Table 1.

Studies on epigenetic treatment alone

Drug (s) and schedule	Study type - histology (number of patients)	Results and data provided	Reference
Abexinostat (S78454/PCI-24781) p.o. 60 mg/m2 bid 4 days on/3 days off	Mixed tumours (15 pts)	PK/PD model predicts thrombocytopenia	[90]
Azacytidine + Valproate Aza s.c. for 10 days q. 28 days. MTD 75 mg/m2/day VPA in plasma 75–100 μg/ml (a)	Dose escalation Mixed tumours (55 pts)	PBMC: DNA methylation decreased. H3 acetylation increased. Patients with stable disease had more H3 acetylation. DLT: neutropenic fever and thrombocytopenia	[68]
Azacytidine +Entinostat Aza 30–40 mg/m2/day for days 1–6 and 8–10 q 28 days Entinostat 7 mg/m2 days 3 and 10	Phase I/II trial NSCLC (45 pts)	Demethylation of 4 epigenetically silenced genes (CDK2a, CDH13, APC, RASSF1a). In plasma DNA was associated with improved progression-free and overall survival	[62]
Azacytidine (AC) Phenylbutyrate (PHB) AC 10-25mg/m2/day for 21 days, 75 mg/m2/day for 7 days PHB 200–400 mg/m2 days 6, 13 and 20	Phase I Mixed tumours (27 pts)	Toxicity: neutropenia, anaemia. No PK interaction “No conclusive statement can be made on histone acetylation or methyltrasferase activity”.	[91]
Decitabine + VPA Dec 5–15 mg/m2/day for 10 days. VPA 10–20 mg/kg/day for days 5–21 q 28 days	Phase I NSCLC (8 pts)	Neurological toxicity. Increase in foetal Hb levels in all pts	[63]
Belinostat 1000 mg/m2/day i.v. for days 1–5 q 21 days	Phase II Ovarian: platinum resistant (18 pts) or micropapillary (14 pts)	Toxicity: thrombosis (3 pts). Increased H3 acetylation in PBMC and in two tumours	[73]
Belinostat 1000 mg/m2/day i.v. for days 1–5 q 21 days	Phase II Refractory Thymic epithelial tumours (41 pts)	Nausea, vomiting, fatigue Modest activity Protein acetylation did not predict outcome	[92]
Belinostat 600–1400 mg/m2/day i.v. for days 1–5 q 3 weeks .	Phase I/II Hepatocarcinoma (60 pts)	PK linear. MTD not reached at 1400 mg/m2. Toxicity: abdominal pain, liver toxicity, vomiting. Plasma concentrations higher than effective in vitro levels for 4 hours. Disease stabilisation. High HR23B associated with more stabilisation.	[93]
Belinostat 1000 mg/m2/day i.v. for days 1–5 q 21 days	Mesothelioma (pre-treated) (13 pts)	Not active in terms of RR toxicitiy: nausea, emesis, fatigue and constipation. One fatal cardiac arrhythmia	[94]
Belinostat, (oral formulation) 150–1000 mg/m2/day for days 1–5 q 21 days	Pharmacological evaluation Mixed tumours (46 pts)	PK and PD: results similar to the parenteral formulation	[95]
CHR-3996 5–160 mg/day p. o. RD 40 mg/day p.o.	Phase I Mixed tumours (39 pts)	DLT: thrombocytopenia, fatigue, atrial fibrillation, ECG alterations, elevated creatinine. AUC proportional to dose, plasma concentration sufficient for preclinical antitumour activity Effect on histone acetylation in PBMC	[45]
CI-994 2–8 mg/m2/day RD 8 mg/m2/day for 8 weeks q 10 weeks	Phase I Mixed tumours (53 pts)	Toxicity: Thrombocytopenia (DLT). PK data.	[48]
MGCD0103 12.5-56 mg/m2/day p.o. 3 times/week for 2 weeks q 3 weeks RD 45 mg/m2/day	Phase I Mixed tumours	Inhibition of HDAC activity and induction of acetylation of H3 histones in peripheral WBCs	[96]
MS-275 MTD 10 mg/m2 q14 days	Phase I Mixed tumours (31 pts)	Toxicities: nausea, vomiting, anorexia, fatigue. Half-life 39–80 hrs (longer than expected). Linear PK. Increased H3 acetylation in PBMC. Peak plasma levels higher than effective in vitro concentration.	[97]
