A multicentre phase 1b/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma

Christos Fountzilas, Medhavi Gupta, Sunyoung Lee, Smitha Krishnamurthi, Bassam Estfan, Katy Wang, Kristopher Attwood, John Wilton, Robert Bies, Wiam Bshara, Renuka Iyer, Christos Fountzilas, Medhavi Gupta, Sunyoung Lee, Smitha Krishnamurthi, Bassam Estfan, Katy Wang, Kristopher Attwood, John Wilton, Robert Bies, Wiam Bshara, Renuka Iyer

Abstract

Background: Hepatocellular carcinoma (HCC) is a major cause of cancer-related death. It is a highly vascular tumour with multiple angiogenic factors, most importantly vascular endothelial growth factor (VEGF), involved in HCC progression. Tivozanib is an oral inhibitor of VEGFR-1/2/3 with promising activity against HCC in vivo.

Methods: We conducted a phase 1b/2 study of tivozanib in patients with advanced HCC. The safety, dosing, pharmacokinetics, pharmacodynamics, and preliminary antineoplastic efficacy of tivozanib were evaluated.

Results: Twenty-seven patients received at least one dose of tivozanib. Using a 3+3 design, the recommended phase 2 dose (RP2D) of tivozanib was determined to be 1 mg per os once daily, 21 days on-7 days off. The median progression-free and overall survival were 24 weeks and 9 months, respectively, for patients treated at RP2D. The overall response rate was 21%. Treatment was well tolerated. A significant decrease in soluble plasma VEGFR-2 was noted, assuring adequate target engagement.

Conclusions: Although this study did not proceed to stage 2, there was an early efficacy signal with a very favourable toxicity profile. A phase 1/2 trial of tivozanib in combination with durvalumab is currently underway.

Trial registration: ClinicalTrials.gov NCT01835223, registered on 15 April 2013.

Conflict of interest statement

C.F.: AstraZeneca (consultation, fees paid to institute, outside the scope of submitted work).

Figures

Fig. 1. Progression-free and overall survival in…
Fig. 1. Progression-free and overall survival in efficacy population.
Progression-free (a) and overall survival (b) in efficacy population.
Fig. 2
Fig. 2
RECIST response, waterfall plot.
Fig. 3
Fig. 3
Pre-dose sVEGFR-2, cycle 1 days 1 and 15.

