for the trial and continue the lipid lowering agents.
• Temsirolimus is primarily metabolized by CYP3A4. 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.
• Patients must have a normal left ventricular ejection fraction (LVEF ≥50%) by MUGA scan.
• 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 receiving anti-retroviral therapy (HAART) for HIV infection are excluded from the study because of possible pharmacokinetic interactions.
• 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.