Official Title: “Phase I Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma”

RATIONALE: Temsirolimus and sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving temsirolimus together with sorafenib tosylate may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of giving temsirolimus together with sorafenib tosylate in treating patients with advanced liver cancer and liver dysfunction.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label

Study Primary Completion Date: December 2012

OBJECTIVES:

Primary - Determine the maximum tolerated dose (MTD) and recommended phase II dose of the combination of temsirolimus and sorafenib tosylate in patients with advanced hepatocellular carcinoma and underlying liver dysfunction.

Secondary - Determine the safety and toxicity profile of this regimen in these patients. - Describe the pharmacokinetics (PK) of temsirolimus alone and in combination with sorafenib tosylate in a cohort of patients treated at the MTD. - Measure the incidence of progression-free survival (PFS) at 6 months in patients treated with this regimen. - Determine the overall survival (OS) and the disease control rate in patients treated with this regimen.

Tertiary - Examine the relationship between changes in tumor blood flow, as measured by dynamic contrast-enhanced CT scan (DCE-CT) after 2 courses of therapy, to determine if there is an association with PFS rate at 6 months in patients treated in the PK cohort at the MTD. (Exploratory) - Assess the tumor response (using Choi response criteria) after 2 courses of therapy to determine if there is an association with PFS rate at 6 months in patients treated in the PK cohort at the MTD. (Exploratory) - Compare the degree of association with PFS rate at 6 months between standard RECIST criteria, Choi response criteria, and DCE-CT parameters after 2 courses of therapy. (Exploratory) - Measure tumor markers AFP, AFP-L3, and DCP to determine if baseline levels are prognostic and/or if a change in levels after 1-2 courses of therapy is predictive of PFS rate at 6 months in patients treated in the PK cohort at the MTD. (Exploratory) - Measure circulating-tumor cell (CTC) levels (high or low) at baseline and after 1-2 courses of therapy to determine if baseline levels are prognostic and/or if a change in levels after 1-2 courses of therapy is predictive of PFS rate at 6 months in patients treated in the PK cohort at the MTD. (Exploratory) - Monitor hepatitis viral load in patients with known hepatitis B or C virus (HBV or HCV) infection to measure rates of reactivation of HBV and/or HCV during and after therapy with temsirolimus. (Exploratory) - Compare PFS and OS in patients with HCV, HBV, and other causes of underlying liver disease. (Exploratory) - Archive tissue (when available) and blood specimens from consenting patients for future correlative studies. (Exploratory)

OUTLINE: This is a multicenter study.

Patients receive temsirolimus IV over 30-60 minutes on days 1, 8, 15, and 22 and oral sorafenib tosylate once or twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Some patients undergo blood sample collection at baseline and periodically during study for pharmacokinetic and tumor marker studies.

After completion of study therapy, patients are followed periodically.

Intervention(s) in this Clinical Trial

• Drug: sorafenib tosylate
• Drug: temsirolimus
• Other: laboratory biomarker analysis
• Other: pharmacological study

Primary Measures

• Maximum tolerated dose and recommended phase II dose
  • Safety Issue?: Yes

Secondary Measures

• Safety and toxicity profile
  • Safety Issue?: Yes
• Pharmacokinetics of temsirolimus alone and in combination with sorafenib tosylate
  • Safety Issue?: No
• Progression-free survival rate at 6 months
  • Safety Issue?: No
• Overall survival
  • Safety Issue?: No
• Disease control rate
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Histologically or clinically confirmed hepatocellular carcinoma
• Clinical diagnosis allowed provided 1 of the following is met:
• Tumor is 1-2 cm in size and demonstrates classic radiographic features of arterial enhancement with venous washout on image
• Tumor > 2 cm and demonstrates these classic radiographic features and/or
• AFP > 200 ng/mL
• Stage III or IV disease not amenable to curative resection
• Radiographically measurable disease in ≥ 1 site that was not previously treated with chemoembolization, radioembolization, or other local ablative procedure
• Must have ≥ 1 untreated target lesion within the liver or in a measurable metastatic site
• No mixed tumor histology or fibrolamellar-variant tumors
• Child-Pugh score A or B (with 7 points only) AND bilirubin ≤ 2 mg/dL
• No symptomatic brain or bone metastases