References

    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492.
    1. Xu, J. Trends in liver cancer mortality among adults aged 25 and over in the United States, 2000–2016. NCHS Data Brief. 1–8 (2018).
    1. Villanueva A. Hepatocellular Carcinoma. N. Engl. J. Med. 2019;380:1450–1462. doi: 10.1056/NEJMra1713263.
    1. Yao DF, Wu XH, Zhu Y, Shi GS, Dong ZZ, Yao DB, et al. Quantitative analysis of vascular endothelial growth factor, microvascular density and their clinicopathologic features in human hepatocellular carcinoma. Hepatobiliary Pancreat. Dis. Int. 2005;4:220–226.
    1. Zhan P, Qian Q, Yu LK. Serum VEGF level is associated with the outcome of patients with hepatocellular carcinoma: a meta-analysis. Hepatobiliary Surg. Nutr. 2013;2:209–215.
    1. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34. doi: 10.1016/S1470-2045(08)70285-7.
    1. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 2008;359:378–390. doi: 10.1056/NEJMoa0708857.
    1. Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, et al. Linifanib versus sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J. Clin. Oncol. 2015;33:172–179. doi: 10.1200/JCO.2013.54.3298.
    1. Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J. Clin. Oncol. 2013;31:4067–4075. doi: 10.1200/JCO.2012.45.8372.
    1. Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J. Clin. Oncol. 2013;31:3517–3524. doi: 10.1200/JCO.2012.48.4410.
    1. Zhu AX, Rosmorduc O, Evans TR, Ross PJ, Santoro A, Carrilho FJ, et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J. Clin. Oncol. 2015;33:559–566. doi: 10.1200/JCO.2013.53.7746.
    1. Nakamura K, Taguchi E, Miura T, Yamamoto A, Takahashi K, Bichat F, et al. KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties. Cancer Res. 2006;66:9134–9142. doi: 10.1158/0008-5472.CAN-05-4290.
    1. Farlow S, Potz D, Zi T, Sun X, Lin J, Chiu MI, et al. Abstract A12: variation in response to triple VEGFR inhibitor tivozanib in mouse models of hepatocellular carcinoma. Mol. Cancer Therapeutics. 2009;8(Suppl.):A12-A.
    1. Eskens FA, de Jonge MJ, Bhargava P, Isoe T, Cotreau MM, Esteves B, et al. Biologic and clinical activity of tivozanib (AV-951, KRN-951), a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients with advanced solid tumors. Clin. Cancer Res. 2011;17:7156–7163. doi: 10.1158/1078-0432.CCR-11-0411.
    1. Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J. Clin. Oncol. 2013;31:3791–3799. doi: 10.1200/JCO.2012.47.4940.
    1. Bruix J, Sherman M. American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–1022. doi: 10.1002/hep.24199.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur. J. Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Cotreau MM, King T, Massmanian L, Strahs A, Slichenmyer W, Vargo D. Abstract 752: the effect of food on the pharmacokinetics of tivozanib. Cancer Res. 2012;72(Suppl.):752.
    1. Beal SL. Ways to fit a PK model with some data below the quantification limit. J. Pharmacokinet. Pharmacodyn. 2001;28:481–504. doi: 10.1023/A:1012299115260.
    1. Fountzilas C, Stuart S, Hernandez B, Bowhay-Carnes E, Michalek J, Sarantopoulos J, et al. Risks and benefits of phase I liver dysfunction studies: should patients with severe liver dysfunction be included in these trials? Invest. N. Drugs. 2017;35:386–391. doi: 10.1007/s10637-017-0425-4.
    1. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–1173. doi: 10.1016/S0140-6736(18)30207-1.
    1. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56–66. doi: 10.1016/S0140-6736(16)32453-9.
    1. Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N. Engl. J. Med. 2018;379:54–63. doi: 10.1056/NEJMoa1717002.
    1. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492–2502. doi: 10.1016/S0140-6736(17)31046-2.
    1. Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19:940–952. doi: 10.1016/S1470-2045(18)30351-6.
    1. Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin. Cancer Res. 2008;14:5459–5465. doi: 10.1158/1078-0432.CCR-07-5270.
    1. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–7109. doi: 10.1158/0008-5472.CAN-04-1443.
    1. Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:282–296. doi: 10.1016/S1470-2045(18)30937-9.
    1. Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015;16:859–870. doi: 10.1016/S1470-2045(15)00050-9.
    1. Ait-Oudhia S, Mager DE, Pokuri V, Tomaszewski G, Groman A, Zagst P, et al. Bridging sunitinib exposure to time-to-tumor progression in hepatocellular carcinoma patients with mathematical modeling of an angiogenic biomarker. CPT Pharmacomet. Syst. Pharmacol. 2016;5:297–304. doi: 10.1002/psp4.12084.
    1. Lindauer A, Di Gion P, Kanefendt F, Tomalik-Scharte D, Kinzig M, Rodamer M, et al. Pharmacokinetic/pharmacodynamic modeling of biomarker response to sunitinib in healthy volunteers. Clin. Pharm. Ther. 2010;87:601–608. doi: 10.1038/clpt.2010.20.
    1. Ebos JM, Bocci G, Man S, Thorpe PE, Hicklin DJ, Zhou D, et al. A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma. Mol. Cancer Res. 2004;2:315–326.
    1. Gabrielson A, Wu Y, Wang H, Jiang J, Kallakury B, Gatalica Z, et al. Intratumoral CD3 and CD8 T-cell densities associated with relapse-free survival in HCC. Cancer Immunol. Res. 2016;4:419–430. doi: 10.1158/2326-6066.CIR-15-0110.
    1. Kalathil S, Lugade AA, Miller A, Iyer R, Thanavala Y. Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality. Cancer Res. 2013;73:2435–2444. doi: 10.1158/0008-5472.CAN-12-3381.
    1. Korangy F, Ormandy LA, Bleck JS, Klempnauer J, Wilkens L, Manns MP, et al. Spontaneous tumor-specific humoral and cellular immune responses to NY-ESO-1 in hepatocellular carcinoma. Clin. Cancer Res. 2004;10:4332–4341. doi: 10.1158/1078-0432.CCR-04-0181.
    1. Iyer, R. V., Maguire, O., Kim, M., Curtin, L. I., Sexton, S., Fisher, D. T. et al. Dose-dependent sorafenib-induced immunosuppression is associated with aberrant NFAT activation and expression of PD-1 in T cells. Cancers (Basel)11, pii: E681, 10.3390/cancers11050681 (2019).
    1. Kalathil, S. G., Lugade, A. A., Miller, A., Iyer, R. & Thanavala, Y. PD-1(+) and Foxp3(+) T cell reduction correlates with survival of HCC patients after sorafenib therapy. JCI Insight. 4, pii: 130116, 10.1172/jci.insight.130116 (2016).
    1. Ikeda M, Sung MW, Kudo M, Kobayashi M, Baron AD, Finn RS, et al. Abstract CT061: a phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): updated results. Cancer Res. 2019;79(Suppl.):CT061-CT.
    1. Lee, K.-H., Hsu, C.-H., Lee, M. S., Ryoo, B.-Y., Verret, W., He, A. R. et al. 150OAtezolizumab + bevacizumab in hepatocellular carcinoma (HCC): safety and clinical activity results from a phase Ib study. Ann. Oncol.29(Suppl. 9), ix46-ix66, 10.1093/annonc/mdy432 (2018).

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