Table 1.

Histone-modification-based epigenetic therapy in clinical trials for NSCLC.

Drug	Target/ Mechanism of Action	Phase of Trial	Number of Patients	Outcomes	Clinical Trial Identifier/ Reference
Histone Deacetylase Inhibitors
Vorinostat	Prevents enzymatic activities of class I and II HDACs, elicits cell arrest, differentiation, and/or apoptosis, antiproliferative, G1/G2 cell cycle arrest, disrupts VEGF signalling	Phase I	2 NSCLC/73 patients	CR = 1, PR = 3, unconfirmed PR = 2, linear pharmacokinetics with good bioavailability	NCT00045006 [72]
		Phase II	16 patients	SD = 8, PR = 1, PD = 3	NCT00565227 [73]
		Phase II	8 patients	SD (3.7 months) = 8, OS = 7.1 months	NCT00126451 [74]
Romidepsin	Triggers p21 expression, H4 acetylation, shift gene signature to normal epithelia	Phase II	19 Lung Cancer patients	Transient SD = 9	NCT00020202 [75]
Pivanex	Induces tumour cell differentiation and/or apoptosis	Phase II	47 refractory NSCLC patients	PR = 6.4%, SD (>12 weeks) = 30%, MS = 6.2 months1 year survival rate = 26%	[76]
Cl-994	Inhibits histone deacetylation, G1-S phase cell arrest	Phase I	53 solid tumours	PR = 1 heavily-pre-treated NSCLC patient SD = 3 (1 NSCLC patient)	[77]
Combination therapy
Vorinostat + Carboplatin /Paclitaxel	-	Phase I	28 advanced solid tumour patients	PR = 11 (10 NSCLC), SD = 7 Linear Pharmacokinetics	[78]
Vorinostat + Carboplatin/ Paclitaxel	Enhances the anti-cancer effects of platinum compounds and taxanes	Phase II	94 advanced (stage IIIB or IV NSCLC patients)	Enhanced response rate (34%) OS = 13 months	NCT01413750 [70]
Vorinostat + Bortezomib	Combined induction proteasome and histone deacetylase inhibition	Phase I	21 patients	Tumour necrosis (30%)	[79]
Vorinostat + Sorafenib	-	Phase I	17 patients with advanced solid tumours	Unconfirmed PR = 2 (1 NSCLC patient)	[80]
Vorinostat + Erlotinib	-	Phase I/II	33 advanced NSCLC EGFR mutant patients	PFS = 8 weeks OS = 10.3 months	NCT00503971 [81]
Panobinostat + Erlotinib	-	Phase I	35 NSCLC/42 patients with advanced tumours	Disease control rate = 54%, NSCLC PR =3, SD = 3 PFS = 4.7 months, OS = 41 months, (EGFR mutation)	NCT00738751 [82]
Entinostat + Erlotinib	-	Phase II	132 stage IIIB and IV NSCLC patients	Longer OS (9.4 months) in high E-cadherin patients	NCT00602030 [71]
Pivanex + Docetaxel	Synergistic action for growth inhibition of NSCLC cell lines in vitro and for improved survival in animal models	Phase I Phase IIb	12 patients 225 patients	Results not published	NCT00073385
Cl-994 + Gemcitabine	-	Phase II	26 NSCLC/174 patients	PR = 8, OR = 12%, MS = 194 days	NCT00005093 [83]
Cl-994 + Carboplatin + Paclitaxel	-	Phase I	30 patients with advanced solid tumours	H3 acetylation levels <1.5-fold times baseline = PD, H3 acetylation levels ≥1.5-fold times baseline = Clinical response/SD, PR = 5 (3 NSCLC)	[84]
Azacitidine + Entinostat	Inhibition of promoter methylation	I/II	45 advanced, refractory NSCLC	MS = 6.4 months, CR =1, PR = 1	NCT00387465 [85]
Decitabine + valproic acid	Inhibitors of DNA methylation and histone deacetylases	I	8 patients with advanced NSCLC with prior chemotherapy	SD = 1	NCT00084981 [86]
Decitabine + vorinostat	Inhibitors of DNA methylation and histone deacetylases	I	2 patients with NSCLC/44 with advanced tumours	SD = 29%	NCT00275080 [85]
Azacitidine + sodium phenylbutyrate	Inhibitors of DNA methylation and histone deacetylases	I	1 NSCLC/27 refractory Solid Tumours	SD = 1, PD = 26	NCT00005639 [87]
Hydralazine+ magnesium valproate	Reduction in global DNA methylation, histone deacetylase activity, and promoter demethylation were observed	II	1 NSCLC/17 refractory solid tumours	PR = 4, SD = 8	NCT00404508 [88]

CR: complete response, PR: partial response, SD: stable disease, PD: progressive disease, MS: median survival, OS: overall survival, PFS: progression-free survival.