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A Phase 1 dose-finding and pharmacodynamic study of rapamycin in combination with bevacizumab in patients with unresectable hepatocellular carcinoma.
- Source :
-
European journal of cancer (Oxford, England : 1990) [Eur J Cancer] 2013 Mar; Vol. 49 (5), pp. 999-1008. Date of Electronic Publication: 2012 Dec 19. - Publication Year :
- 2013
-
Abstract
- Background & Aims: Preclinical studies have demonstrated the additive effect of rapamycin with bevacizumab for hepatocellular carcinoma treatment. We conducted a Phase 1 study to evaluate the safety and pharmacokinetics of the combination in patients with hepatocellular carcinoma.<br />Methods: Adult participants with advanced hepatocellular carcinoma received intravenous bevacizumab (5mg/kg every 14 days) and oral rapamycin (1-6 mg/day; 3+3 dose escalation design). Computed tomography assessed tumour response and treatment safety. Pharmacokinetics assessment established rapamycin blood concentrations pre- and post-dose. Dynamic contrast-enhanced computed tomography analysed the tumour region for blood flow, permeability surface area product, fractional intravascular blood volume and extracellular-extravascular volume.<br />Results: Twenty-four participants were treated. There were two dose limiting toxicities with rapamycin 5mg: grade 3 thrombocytopenia and grade 3 mucositis. The maximally tolerated dose of rapamycin was 4 mg. Adverse events (grade 1-2) included hyperglycaemia (83%), thrombocytopenia (75%), fatigue (46%), mucositis (46%), anorexia (42%), diarrhoea (33%) and proteinuria (12.5%). Of 20 evaluable participants, one reached complete response that lasted 4.5 months, two reached partial response, 14 reached stable disease and three had progressive disease. Median overall survival was 9.4 months; progression-free survival was 5.5 months. Dose level and steady state area under the concentration time curve for hour zero to infinity of rapamycin correlated inversely with blood flow rate and change in permeability-surface area. After 22 days of treatment, there were significant reductions from baseline in blood flow rate, permeability-surface area and fractional intracellular blood volume.<br />Conclusions: The recommended Phase 2 dose of rapamycin is 4 mg in combination with bevacizumab. Evidence of anti-vascular activity was observed together with promising clinical activity.<br /> (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized administration & dosage
Antibodies, Monoclonal, Humanized adverse effects
Antineoplastic Combined Chemotherapy Protocols adverse effects
Bevacizumab
Carcinoma, Hepatocellular metabolism
Carcinoma, Hepatocellular pathology
Dose-Response Relationship, Drug
Female
Hepatectomy
Humans
Liver Neoplasms metabolism
Liver Neoplasms pathology
Male
Maximum Tolerated Dose
Middle Aged
Sirolimus administration & dosage
Sirolimus adverse effects
Treatment Outcome
Antibodies, Monoclonal, Humanized pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols administration & dosage
Antineoplastic Combined Chemotherapy Protocols pharmacokinetics
Carcinoma, Hepatocellular drug therapy
Liver Neoplasms drug therapy
Sirolimus pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0852
- Volume :
- 49
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- European journal of cancer (Oxford, England : 1990)
- Publication Type :
- Academic Journal
- Accession number :
- 23265712
- Full Text :
- https://doi.org/10.1016/j.ejca.2012.11.008