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Phase II, Open-Label Study of Brivanib As First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma

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Phase II, Open-Label Study of Brivanib As First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma Published OnlineFirst February 24, 2011; DOI: 10.1158/1078-0432.CCR-10-2011 Clinical Cancer Cancer Therapy: Clinical Research Phase II, Open-Label Study of Brivanib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma Joong-Won Park1, Richard S. Finn2, Jun Suk Kim3, Mark Karwal4, Ruby K. Li5, Fuad Ismail6, Melanie Thomas7, Rosemarie Harris8, Christine Baudelet8, Ian Walters8, and Jean-Luc Raoul9 Abstract Purpose: Brivanib, a selective dual inhibitor of fibroblast growth factor and VEGF signaling, has demonstrated encouraging antitumor activity in preclinical and phase I studies. We performed a phase II open-label study of brivanib as first-line therapy in patients with unresectable, locally advanced, or metastatic hepatocellular carcinoma. Experimental Design: Brivanib was administered orally at a dose of 800 mg once daily. The primary objective was 6-month progression-free survival, progression-free survival rate; secondary objectives were tumor response rate, time to response, duration of response, median progression-free survival, median overall survival, disease control rate (complete response, partial response, or stable disease 42 days), and safety and tolerability. Results: Between March 2007 and May 2009, 55 patients were treated and were evaluable for response. Patients were assessed using modified World Health Organization (mWHO) criteria. Accord- ing to mWHO criteria and as assessed by Independent Response Review Committee, the six-month progression-free survival rate (95% CI) was 18.2% (9.1%–30.9%). Median progression-free survival (95% CI) was 2.7 months (1.4–3.0). One patient achieved a complete response and three achieved a partial response. Twenty-two had stable disease. Median overall survival (95% CI) was 10 (6.8–15.2) months. Brivanib was generally well tolerated; the most common adverse events included fatigue, hypertension, and diarrhea. Conclusion: Brivanib as first-line therapy demonstrates promising antitumor activity and a manageable safety profile in patients with advanced, unresectable HCC. Clin Cancer Res; 17(7); 1973–83. Ó2011 AACR. Introduction cirrhosis, making it difficult to interpret composite end points (3). As HCC is a highly vascularized tumor, ther- Hepatocellular carcinoma (HCC) is the fifth most com- apeutic concepts targeting key molecular pathways mon malignancy worldwide (1) and the third largest cause involved in tumor angiogenesis are of particular interest of cancer-related deaths (2). HCC is unique in that it in targeting malignancy. Sorafenib, an inhibitor of VEGFR- represents 2 diseases, primary liver dysfunction/cirrhosis 2, c-Kit, and raf, has demonstrated activity and tolerability and malignancy. These 2 comorbid conditions create in advanced HCC (4, 5). unique clinical challenges, particularly because agents with Fibroblast growth factor-2 (FGF-2) is a potent angiogenic efficacy against malignant growth may worsen underlying factor in HCC (6–9). Upregulation of alternate proangio- genic signals, such as the FGF signaling pathway, may play a role in evasive resistance to VEGF-targeted antiangiogenic 1 Authors' Affiliations: National Cancer Center, Goyang, Republic of therapy (10). Moreover, preclinical data suggest that Korea; 2Geffen School of Medicine, UCLA, Los Angeles, California; 3Korea 4 University Guro Hospital, Seoul, Republic of Korea; Holden Comprehen- although VEGF inhibitors reduce primary tumor growth, sive Cancer Center at University of Iowa, Iowa City, Iowa; 5St. Lukes they also promote tumor invasiveness and metastasis in 2 Medical Center, Quezon City, Philippines; 6Hospital Universiti Kebang- 7 mouse models with melanoma or pancreatic cancer (11– saan, Kuala Lumpar, Malaysia; Department of Hematology/Oncology, Hollings Cancer Center, Medical University of South Carolina, Charleston, 13). Brivanib, the first oral selective dual inhibitor of FGF South Carolina; 8Bristol-Myers Squibb, Princeton, New Jersey; and 9Cen- and VEGF signaling, is formulated as an orally adminis- tre E Marquis, INSERM U911, Rennes, France tered L-alanine ester prodrug, brivanib alaninate (14). Note: Supplementary data for this article are available at Clinical Cancer Brivanib has strong antiangiogenic effects, as well as potent Research Online (http://clincancerres.aacrjournals.org/). direct effects, on tumor cells across a range of tumor types, Corresponding Author: Joong-Won Park, Center for Liver Cancer, National Cancer Center, 809 Madu 1-dong Ilsan-gu, Goyang, Gyeonggi including liver and colon(15–17). In addition, brivanib 411-764, South Korea. Phone: 82-31-920-1605; Fax: 82-31-920-1520. has