Study of Pegylated Liposomal Doxorubicin and Temsirolimus in Patients With Advanced Hepatocellular Cancer
Study of Pegylated Liposomal Doxorubicin and Temsirolimus in Patients With Advanced Hepatocellular Cancer
This Phase II study will use the MTD from a previous Phase I study at the recommended dose
 for the combination regimen from the Phase I trial, Doxil 25mg/m2 IV Q 4 weeks and
 temsirolimus 25mg IV Q week.
This proposal aims to capitalize on the consensus recommendations of the NCI panel, the known
 antitumor activity of doxorubicin in HCC, and the as yet unpublished results of a recently
 completed Phase I clinical trial (WU HRPO# 07-0447, NCT00703170) combining pegylated
 liposomal doxorubicin (Doxil®) and temsirolimus (Torisel®) in patients with advanced solid
 tumors. In this Phase I study, twenty-two patients were enrolled and treated. The MTD and
 recommended Phase II dose for the combination regimen from this trial is is Doxil 25mg/m2 IV
 Q 4 weeks and temsirolimus 25mg IV Q week. During the conduct of this study two patients
 experienced confirmed partial responses (PR). One patient had heavily pretreated metastatic
 breast cancer and remained on the study for 6 months. The second patient with a PR had HCC
 that was previously treated with sorafenib. She remained on the study regimen for 14 months
 and tolerated this treatment well. Based on the tolerability of the drug combination and the
 observed anti-tumor activity in HCC, the current Phase II study in HCC is proposed.
Inclusion Criteria:

 -  Histologic Diagnosis: Patients must have a histologically or cytologically proven
 hepatocellular cancer (HCC) that is not amenable to treatment via resection or liver
 transplantation. In the absence of a tissue diagnosis, nodules on CT with a
 characteristic appearance of HCC plus Alpha Fetoprotein (AFP) > 400ng/ml will be
 considered diagnostic of HCC.

 -  Measurable Disease: Patients must have measurable disease.

 Measurable lesions are defined as those that can be accurately measured in at least one
 dimension (longest diameter to be recorded) as ≥20 mm with conventional techniques (PET,
 CT, MRI, x-ray) or as ≥10 mm with spiral CT scan. All tumor measurements must be recorded
 in millimeters (or decimal fractions of centimeters).

 A positive bone scan, osteoblastic metastases, and pleural or peritoneal effusions are not
 considered measurable. Patients with only these lesions are not eligible for entry to the
 study.

 -  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.

 -  Known Allergies: Patients with known hypersensitivity reactions to macrolide
 antibiotics (such as erythromycin, clarithromycin, and azithromycin) are not eligible
 for this trial.

 -  Cardiac Function: Patients must have a normal left ventricular ejection fraction (LVEF
 ≥50%) by MUGA scan.

 -  Sexually Active Patients: 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.

 -  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.