Table 1.

Selected trials of epigenetic therapy

Regimen	n	Dose	Study design	Clinical results	Survival benefit
Cutaneous T-cell lymphoma
Romidepsin28	71	14mg/m2 on day 1, 8 and 15 of a 28-day cycle	Single arm, phase II	34% response rate with 6% complete responses	Median duration 11–15 months in one study
Vorinostat123	74	400mg/day	Phase II (multiple doses)	24% response rate	Not assessed/median time to progression 30 weeks
Myelodysplasia
5-azacitidine versus best supportive care25	191	75mg/m2 per day subcutaneously for 7 days every 28 days	Randomized phase III with crossover design*	23% response rate versus 0%; Improved time to leukaemia (21 months versus 13 months); Improved quality of life	After 6 months, median overall survival of 18 months versus 11 months (P=0.03)
Decitabine versus best supportive care27	170	5mg/m2 intravenously over 4 hours every 8 hours for 3 consecutive days every 6 weeks	Randomized phase III	17% response rate versus 0%; Trend to increased time to leukaemic transformation or death (12 months versus 8 months, P=0.16)	None
SGI-110‡	78	Ongoing testing of dosing schedules in phase I study	Phase I/II§	Heavily pretreated AML group: 1 patient with complete response without platelet recovery and 1 patient with complete response but incomplete blood count recovery; Myelodysplasia group previously treated with azacitidine: 1 patient with marrow complete remission and 1 patient with haematological improvement	Not assessed
Ovarian cancer
Decitabine + carboplatin88	17	Decitabine: 10mg/m2 intravenously on days 1–5 of a 28-day cycle Carboplatin: AUC 5 intravenously on day 8 of a 28-day cycle	Phase II	35% response rate	PFS of 10.2 months with 53% progression-free at 6 months
5-azacitidine + carboplatin87	30	Azacitidine: 75mg/m2 subcutaneously daily for days 1–5 of a 28-day cycle Carboplatin: AUC 5 intravenously on day 2 of a 28-day cycle	Phase Ib/II	13.8% response rate	7.5-month duration of benefit 23-month overall survival 5.6-month PFS
Non-small-cell lung cancer
5-azacitidine + entinostat||62	45	5-Azacitidine: 40mg/m2 on days 1–6 and days 8–10 of a 28-day cycle Entinostat: 7mg on days 3 and 10 of a 28-day cycle	Phase I/II	1 patient with complete response 1 patient with partial response 4 out of 19 patients treated with subsequent therapy with partial response	6.4-month overall survival 20% of patients with ≥1-year survival (range 1–4 years)
Entinostat + erlotinib versus unreported placebo112	132	Erlotinib: 150mg daily for 28 days Entinostat: 10mg on days 1 and 15 of a 28-day cycle	Randomized phase II	4-month PFS similar (18% versus 20%)	In subset of patients with high E-cadherin levels, improved overall survival compared with placebo (9.4 months versus 5.4 months; HR 0.35, 95% CI 0.13–0.92; P=0.03)
Carboplatin + paclitaxel + vorinostat or placebo113	94	Carboplatin: AUC 6 on day 3 of a 3-week cycle Paclitaxel: 200mg/m2 on day 3 of a 3-week cycle Vorinostat: 400mg daily on days 1–14 of a 3-week cycle	Randomized, blinded phase II	34% versus 12.5% response rate	No survival benefit, but trend to overall survival benefit in vorinostat arm
ER-positive breast cancer
Exemestane + entinostat versus placebo114	130	Exemestane: 25mg daily Entinostat: 5mg weekly	Randomized phase II	Decreased risk of progression by 27%	PFS 4.3 months versus 2.3 months (P=0.06) Overall survival 26.9 months versus 19.8 months (P=0.04)

^*Patients randomly assigned to supportive care could cross over to azacitidine treatment if their disease worsened. Worsening was considered an increased FAB subtype (to RAEB or RAEB-T), progression to AML, remaining RBC transfusion-dependent before and during study or progressive bone marrow failure.

^‡Patients with AML.

^§Trial is ongoing.

^||Refractory disease.

Abbreviations: AML, acute myeloid leukaemia; AUC, area under the plasma drug concentration-time curve; ER, oestrogen receptor; FAB, French–American–British; HR, hazard ratio; PFS, progression-free survival; RAEB, refractory anaemia with excessive blasts; RAEB-T, RAEB in transformation; RBC, red blood cell.