Hepatocellular carcinoma: Will novel targeted drugs really impact the next future?

Table 1 On-going National Cancer Institute-sponsored phase III trials

Target molecule	Molecule	trial	Phase	Details	Locoregional treatment	Primary outcome	Estimated enrollment	Start date	Estimated study completion date	Ref.
VEGFR	Ramucirumab	Ramucirumab (LY3009806) vs placebo in participants with hepatocellular carcinoma and elevated baseline alpha-fetoprotein (REACH-2)	III	CPA, BCLC Stage C disease or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, Prior sorafenib treatment		OS	399 pts	July 2015	April 2018	NCT02435433
VEGF	Sorafenib	TACE with or without Sorafenib	III	CPA or B7, first line treatment, branch not main PVI	Y	PFS	400 pts	October 2009	February 2018	NCT01004978
	Sorafenib	A randomized, controlled phase III trial of sorafenib with or without conventional TACE in patients with advanced HCC (STAH Study)	III	CPA or B7		OS	338 pts	February 2013	October 2017	NCT01829035
	Regorafenib	Study of regorafenib after sorafenib in patients with hepatocellular carcinoma (RESORCE)	III	CPA		OS	573 pts	May 2013	October 2016	NCT01774344
VEGF, FGF, PDGF, RET,KIT	Lenvatinib	A multicenter, open-label, phase 3 trial to compare the efficacy and safety of lenvatinib (E7080) vs sorafenib in first-line treatment of subjects with unresectable hepatocellular carcinoma	III	CPA, BCLC Stage B or C		OS	954 pts	March 2013	April 2016	NCT01761266
MET, RET, VEGF	Cabozantinib (XL 184)	Randomized controlled trial of XL184 vs placebo after sorafenib (CELESTIAL)	III	CPA		OS	760 pts	August 2013	October 2016	NCT01908426
MET	Tivantinib (ARQ197)	Study of tivantinib in subjects with inoperable hepatocellular carcinoma who have been treated with one prior therapy (METIV-HCC)	III	MET Diagnostic-High tissue		OS	368 pts	December 2012	June 2017	NCT01755767
	Tivantinib (ARQ197)	A randomized double-blind, placebo-controlled Japanese phase III trial of ARQ 197 in hepatocellular carcinoma (HCC) (JET-HCC)	III	c-Met high in tumor sample, CPA		PFS	160 pts	January 2014	December 2016	NCT02029157
PD-1	Nivolumab	First line treatment with nivolumab vs sorafenib (CheckMate 459: CHECKpoint pathway and nivoluMAb clinical trial evaluation 459)	III	CPA		TTP, OS	726 pts	November 2015	June 2019	NCT02576509
PD-1	Pembrolizumab	Study of pembrolizumab (MK-3475) vs best supportive care in participants with previously Systemically treated advanced hepatocellular carcinoma (MK-3475-240/KEYNOTE-240)	III	CPA, BCLC Stage C disease or BCLC Stage B disease not amenable to locoregional therapy		PFS, OS	408 pts	April 2016	April 2018	NCT02702401

PFS: Progression free survival; TTP: Time to progression; ORR: Overall response rate; OS: Overall survival; VEGF: Vascular endothelial growth factor; PDGF: Platelet derived growth factor; FGF: Fibroblast derived growth factor; PD-1: Programmed death-1; CP: Child-Pugh class; BCLC: Barcelona Clinic Liver Cancer; PVI: Portal vein invasion; TACE: Transarterial chemoembolization.

