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Conference Paper: Phase I study of everolimus in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC)

TitlePhase I study of everolimus in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC)
Authors
KeywordsMedical sciences
Oncology medical sciences
Radiology and nuclear medicine pharmacy and pharmacology biology
Cytology and histology
Issue Date2011
PublisherAmerican Society of Clinical Oncology. The Journal's web site is located at http://www.jco.org/
Citation
The 2011 Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago, IL., 4-8 June 2011. In Journal of Clinical Oncology, 2011, v. 29 n. 15 suppl., abstract no. 4074 How to Cite?
AbstractBACKGROUND: The PI3K/Akt/mTOR pathway, a key regulator of cellular proliferation and angiogenesis, has emerged as a contributor to hepatocarcinogenesis. Everolimus, an mTOR inhibitor, exhibits antineoplastic activity in preclinical and experimental models of HCC. Sorafenib, a multi-tyrosine kinase (including Raf) inhibitor, is the only targeted therapy demonstrating a survival benefit and approved for first-line treatment in patients with unresectable HCC. Enhanced efficacy may be achieved through dual inhibition of key signaling pathways involved in hepatocarcinogenesis. We evaluated the maximum tolerated dose (MTD) and pharmacokinetics of everolimus in combination with 400 mg bid of sorafenib in patients with advanced HCC. METHODS: In this phase I study (NCT00828594) patients ≥18 years of age with measurable, previously untreated, BCLC Stage B or C HCC and ECOG score of 0-1, Child-Pugh’s A (5-6 points) received escalating doses of everolimus starting at 2.5 mg qd + sorafenib 400 mg bid for 28 days. Primary endpoint was MTD. RESULTS: Thirty patients with advanced HCC were enrolled (everolimus 2.5 mg qd, n=16; everolimus 5 mg qd, n=14). Most patients were Asian (73%) and HBsAg positive (63%), with BCLC Stage C HCC (93%). Dose escalation above 5 mg qd was not achieved. Dose-limiting toxicity was grade 3 AST elevation (n=1) in the 2.5 mg group and grade 3/4 thrombocytopenia (n= 5) and hyperbilirubinemia (n=1) in the 5.0 mg group. Drug-related AE rates leading to dose reductions (42.9% vs 0%) and interruptions (71.4% vs 37.5%) were more common in the 5 mg cohort than the 2.5 mg group. Everolimus pharmacokinetics in this population were dose proportional and comparable to that previously reported for monotherapy in non-HCC patients. Disease stabilization occurred in 10 (62.5%) patients and 5 (35.7%) in the 2.5 mg and 5.0 mg groups, respectively. Median time to progression was 3.5 and 3.6 months in the 2.5 mg and 5.0 mg groups, respectively. CONCLUSIONS: The MTD of everolimus in combination with sorafenib 400 mg bid was 2.5 mg qd in this population. The inability to achieve what is deemed a biologically effective dose of everolimus in combination with sorafenib will preclude progression to phase II in this study.
DescriptionIn Journal of Clinical Oncology, 2011, v. 29 n. 15 suppl., abstract no. 4074
General Poster Session - Gastrointestinal (Noncolorectal) Cancer: abstract no. 4074
Persistent Identifierhttp://hdl.handle.net/10722/137892
ISSN
2015 Impact Factor: 20.982
2015 SCImago Journal Rankings: 9.204

 