Panobinostat 20 mg p.o. twice/week	Pharmacological study Mixed tumours (36 pts)	No effect of food on PK parameters	[98]
Panobinostat 40 mg p.o. three times/week	Sarcoma (47 pts) Ovarian Sex Cord Tumours (5 pts)	Poorly tolerated. No activity in sarcoma. Activity in OSCT Toxicity: thrombocytopenia, fatigue, anaemia	[99]
Panobinostat 20 mg/m2 for days 1 and 8 q 21 days	Prostate (35 pts)	No clinical activity Toxicity: fatigue, thrombocytopenia, nausea	[100]
Panobinostat 20 mg	Mixed tumours (4 pts)	PK determined by trace radiolabelled 14C excretion Rapid oral absorption, liver and renal excretion	[101]
Pivanex 2.34 g/m2/day in 6 h for 3 days q 21 days	Phase II NSCLC (47 pts)	Toxicity: fatigue, nausea, dysgeusia- 3 partial responses (6%)	[102]
Quisinostat (JNJ-26481585)	Mixed tumours (92 pts) Phase I RD 12 mg days 1,3 and 5	Toxicity: cardiovascular, fatigue, nausea PD: increased H3Ac in hair follicles, skin and tumour.	[103]
Resminostat RD 600 mg/day p.o. for 5 days q 14 days	Phase I Head-and-neck refractory	Toxicity: nausea, vomiting, fatigue. PK data, HDAC inhibition, H4Ac increase in PBMC	[69]
Romidepsin 13 mg/m2 i.v. in 4 h for days 1, 8 and 15 q 28 days	Phase II Refractory Prostate (35 pts)	Toxicity: nausea, fatigue, vomiting and anorexia No antitumour activity	[104]
Romidepsin 13 mg/m2 in 4 h, for days 1, 8 and 15 q 28 days	Phase II Head and Neck (14 pts)	Toxicity: nausea, vomiting, constipation, fatigue H3 hyperacetylation in PBMC Reduced or stable Ki67 On microarray 641 differentially expressed genes No consistent change ion methylation of specific genes Upregulation of p21Waf1/Cip1.	[70]
Romidepsin New schedule: 1–9 mg/m2 in 4 h for days 1, 3, and 5 q 21 days RD 7 mg/m2	Phase I Mixed tumours (28 pts)	Increase in 3HAc in PBMC. PK data described. Toxicity: ECG changes	[54]
SAHA 400 mg/day p.o.	Phase II Head-and-neck, refractory (13 pts)	No response. Toxicity: anaemia, anorexia, hyperglycemia, thrombocytopenia, dehydration	[82]
SAHA 400 mg/day p.o.	Phase II Refractory Prostate (27 pts)	IL-6 was higher in patients with toxicity (Fatigue, nausea)	[105]
SAHA 400 mg for 14 days q 21 days	Phase II Glioblastoma (66 pts)	Analysis of tumour tissue. Increased Acetylation of H2A, H3, H4. up-regulation of e-regulin. PK influenced by enzyme-inducing drugs. Toxicity: fatigue, thrombocytopenia. nausea, diarrhoea	[75]
SAHA 400 mg for 14 days q 21 days	Phase II Breast (14 pts)	No antitumour activity. Toxicity: Fatigue, nausea, diarrhoea, and lymphopenia	[106]
SAHA 400 mg for 14 days q 21 days	Phase II Ovarian (27 pts)	No antitumour activity Toxicity: Neutropenia, Leukopenia, Thrombocytopenia, Constitutional, Gastrointestinal, Metabolic	[107]
SAHA 400 mg for 14 days q 21 days	Phase II NSCLC second line (16 pts)	No antitumour activity Toxicity: fatigue, dehydration, hyperglycemia, mild myelosuppression	[108]
SAHA 400–800 mg for 14 days q 21 days RD 400 mg for 14 days q 21 days	Breast, colorectal, NSCLC (16 pts)	No antitumour activity. Toxicity anorexia, asthenia, nausea, thrombocytopenia, vomiting, weight loss	[60]
SAHA 400 mg for 14 days q 21 days	Thyroid (19 pts)	No antitumour activity Toxicity: fatigue, dehydration, ataxia, pneumonia, bruises, thrombosis, thrombocytopenia	[109]
SAHA 600 mg bid days 1–3 q 7 days or 400 mg for 14 days q 21days	Phase I Gastrointestinal (16 pts)	DLT thrombocytopenia. Some PK data: AUC μM/h 7.75±2.79 for 400 mg; 3.94±1.56 with 300 mg. t ½ 1.05±0.32 – 1.49±0.82 hours	[110]