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Life expectancy > 3 months
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 75,000/mm^3
• Hemoglobin ≥ 8.5 g/dL
• Total bilirubin ≤ 2 mg/dL OR ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 5 times ULN
• INR ≤ 1.5 times ULN
• Albumin ≥ 2.8 g/dL
• Creatinine ≤ 1.5 times ULN
• Cholesterol < 350 mg/dL at baseline (with or without anti-hyperlipidemic medication)
• Triglycerides < 300 mg/dL at baseline (with or without anti-hyperlipidemic medication)
• Fasting blood glucose and hemoglobin A1c normal at baseline (with or without anti-diabetic medications)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must agree to use effective double-method contraception during and for 3 months after completion of study therapy
• Able to tolerate oral therapy
• No known HIV infection
• No history of seizure disorder requiring antiepileptic medication or seizures secondary to brain metastases
• No serious non-healing wound, ulcer, bone fracture, or abscess
• No active second malignancy except non-melanoma skin cancer or cervical carcinoma in situ
• Patients with history of malignancy are not considered to have a "currently active" malignancy if they have completed therapy and are now considered by their physician to be at < 30% risk for relapse
• No concurrent uncontrolled illness including, but not limited to, any of the following:
• Ongoing or active infection
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Uncontrolled hypertension (i.e., blood pressure > 150/100 mm Hg)
• Uncontrolled cardiac arrhythmia
• Uncontrolled peripheral vascular disease
• Myocardial infarction within the past 12 months
• Cerebrovascular accident within the past 12 months
• Pulmonary disease impairing functional status or requiring oxygen
• Impairment in gastrointestinal function that may affect or alter absorption of oral medications (e.g., malabsorption, history of gastrectomy, or bowel resection)
• No history of allergic reaction(s) attributed to compounds of similar composition to temsirolimus, sorafenib tosylate, or their metabolites or to any component of their formulation, including excipients and polysorbate 80 (e.g., hypersensitivity to macrolide antibiotics due to potential for cross-reactivity with temsirolimus)
• No psychiatric illness, other significant medical illness, or social situation that, in the investigator's opinion, would limit compliance or ability to comply with study requirements
• No other condition that, in the judgement of the principal investigator, would compromise compliance with study objectives and procedures

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 6 weeks since prior chemoembolization, local ablative therapies, or hepatic resection
• More than 6 weeks since prior major surgical procedures
• At least 2 weeks since prior radiotherapy and/or steroid therapy for brain or bone metastases
• No prior antiangiogenic therapy, including thalidomide, sorafenib tosylate, sunitinib malate, or bevacizumab
• No prior mTOR inhibitor or other molecularly targeted therapy
• No prior systemic cytotoxic therapies (other than chemoembolization)
• No prior liver transplantation
• No concurrent inducers or strong inhibitors of CYP3A4
• No concurrent substrates of CYP3A4, CYP2B6, CYP2C8, or CYP2C9 that are sensitive or have a narrow therapeutic range
• No other concurrent investigational agents
• No concurrent immunosuppressive medications, including systemic corticosteroids, unless used for adrenal replacement, appetite stimulation, acute therapy for asthma or bronchitis exacerbation (< 2 weeks), or antiemesis
• No concurrent chronic anticoagulation therapy
• Concurrent antiviral therapy for active hepatitis B virus infection required
• Concurrent treatment for clinically significant hyperglycemia, hyperlipidemia, or hypertension that develops during study required

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of California, San Francisco

Overall Clinical Trial Officials and Contacts

Alan P. Venook, MD Principal Investigator University of California, San Francisco  

Information obtained from ClinicalTrials.gov on February 04, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01013519

Study ID Number: CDR0000658667

ClinicalTrials.gov Identifier: NCT01013519

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database