Study of Pegylated Liposomal Doxorubicin and Temsirolimus in Patients With Advanced Hepatocellular Cancer

Exclusion Criteria

• •Prior Therapy: Patients may or may not have received prior systemic therapy in the metastatic setting. No prior treatment with an mTOR inhibitor or with doxorubicin is permitted. Participants 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.
• •Age: Patients must be ≥18 years old. Because no dosing or toxicity data are currently available on the use of temsirolimus in combination with pegylated liposomal doxorubicin in patients \<18 years of age, children are excluded from this study.
• •Performance Status: ECOG 0-2 at study entry.
• •Life Expectancy: Patients must have a life expectancy of greater than 12 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
• •* 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.
• •* Child-Pugh (CP) A or B liver dysfunction are eligible unless the bilirubin is \>1.5 x ULN. If non-contraindicated, hepatic impairment (bilirubin \>1-1.5 x ULN or AST \>ULN but bilirubin ≤ULN) is present patients can be treated at a lower dose (15 mg/week) of temsirolimus.
• •Concomitant Medications: 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. A partial list of agents which interact with cytochrome P450 (CYP3A) is found in Appendix B. Use of agents that potently inhibit CYP3A (and hence may raise temsirolimus levels), such as ketoconazole, is discouraged, but not specifically prohibited. Temsirolimus can inhibit CYP2D6, and may decrease metabolism (and increase drug levels) of drugs that are substrates for CYP2D6, such as codeine. The appropriateness of use of such agents is left to physician discretion. A list of drugs that may have potential interactions with CYP2D6 is found in Appendix A. If there is any doubt about eligibility based on concomitant medication, the Principal Investigator should be contacted. All concomitant medications must be recorded.
• •Cardiac Function: Patients must have a normal left ventricular ejection fraction (LVEF ≥50%) by MUGA scan.
• •HIV-Positive Patients: Patients receiving anti-retroviral therapy (HAART) for HIV infection are excluded from the study because of possible pharmacokinetic interactions. Appropriate studies will be undertaken in patients receiving HAART therapy, when indicated.
• •Neurologic Status: Patients must not have active CNS disease.
• •Recovery from Intercurrent Illness: 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.
• •Informed Consent: 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.
• •Inclusion of Women and Minorities: Entry to this study is open to both men and women and to all racial and ethnic subgroups.