DC FieldValueLanguage
dc.contributor.authorFinn, RSen_US
dc.contributor.authorPoon, RTPen_US
dc.contributor.authorYau, Ten_US
dc.contributor.authorKlumpen, Hen_US
dc.contributor.authorChen, Len_US
dc.contributor.authorKang, Yen_US
dc.contributor.authorKim, Ten_US
dc.contributor.authorGomez-Martin, Cen_US
dc.contributor.authorRodriguez-Lope, Cen_US
dc.contributor.authorKunz, Ten_US
dc.contributor.authorPaquet, Ten_US
dc.contributor.authorAsubonteng, Ken_US
dc.contributor.authorWinkler, REen_US
dc.contributor.authorAnak, Oen_US
dc.contributor.authorSellami, DBen_US
dc.contributor.authorBruix, Jen_US
dc.date.accessioned2011-08-26T14:36:30Z-
dc.date.available2011-08-26T14:36:30Z-
dc.date.issued2011en_US
dc.identifier.citationThe 2011 Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago, IL., 4-8 June 2011. In Journal of Clinical Oncology, 2011, v. 29 n. 15 suppl., abstract no. 4074en_US
dc.identifier.issn0732-183X-
dc.identifier.urihttp://hdl.handle.net/10722/137892-
dc.descriptionIn Journal of Clinical Oncology, 2011, v. 29 n. 15 suppl., abstract no. 4074-
dc.descriptionGeneral Poster Session - Gastrointestinal (Noncolorectal) Cancer: abstract no. 4074-
dc.description.abstractBACKGROUND: The PI3K/Akt/mTOR pathway, a key regulator of cellular proliferation and angiogenesis, has emerged as a contributor to hepatocarcinogenesis. Everolimus, an mTOR inhibitor, exhibits antineoplastic activity in preclinical and experimental models of HCC. Sorafenib, a multi-tyrosine kinase (including Raf) inhibitor, is the only targeted therapy demonstrating a survival benefit and approved for first-line treatment in patients with unresectable HCC. Enhanced efficacy may be achieved through dual inhibition of key signaling pathways involved in hepatocarcinogenesis. We evaluated the maximum tolerated dose (MTD) and pharmacokinetics of everolimus in combination with 400 mg bid of sorafenib in patients with advanced HCC. METHODS: In this phase I study (NCT00828594) patients ≥18 years of age with measurable, previously untreated, BCLC Stage B or C HCC and ECOG score of 0-1, Child-Pugh’s A (5-6 points) received escalating doses of everolimus starting at 2.5 mg qd + sorafenib 400 mg bid for 28 days. Primary endpoint was MTD. RESULTS: Thirty patients with advanced HCC were enrolled (everolimus 2.5 mg qd, n=16; everolimus 5 mg qd, n=14). Most patients were Asian (73%) and HBsAg positive (63%), with BCLC Stage C HCC (93%). Dose escalation above 5 mg qd was not achieved. Dose-limiting toxicity was grade 3 AST elevation (n=1) in the 2.5 mg group and grade 3/4 thrombocytopenia (n= 5) and hyperbilirubinemia (n=1) in the 5.0 mg group. Drug-related AE rates leading to dose reductions (42.9% vs 0%) and interruptions (71.4% vs 37.5%) were more common in the 5 mg cohort than the 2.5 mg group. Everolimus pharmacokinetics in this population were dose proportional and comparable to that previously reported for monotherapy in non-HCC patients. Disease stabilization occurred in 10 (62.5%) patients and 5 (35.7%) in the 2.5 mg and 5.0 mg groups, respectively. Median time to progression was 3.5 and 3.6 months in the 2.5 mg and 5.0 mg groups, respectively. CONCLUSIONS: The MTD of everolimus in combination with sorafenib 400 mg bid was 2.5 mg qd in this population. The inability to achieve what is deemed a biologically effective dose of everolimus in combination with sorafenib will preclude progression to phase II in this study.-
dc.languageengen_US
dc.publisherAmerican Society of Clinical Oncology. The Journal's web site is located at http://www.jco.org/-
dc.relation.ispartofJournal of Clinical Oncologyen_US
dc.subjectMedical sciences-
dc.subjectOncology medical sciences-
dc.subjectRadiology and nuclear medicine pharmacy and pharmacology biology-
dc.subjectCytology and histology-
dc.titlePhase I study of everolimus in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC)en_US
dc.typeConference_Paperen_US
dc.identifier.emailPoon, RTP: poontp@hku.hken_US
dc.identifier.emailYau, T: tyaucc@hku.hken_US
dc.identifier.authorityPoon, RTP=rp00446en_US
dc.identifier.authorityYau, T=rp01466en_US
dc.identifier.hkuros189737en_US
dc.identifier.volume29en_US
dc.identifier.issue15 suppl.en_US
dc.description.otherThe 2011 Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago, IL., 4-8 June 2011. In Journal of Clinical Oncology, 2011, v. 29 n. 15 suppl., abstract no. 4074-

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