This trial is active, not recruiting.

Conditions hepatic complications, liver cancer
Treatments sorafenib tosylate, temsirolimus, laboratory biomarker analysis, pharmacological study
Phase phase 1
Sponsor University of California, San Francisco
Collaborator National Cancer Institute (NCI)
Start date November 2009
End date December 2013
Trial size 25 participants
Trial identifier NCT01013519, 09455, CDR0000658667, H5535-34892, UCSF-09455


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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation non-randomized
Intervention model single group assignment
Masking open label
Primary purpose treatment
sorafenib tosylate
laboratory biomarker analysis
pharmacological study

Primary Outcomes

Maximum tolerated dose and recommended phase II dose
time frame: every 2 months or until progression, approximately 6 months

Secondary Outcomes

Safety and toxicity profile
time frame: every 2 months or until progression, approximately 6 months
Pharmacokinetics of temsirolimus alone and in combination with sorafenib tosylate
time frame: every 2 months or until progression, approximately 6 months
Progression-free survival rate at 6 months
time frame: every 2 months or until progression, approximately 6 months
Overall survival
time frame: every 2 months or until progression, approximately 6 months
Disease control rate
time frame: every 2 months or until progression, approximately 6 months

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria 1. Histologically or clinically* diagnosed AJCC stage II, III, or IV HCC not amenable to curative resection and with no prior systemic cytotoxic or molecularly-targeted therapies. *Clinical diagnosis is acceptable if tumor is 1-2 cm in size and demonstrates classic radiographic features of arterial enhancement with venous washout on imaging; if > 2 cm, clinical diagnosis is acceptable if tumor demonstrates these classic radiographic features and/or AFP > 200 ng/mL.64-65 2. Age ≥ 18 years. 3. Child-Pugh score A or score of B with 7 points only and bilirubin ≤ 2 mg/dL. 4. ECOG performance status ≤ 2 (see Appendix A). 5. Life expectancy greater than 3 months. 6. Radiographically measurable disease in at least one site not previously treated with chemoembolization, radioembolization, or other local ablative procedures (i.e. must have at least one measurable target lesion, either within the liver or in a measurable metastatic site). A new area of tumor progression within or adjacent to a previously-treated lesion, if clearly measurable by a Radiologist, is acceptable. 7. Prior chemoembolization, local ablative therapies, or hepatic resection permitted if completed ≥ 6 weeks prior to study enrollment and if criterion 6 is present. 8. Prior radiation for bone or brain metastases is permitted if patient is now asymptomatic and has completed all radiation and steroid therapy (if applicable) for brain or bone metastases ≥ 2 weeks prior to study enrollment. 9. Treatment with appropriate antiviral therapy for patients with active HBV infection is required. 10. Treatment for clinically-significant hyperglycemia, hyperlipidemia, or hypertension that develops on study is required. 11. Baseline blood pressure must be adequately controlled with or without antihypertensive medications prior to enrollment (systolic ≤ 140 mm Hg, diastolic ≤ 90 mm Hg). 12. Baseline cholesterol must be < 350 mg/dL and triglycerides < 300 mg/dL (with or without the use of antihyperlipidemic medications). 13. Baseline fasting blood glucose must be ≤ 140 mg/dL and hemoglobin A1c less than 7.5% (with or without the use of anti-diabetic medications). 14. Adequate baseline organ and marrow function as defined below: - Absolute neutrophil count ≥ 1,500/mcL - Platelets ≥ 75,000/mcL - Hemoglobin ≥ 8.5 g/dL - Total bilirubin ≤ 2 mg/dL or ≤ 1.5 times ULN - AST(SGOT)/ALT(SGPT) ≤ 5 times ULN - INR ≤ 1.5 times ULN - Albumin ≥ 2.8 g/dL - Creatinine ≤ 1.5 times ULN 15. Able to tolerate oral therapy. 16. Ability to give written informed consent and willingness to comply with the requirements of the protocol. 17. Women of child-bearing potential must have a negative pregnancy test within 14 days of study enrollment and must agree to use an effective double method of birth control during treatment and for three months after receiving their last dose of study drug; men must be surgically sterile or agree to use an effective double method of birth control during treatment and for three months after receiving their last dose of study drug; all patients must notify treating provider immediately if any suspicion of pregnancy or conception. 18. Eligibility of patients receiving any medications or substances known to affect or with potential to affect the activity or pharmacokinetics of temsirolimus and/or sorafenib will be determined following review of the case by the Study Chair. Efforts should be made to switch patients who are taking enzyme-inducing anti-convulsant agents to other medications. A list of medications and substances known or with the potential to interact with selected relevant CYP450 isoenzymes, P-glycoprotein pathway, and/or UGT1A1 glucuronidation is provided in Appendix B. Exclusion Criteria 1. Mixed tumor histology or fibrolamellar variant tumors are excluded. 2. Prior antiangiogenic therapy (including thalidomide, sorafenib, sunitinib, or bevacizumab). 3. Prior treatment with mTOR inhibitor or other molecularly targeted therapy. 4. Prior systemic cytotoxic therapies for HCC (chemoembolization is permitted if inclusion criteria are met). 5. Treatment with other investigational agents. 6. Immunosuppressive medications including systemic corticosteroids unless used for adrenal replacement, appetite stimulation, acute therapy for asthma or bronchitis exacerbation (≤ 2 weeks), or antiemesis. 7. Patients with known HIV infection are excluded. 8. Patients who have undergone liver transplantation are excluded. 9. Uncontrolled hypertension (> 140/90 mmHg). 10. Uncontrolled hyperlipidemia (total cholesterol > 350 or triglycerides > 300). 11. Symptomatic brain or bone metastases; prior radiation and/or steroid therapy for brain or bone metastases (if applicable) must be completed ≥ 2 weeks prior to study enrollment. 12. History of seizure disorder requiring antiepileptic medication or brain metastases with seizures. 13. Serious non-healing wound, ulcer, bone fracture, or abscess. 14. Major surgical procedure within 6 weeks of enrollment. 15. Patients requiring chronic anticoagulation with warfarin are excluded. Patients on other forms of anticoagulation may be eligible if on a stable dose without evidence of clinically significant bleeding for at least 2 weeks prior to enrollment. 16. Active second malignancy other than 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 less than 30% risk for relapse.) 17. Uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, uncontrolled peripheral vascular disease, myocardial infarction within preceding 12 months, cerebrovascular accident within preceding 12 months, pulmonary disease impairing functional status or requiring oxygen, impairment in gastrointestinal function that may affect or alter absorption of oral medications (such as malabsorption or history of gastrectomy or bowel resection). 18. Patients will be excluded if there is any history of allergic reaction(s) attributed to compounds of similar composition to temsirolimus, sorafenib, their metabolites, or any component of their formulation (including excipients and polysorbate 80). This includes hypersensitivity to macrolide antibiotics due to potential for cross-reactivity with temsirolimus. 19. Pregnant or lactating women and fertile women and men who are not willing to comply with an effective double method of birth control will be excluded. 20. Psychiatric illness, other significant medical illness, or social situation which, in the investigator's opinion, would limit compliance or ability to comply with study requirements. 21. Any other condition that compromises compliance with the objectives and procedures of this protocol, as judged by the Study Chair, is also grounds for exclusion.

