Efficacy, safety, pharmacokinetics, and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: a phase II study.
OBJECTIVE
We conducted a single-arm phase II study of cediranib, a pan-VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC).


METHODS
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.
Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA. azhu@partners.org
Andrew X
AX
Zhu
Marek
M
Ancukiewicz
Jeffrey G
JG
Supko
Dushyant V
DV
Sahani
Lawrence S
LS
Blaszkowsky
Jeffrey A
JA
Meyerhardt
Thomas A
TA
Abrams
Nadine Jackson
NJ
McCleary
Pankaj
P
Bhargava
Alona
A
Muzikansky
Susan
S
Sheehan
Eileen
E
Regan
Eamala
E
Vasudev
Michelle
M
Knowles
Charles S
CS
Fuchs
David P
DP
Ryan
Rakesh K
RK
Jain
Dan G
DG
Duda
D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors; D007211:Indoles
D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D040281:Vascular Endothelial Growth Factor Receptor-1; C500926:cediranib; D007211:Indoles