Skip to main content

Table 2 Epigenetic treatment associated with a conventional anticancer agent

From: Epigenetic treatment of solid tumours: a review of clinical trials

Epigenetic drug Tumour type and chemo Results and data provided Reference
5-azacytidine
RD 75 mg/m2/day
days 1–4 and 15–18 q 28 days
Phase I
Erlotinib 150 mg/day
Mixed tumours (30 pts)
Aza: increasing dose (75–100) and days of treatment (2–8)
Toxicity: rash, diarrhoea, nausea, and fatigue
[119]
5-azacytidine Ovarian cancer, platinum insensitive (30 pts) Toxicity: fatigue, myelosuppression
DR4 methylation in PBMC related to activity
[120]
5-azacytidine
75 mg/m2/day for days 1-5
Prostate cancer (22 pts)
Docetaxel (day6) , prednisone
Toxicity: myelosuppression
Reduction in GADD-45 methylation (peripheral DNA) on day 5
Only pts that had a reduction had a response.
[61]
Abexinostat
15–45 mg tid days 1-5
Sarcoma 22 pts
Doxorubicin 75 mg/m2 day 4
Neutropenia (growth factors required), fatigue, thrombocytopenia, and anemia.
PK of Abexinostat described. HDAC levels inhibited in PBMC
[121]
Belinostat
1000 mg/m2/day for 5 days
Carboplatin AUC 5 day 3
Resistant ovarian cancer (29 pts)
Toxicity: neutropenia, thrombocytopenia, vomiting
No effect, study closed
[122]
Belinostat
1000 mg/m2, 48 h c.i.
Thymic epithelial (26 pts)
Cisplatin, doxorubicin, cyclophosphamide
Toxicity: nausea, diarrhea, neutropenia, thrombocytopenia,
Immunomodulatory effect observed
[123]
Belinostat 1000 mg/m2 i.v. for days 1–3 then p.o. 2000 mg for days 4-5 Unknown primary (44 pts)
Paclitaxel, carboplatin
Randomised phase II. No clinical benefit [124]
CI-994
6 mg/m2/day for days 1–21, 28-day cycle
Phase II Pancreas.
Gemcitabine 1000 mg/m2 days 1, 8 and 15 (174 pts)
Increased incidence of neutropenia and thrombocytopenia
No improvement of gemcitabine activity
[125]
CI-994
4–10 mg/m2/day
RD 6 mg/m2/day for days 1–14 q 21 days
Phase I
Mixed tumours (54pts)
Capecitabine 1650–2000 mg/m2/day for 14 days q 21 days
PK not altered by capecitabine.
Toxicity: Thrombocytopenia
[49]
Decitabine
45–135 mg/m2 6 h infusion for day 1
RD 90mg/m2
Phase I
Carboplatin (AUC 5 or 6) day 8
Mixed tumours (33 pts)
Dose dependent, reversible demethylation in PBMC maximally at day 10. Demethylation of the MAGE1A gene
Toxicity: myelosuppression
[42]
Decitabine
10 mg/m2/day for 5 days
Carboplatin AUC 5 day 8
Ovarian cancer (17 pts)
35% RR 10.2 months PFS
In PBMC and tumours global and gene-specific demethylation.
Demethylation of MLH1, RASSF1A, HOXA10, HOXA11 correlated with PFS
[74]
Decitabine
0.15 mg/kg i.v. daily × 5 days/wk for 2 wks
Phase I-II
Temozolomide
p.o. 75 mg/m2 daily for weeks 2–5 of a 6-week cycle
Refractory Melanoma (35 pts)
Toxicity: mainly haematological
No effect on promoters of DNA repair genes
Excellent PK and PD data (also in tumours)
[55]
Decitabine
days 1–5 q 28 days
10–20 mg/m2/day
Phase I
Ovarian, recurrent (10 pts)