Additional Information

Official title Phase I Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma
Principal investigator Robin-Kate Kelley, MD
Description OBJECTIVES: Primary - Determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of temsirolimus and sorafenib in combination in patients with advanced HCC and underlying liver dysfunction. Phase I Secondary Objectives 1. Determine safety and toxicity profile. 2. Describe pharmacokinetics of temsirolimus alone and in combination with sorafenib in cohort of 6 to 9 patients treated at MTD. 3. Observe PFS at 6 months. Exploratory/Correlative Objectives (To be Combined with Future Phase II Data) 4. Evaluate for tumor necrosis radiographically after 2 cycles of therapy to determine if there is a relationship with PFS at 6 months in 6 to 9 patients treated in PK cohort at MTD.* 5. Compare degree of association with proportion with PFS at 6 months between standard RECIST (version 1.1, see section 11.2) and tumor necrosis measurements after 2 cycles of protocol therapy.* 6. Measure tumor markers AFP, AFP-L3, and DCP at baseline and after 1 and 2 cycles to evaluate for any relationship with PFS at 6 months in 6 to 9 patients treated in PK cohort at MTD.* 7. Measure baseline circulating tumor cell (CTC) levels (high or low) as well as after 1 and 2 cycles of therapy to evaluate for any relationship with PFS at 6 months in 6 to 9 patients treated in PK cohort at MTD.* 8. In patients with known HBV or HCV infection in all dose cohorts, monitor hepatitis viral load to measure rates of reactivation HBV and/or HCV during and after therapy with an mTOR inhibitor. 9. Observe PFS at 6 months in patients with HCV, HBV, and other causes of underlying liver disease. 10. Archive blood specimens from consenting patients for future correlative studies. - These results will be analyzed as part of the future Phase II study of this combination only for patients in the PK expansion cohort treated at the recommended Phase II dose. 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.
Trial information was received from ClinicalTrials.gov and was last updated in June 2013.
Information provided to ClinicalTrials.gov by University of California, San Francisco.