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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]
  1. The references are included at the end of the text
  2. 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
  3. (1) Oral dose of VPA titrated in each patient to obtain adequate plasma concentrations.