Table 1 Studies on epigenetic treatment alone
From: Epigenetic treatment of solid tumours: a review of clinical trials
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] |