Efficacy, safety, pharmacokinetics, and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: a phase II study
Andrew X Zhu, Marek Ancukiewicz, Jeffrey G Supko, Dushyant V Sahani, Lawrence S Blaszkowsky, Jeffrey A Meyerhardt, Thomas A Abrams, Nadine Jackson McCleary, Pankaj Bhargava, Alona Muzikansky, Susan Sheehan, Eileen Regan, Eamala Vasudev, Michelle Knowles, Charles S Fuchs, David P Ryan, Rakesh K Jain, Dan G Duda, Andrew X Zhu, Marek Ancukiewicz, Jeffrey G Supko, Dushyant V Sahani, Lawrence S Blaszkowsky, Jeffrey A Meyerhardt, Thomas A Abrams, Nadine Jackson McCleary, Pankaj Bhargava, Alona Muzikansky, Susan Sheehan, Eileen Regan, Eamala Vasudev, Michelle Knowles, Charles S Fuchs, David P Ryan, Rakesh K Jain, Dan G Duda
Abstract
Purpose: We conducted a single-arm phase II study of cediranib, a pan-VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC).
Experimental design: Patients with histologically confirmed measurable advanced HCC and adequate hematologic, hepatic, and renal functions received cediranib 30-mg orally once daily (4 weeks/cycle). The primary endpoint was progression-free survival (PFS) rate at 3 months. Other endpoints included response rates, overall survival (OS), pharmacokinetics (PK), and biomarkers for cediranib.
Results: Cediranib treatment resulted in an estimated 3-month PFS rate of 77% (60%, 99%). Median PFS was 5.3 (3.5,9.7) months, stable disease was seen in 5/17 patients (29%), and median OS was 11.7 (7.5-13.6) months. Grade 3 toxicities included hypertension (29%), hyponatremia (29%), and hyperbilirubinemia (18%). Cediranib PK were comparable to those seen in cancer patients with normal hepatic function. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2, and Ang-2 decreased after cediranib treatment. PFS was inversely correlated with baseline levels of VEGF, sVEGFR2, and bFGF and with on-treatment levels of bFGF and IGF-1, and directly associated with on-treatment levels of IFN-γ. OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-α, CAIX, and CD34(+)CD133(+)CD45(dim) circulating progenitor cells and on-treatment levels of sVEGFR2.
Conclusions: Despite the limitations of primary endpoint selection, cediranib at 30-mg daily showed a high incidence of toxicity and preliminary evidence of antitumor activity in advanced HCC. Hepatic dysfunction did not seem to affect the steady-state PK of cediranib. Exploratory studies suggested proangiogenic and inflammatory factors as potential biomarkers of anti-VEGF therapy in HCC.
Conflict of interest statement
CONFLICT OF INTEREST DISCLOSURES: AXZ has had advisory/consulting roles for sanofi Aventis, Abbott, Bristol-Myers Squibb, Eisai, Daiichi Sankyo, Exelixis; and research support from Bayer, Onyx, ImClone-Lilly and Novartis. CSF has served as a consultant/advisor for Bayer, Sanofi, Pfizer, Genentech, Roche, Amgen, Infinity Pharm, Momenta Pharm, Metamark Genetics and Bristol Myers Squibb. DPR has had advisory/consulting roles for Boehringer Ingelheim and Genomic Health. RKJ received research grants from Dyax, MedImmune and Roche; consultant fees from Dyax, Enlight, Noxxon and SynDevRx; owns equity in Enlight, SynDevRx and XTuit, serves on the Board of Directors of XTuit and Boards of Trustees of H&Q Healthcare Investors and H&Q Life Sciences Investors. No reagents or funding from these companies was used in these studies. Therefore, there is no significant financial or other competing interest in the work.
Figures
Source: PubMed