Table 2 On-going National Cancer Institute-sponsored phase II trials

Target molecule	Molecule	Trial	Phase	Details	Primary outcome	Estimated enrollment	Start date	Estimated study completion date	Ref.
VEGFR	Ramucirumab	A study of LY2875358 in combination with ramucirumab (LY3009806) in participants with advanced cancer	I/II	Part A: Escalating doses of LY2875358 will be given in combination with a fixed dose of ramucirumab to evaluate the safety of the combination Part B: evaluation of safety and activity	Dose-limiting toxicities in part A ORR in part B	70 pts	March 2014	April 2017	NCT02082210
VEGF	Sorafenib	Sorafenib with Capecitabine and Oxaliplatin (SECOX)	II		PFS	52 pts	September 2007	December 2008 (status unknown)	NCT00752063
	Sorafenib	Sorafenib + mFOLFOX for hepatocellular carcinoma (HCC)	II	CPA, BCLC C or B not suitable for TACE	TTP	40 pts	January 2013	December 2017	NCT01775501
	Sorafenib	Sorafenib plus doxorubicin in patients with advanced HCC with disease progression on sorafenib	II	CPA	OS	30 pts	April 2013	April 2016	NCT01840592
	Sorafenib	Comparison study of sorafenib and 5-fluorouracil/mitomycin for metastatic HCC	II	Eligible patients have pulmonary metastasis and intrahepatic tumors controlled with locoregional therapies	PFS	40 pts	November 2010	July 2016	NCT01171482
	Sorafenib	Palliative treatment of HCC in patient with CHILD B cirrhosis (PRODIGE 21)	II	Sorafenib vs pravastatin vs sorafenib + pravastatin	Time to radiologic progression	160 pts	November 2011	February 2016	NCT01357486
				BCLC B or C
	Sorafenib	A study of LY2157299 in participants with advanced HCC	II	LY2157299 vs sorafenib vs placebo CPA	OS	120 pts	August 2014	December 2016	NCT02178358
	Axitinib	Axitinib as second-line treatment for advanced HCC	II	CPA	disease stabilization	45 pts	April 2011	December 2016	NCT01273662
TβRI	Galunisertib (LY2157299)	Galunisertib with nivolumab	I/II	A study of galunisertib (LY2157299) in combination with nivolumab in advanced refractory solid tumors and in recurrent or refractory NSCLC, HCC, or glioblastoma CPA	Phase 1b: MTD of Galunisertib in combination with nivolumab	100 pts	October 2015	March 2019	NCT02423343
	Galunisertib (LY2157299)	A study of LY2157299 in participants with advanced HCC	II	A Randomized phase 2 study of LY2157299 vs LY2157299 - sorafenib combination vs sorafenib in patients with advanced HCC	OS	120 pts	August 2014	October 2016	NCT02178358
				CPA
	Galunisertib (LY2157299)	A study of LY2157299 in participants with HCC	II	The study consists of three parts: Part A: HCC participants with an increased alpha feto protein (AFP) level are treated with either 160 mg LY2157299 or 300 mg LY2157299; Part B: HCC participants with a normal AFP level are treated with 300 mg LY2157299; Part C: treatment-naïve HCC participants are treated with 160 mg LY2157299 + sorafenib or 300 mg LY2157299 + Sorafenib	TTP Relation-ship of change in response biomarker to clinical benefit	190 pts	March 2011	October 2016	NCT01246986
mTOR	Temsirolimus plus sorafenib	Phase II combination of temsirolimus and sorafenib in advanced hepatocellular carcinoma	II	TEM 10 mg iv weekly + SOR 200 mg bid CPA, CPB ≤ 7	TTP	27 pts	September 2012	September 2017	NCT01687673
VEGF, PDGF, FGF	Nindetanib	Phase I/II comparison of efficacy and safety of BIBF 1120 and sorafenib in patients with advanced hepatocellular carcinoma	I/II	Nindetanib 200 mg bid or sorafenib 400 mg bid CPA	MTD in phase I TTP in phase II	125 pts	October 2009	January 2016	NCT01004003
PD-1	Pembrolizumab	Pembrolizumab (Keytruda) in advanced hepatocellular carcinoma	II	CP < 7, at sorafenib progression	Disease control rate	28 pts	March 2016	March 2019	NCT02658019
	Pembrolizumab	Study of Pembrolizumab (MK-3475) as monotherapy in adults with previously systemically treated advanced hepatocellular carcinoma (MK-3475-224/KEYNOTE-224)	II	CPA	ORR	100 pts	April 2016	November 2017	NCT02702414
	Pembrolizumab	Study of pembrolizumab (MK-3475) in participants with advanced solid tumors (MK-3475-158/KEYNOTE-158)	II	Multiple types of advanced (unresectable and/or metastatic) solid tumors that have progressed on standard of care therapy may be enrolled	ORR	1100 pts	December 2015	April 2018	NCT02628067
S100A9	Tasquinimob	A study with tasquinimod treating patients in four independent cohorts of hepatocellular, ovarian, renal cell and gastric cancers	II	BCLC C or B not amenable to locoregional therapy, CPA, previous treatment with sorafenib	PFS	201 pts	December 2012	February 2016	NCT01743469
PD-1	Nivolumab, nivolumab plus ipilimumab	Study to evaluate the effectiveness, safety and tolerability of nivolumab and the combination nivolumab plus ipilimumab in subjects with advanced liver cancer	I/II		Safety, ORR	600 pts	September 2012	July 2018	NCT01658878
PD-L1	MEDI4736	Biological/vaccine: MEDI4736 + tremelimumab	II		Safety	120 pts	October 2015	April 2018	NCT02519348
		Biological/vaccine: MEDI4736
		Biological/vaccine: Tremelimumab

PFS: Progression free survival; TTP: Time to progression; ORR: Overall response rate; MTD: Maximum tolerated dose; OS: Overall survival; VEGF: Vascular endothelial growth factor; PDGF: Platelet derived growth factor; FGF: Fibroblast derived growth factor; PD-1: Programmed death-1; PD-L1: Programmed death ligand 1; CP: Child-Pugh class; BCLC: Barcelona Clinic Liver Cancer.