RATIONALE: Drugs used in chemotherapy, such as doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Chemoembolization kills tumor cells by carrying drugs directly into the tumor and blocking the blood flow to the tumor. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It is not yet known whether transarterial chemoembolization with doxorubicin is more effective when given alone or when given together with everolimus in treating patients with liver cancer. PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of everolimus when given together with transarterial chemoembolization with doxorubicin and to see how well it works compared with giving transarterial chemoembolization with doxorubicin alone in treating patients with liver cancer.
OBJECTIVES: * Determine the recommended dose of everolimus in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization with doxorubicin-eluting beads (TACE). (Phase I) * Determine the efficacy and tolerability of everolimus in patients with HCC treated with TACE as compared to TACE alone. (Phase II) OUTLINE: This is a multicenter, dose-escalation phase I study followed by a randomized phase II study. * Phase I: Patients receive oral everolimus once daily in the absence of disease progression or unacceptable toxicity. Beginning 7 days after the start of everolimus patients undergo transarterial chemoembolization (TACE) comprising doxorubicin-eluting beads into the hepatic artery followed in 4 weeks by an MRI. If viable tumor is found patients undergo another TACE treatment continuing every 4 weeks for up to 5 treatments. * Phase II: Patients are stratified according to center, age (≤ 60 vs \> 60 years), and number of lesions (≤ 3 vs \> 3). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive oral placebo once daily for up to 12 months and undergo TACE comprising doxorubicin-eluting beads as in phase I at the maximum tolerated dose (MTD). * Arm II: Patients receive oral everolimus once daily for up to 12 months and undergo TACE comprising doxorubicin-eluting beads as in phase I at the MTD. In both arms, patients receive treatment for up to 12 months in the absence of disease progression or unacceptable toxicity. Blood samples are collected periodically for analysis of AFP tumor markers. Patients also complete quality of life questionnaires, Health Economic Assessment, and EQ5D questionnaires at baseline and periodically during the study. After completion of study treatment, patients are followed on day 30, and then every 3 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
27
Patients receive oral placebo or everolimus once daily for up to 12 months and undergo TACE comprising doxorubicin-eluting beads as in phase I at the MTD.
Patients receive oral everolimus once daily for up to 12 months and undergo TACE comprising doxorubicin-eluting beads as in phase I at the MTD.
Patients receive oral placebo once daily for up to 12 months and undergo TACE comprising doxorubicin-eluting beads as in phase I at the MTD.
Inselspital Bern
Bern, Switzerland
Kantonsspital Graubuenden
Chur, Switzerland
Hopital Cantonal Universitaire de Geneve
Geneva, Switzerland
Centre Hospitalier Universitaire Vaudois
Lausanne, Switzerland
Clinica Luganese di Moncucco
Lugano, Switzerland
Kantonsspital - St. Gallen
Sankt Gallen, Switzerland
Institut Central des Hopitaux Valaisans / Hôpital de Sion
Sion, Switzerland
UniversitaetsSpital Zuerich
Zurich, Switzerland
Dose-limiting toxicity (Phase I)
Dose limiting toxicity (DLT) (observed within the first TACE period)
Time frame: after 6 weeks from registration
Time to progression (Phase II)
Time frame: 12 weeks after randomisation
Time to progression (Phase I)
Time frame: 12 weeks after registration
Progression-free survival (Phase II)
* Relapse or progression assessed according to the modified RECIST criteria * Death of any cause * Metastasis outside of liver
Time frame: Time from randomization until event occurs (see description):
Progression-free survival at 12 months (Phase II)
Time frame: within 12 months after randomisation
Tumor response according to adapted RECIST criteria (Phase II)
Time frame: during treatment
Overall survival (Phase II)
Time frame: Time from randomisation until death from any cause
Response duration (Phase II)
From the time when criteria for response (CR or PR) are met, until documentation of relapse or progression thereafter.
Time frame: See description
Time to treatment failure (Phase II)
Time from registration to any treatment failure including disease progression or premature (within 12 months) discontinuation of treatment for any reason (e.g., disease progression, toxicity, patient preference, initiation of new treatment without documented progression, Initiation of second line of TACE, Initiation of sorafenib therapy or death).
Time frame: See description
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