demonstrated antitumor activity in xenograft HCC E-mail: [email protected] models expressing FGF receptors (17). Thus, targeting both doi: 10.1158/1078-0432.CCR-10-2011 the VEGF and FGF signaling pathways may provide clinical Ó2011 American Association for Cancer Research. benefits to HCC patients. Brivanib has a half-life of 12 www.aacrjournals.org 1973 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst February 24, 2011; DOI: 10.1158/1078-0432.CCR-10-2011 Park et al. Translational Relevance [a-fetoprotein (AFP) levels 400 mg/L and standard imaging criteria; ref.21] and were serology positive for Cytotoxic chemotherapy has not been shown to hepatitis B or C, with a Cancer of the Liver Italian Program improve outcomes for patients with advanced hepato- (CLIP) score 3 or less and Eastern Cooperative Oncology cellular carcinoma (HCC). Recently sorafenib, a small Group (ECOG) performance status of 0 to 2, and adequate molecule, multitargeted tyrosine kinase inhibitor of the hepatic function and renal function, were eligible for VEGFR, was shown to improve survival for these inclusion in the study (see online Supplementary section patients. These benefits appear to be variable, modest, A for full criteria). and with some toxicities, thus highlighting that there are still many unmet needs. An increased understanding of Study objectives the pathogenesis of HCC suggests a role for the fibro- The primary objective was to estimate the 6-month blast growth factor (FGF) family. These data provide progression-free survival rate. Six-month progression-free rationale for the current phase II study evaluating bri- survival rate was defined as the proportion of treated vanib, a first in class, oral, selective dual inhibitor of FGF patients who had not progressed or expired prior to and VEGF signaling in HCC. This study demonstrates 6 months from the first dose. Secondary objectives were the antitumor activity and tolerability of brivanib and median progression-free survival, tumor response rate, supports the ongoing phase III program of brivanib in time to response, duration of response, disease control HCC. In addition, the current study incorporates the rate, time to progression, overall survival (see online Sup- newly proposed modified RECIST criteria to assess plementary section B for full definition of efficacy end- antitumor activity in HCC. points), and safety and tolerability. Treatment and dose modifications hours and is administered once daily at a dose of 800 mg, Brivanib was administered orally on a continuous daily with no reported differences in pharmacokinetics between schedule of 800 mg. Patients continued treatment until first Asian versus nonAsian races and patients with mild hepatic evidence of disease progression on imaging by World impairment versus patients with no hepatic impairment Health Organization (mWHO) criteria or earlier if unac- (18, 19). ceptable toxicity was observed. Doses were reduced or Here we present the results from a study of brivanib as delayed according to protocol-specified criteria or, for first-line therapy in patients with unresectable, advanced lower-grade toxicities, if the investigator deemed dose HCC. reduction or delay was required in the interest of the patients’ safety (online Supplementary section C). Study design This was originally a randomized study of brivanib Tumor assessments versus doxorubicin in newly diagnosed HCC patients. Tumor response was assessed every 6 weeks using the At the time the protocol was initiated, no agent was tumor response criteria via computed tomography/mag- proven to extend survival in HCC and doxorubicin was netic resonance imaging. Tumor assessment was per- used as a comparator arm based on historical data report- formed by an Independent Radiological Review ing response rates of 10% to 20%.(20) Based on positive Committee (IRRC; primary analysis) and by study inves- sorafenib phase III results, the protocol was amended to tigators. In addition, we also performed a retrospective discontinue the doxorubicin arm. Accordingly, this was a exploratory analysis to reassess tumor response and pro- multicenter, open-label, phase II, single-agent study of gression using the new proposed modified Response once-daily brivanib alaninate 800 mg in patients with Evaluation Criteria in Solid Tumors (mRECIST) for unresectable, locally advanced, or metastatic HCC who HCC criteria. Indeed, this study was designed in April had received no prior systemic therapy (cohort A) or 1 2006 before the publication of the American Association prior regimen of angiogenesis inhibitor therapy (cohort for the Study of Liver Disease-Journal of the National B). This study was conducted in accordance with the Cancer Institute (AASLD-JNCI) guidelines for HCC that Declaration of Helsinki and International Conference recommend assessment of tumor
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