SAHA 100–500 mg once or twice daily for 14 days q 21 days	Phase I Mixed tumours (18 pts)	MTD not reached. Recommended dose 500 for once, 200 for twice daily. Some PK data: AUC linear with dose	[111]
SAHA 300 or 400 mg bid days 1–3 q 7 days	Mesothelioma (pretreated) (13 pts)	2 PR. Toxicity: fatigue, anorexia, dehydration, diarrhea, nausea, and vomiting	[112]
SAHA 2 h i.v. infusion 75–900 mg/m2/day days 1–3 q 21 days or 300–900 mg/m2/day days 1–5 q 21 days	Phase I Mixed tumours (37 pts)	Toxicity: myelotoxicity, fatigue, anorexia, hyperglicemia Increase in acetylated histones in PBMC and in tumour cells. PK data.	[113]
SAHA oral MTD 400 mg/day or 600 mg/day days 1–3 q 7 days	Phase I Mixed tumours (73 pts)	Toxicity: anorexia, dehydration, diarrhea, and fatigue. In PBMC acetylation increased 2 hrs after dose, back to basal levels at 8 hours	[114]
SAHA 300 mg tid	Breast (25 pts)	Decrease of proliferation-associated genes. No effect on methylation	[115]
SAHA 400 mg daily continuously	Melanoma (39 pts)	Toxicity fatigue, nausea, lymphopenia, and hyperglycemia. Some biochemical correlative data presented.	[116]
SAHA 300 mg tid days 1–3, 8–10, 15–17 q 21 days	Mesothelioma (pretreated) (329 pts)	Randomised phase III: no benefit Toxicity: fatigue or malaise	[117]
SB939 10–80 mg/day p. o. 3 times/week for 3 weeks q 4 weeks RD 60 mg/day	Phase I Mixed tumours (30 pts)	DLT: fatigue, hypokalemia, ECG alterations. AUC proportional to dose. HDAC increases at doses 60 mg.	[118]
SB939 10–90 mg daily five times a week q 2 wks RD 60 mg/day	Phase I Mixed tumours (38 pts)	PK data. No correlation of AcH3 and response. Toxicity: fatigue, nausea, vomiting.	[83]
Valproate intravenous infusion in 1 h 30-250 mg/kg/day for days 1–5 q 21 days RD 60 mg/kg/day	Phase I Mixed tumours (26 pts)	Toxicity: neurological. HDAC2 decreased; H3 Acetylation increased; VPA plasma levels 0.3-0.9 mM.	[80]
Valproate p. o. 20-40mg/kg/day for 5 days	Phase I Cervical cancer (12 pts)	VPA in plasma 73–170 μg/ml. (0.4-1 mM) No correlation of H3 acetylation in tumour biopsies and plasma VPA. Toxicity: Depressed consciousness	[79]
Valproate 500 mg p. o. tid (target concentration 50–100 μg/ml) (0.3-0.6 mM)	Phase II Low-grade Neuroendocrine (8 pts)	Two tumours had a 2-4-fold increase in Notch-1 mRNA, 3 had a decrease.	[71]

The references are included at the end of the text

5FU 5-Fluorouracil, 5mC 5-methyl Cytosine, AUC area under the curve (also a dosing calculation for Carboplatin), Bid bis in die (twice a day), DLT dose-limiting toxicity, FEC combination of Fluorouracil, Epirubicin, Cyclophosphamide, FolFOx combination chemotherapy of Folinic acid, 5-Fluorouracil and Oxaliplatin, GI gastrointestinal, i.v. intravenously, MTD maximum tolerated dose, NSCLC non-small cell lung cancer, PBMC peripheral blood mononuclear cells, PD pharmacodynamic, PFS progression-free survival, PK pharmacokinetics, p.o. per os (orally), PR partial response, Pt patient, q every (Latin “quaque”), RA rapid acetylator (Hydralazyne metabolism), RD recommended dose, RR response rate, SA slow acetylator (Hydralazyne metabolism), SAHA Vorinostat, Zolinza ®, TS thymidylate Synthetase, target enzyme for 5FU activity, VPA Valproic Acid, WBC white blood cells

(1) Oral dose of VPA titrated in each patient to obtain adequate plasma concentrations.