Carboplatin AUC 5 day 5
Toxicity: myelosuppression, nausea, fatigue
global and gene-specific DNA methylation
[126]
Decitabine i.v. day 1
45 mg/m2
Carboplatin AUC 6 day 8
Ovarian cancer (15 pts)
Patients with methylated hMLH1 tumour DNA in plasma
Decitabine appears to reduce the efficacy of carboplatino
Decrease in global levels of methylation with Decitabine.
[127]
Decitabine
01–0.2 mg/kg 3 days weekly
Panobinostat
10-30mg q 4 days
Temozolomide 150–200 mg/m2/day
Resistant melanoma
Toxicity: myelosuppression, fatigue, nausea
No antitumour acitivity.
[128]
Entinostat
10 mg p.o. day 1 and 15 q 28 days
Randomised phase II
NSCLC (132 pts)
Erlotinib 150 mg/day
Toxicity: rash, fatigue, diarrhoea, nausea
High E-caderin levels associated with longer PFS
[86]
Entinostat
1–5 mg/kg days 1,8,15 q 28 days
Phase I
Mixed tumours (19pts)
13-cis retinoic acid 1 mg/kg
Toxicity: hyponatremia, neutropenia, anaemia.
PD: Increased histone acetylation
[129]
Entinostat
5 mg/week
Breast (64pts)
Examestane 25 mg/day
Randomised phase II. Patients had progressed with AI.
Protein lysine hyperacetylation associated with prolonged PFS
[130]
Entinostat
10 mg/2 weeks
Phase I
Mixed tumours (31 pts)
Sorafenib (400 mg tid)
Toxicity: Handfoot syndrome, nausea/vomiting, and fatigue [131]
Hydralazine (182 mg RA; 83 mg SA)
+ Valproate (40 mg)
Phase II (17 pts)
Mixed tumours: re-treatment of resistant patients with same chemo as before
Toxicity: mainly haematological
Reduction in global DNA methylation, histone deacetylase
activity, and promoter demethylation
[58]
Hydralazine
(182 mg RA; 83 mg SA)
+ Valproate (30 mg)
Phase II
Progressive Cervical cancer (36 pts)
Cisplatin + Topotecan
Advantage in PFS (10 vs. 6 months)
Molecular correlates pending.
[59]
Hydralazine
(182 mg RA; 83 mg SA)
+ Valproate (30 mg)
Phase II
Breast (16 pts)
Doxorubicin, cyclophosphamide
Decrease in 5mC content and HDAC activity.
Up- and down-regulation of many genes.
[57]
Panobinostat
alone: 20 mg for days 1,3 and 5 for 2 weeks q 3weeks
with chemo: 15 mg
Prostate (pretreated) (16 pts)
Docetaxel 75 mg/m2 q 21 days
Toxicity: dyspnea, neutropenia
Increase in histone acetylation in PBMC
No relevant antitumour actitvity
[132]
Panobinostat
30 mg/day, days 1,3 and 5 q 14 days
Recurrent glioma (12 pts)
Bevacizumab 10 mg/kg q 14 days
Toxicity: thrombocytopenia, hypophosphatemia, hemorrhage, thrombosis. [133]
Panobinostat
10 mg days 1,3 and 5 q 14 days
Phase I
Mixed tumours (12 pts)
Bevacizumab 10 mg/kg q 14 days
Everolimus 5 or 10 mg
Toxicity: Mucositis, arrhythmia.
No consistent change in HDAC activity in PBMC
[134]
Panobinostat
30 mg days 1 and 4
NSCLC, HNC
Erlotinib 100 mg/day
DLT: cardiac, nausea. Fatigue.
PK and PD data.
[135]
Panobinostat
20 mg
Gleevec-resistant GIST (12 pts) No actibvity but evidence of 3HAc increase in PBMC [136]
Panobinostat 10 mg days 1, 3 and 5 Paclitaxel, Carbopaltin AUC=5
Phase I
Miscellaneous tumours (12 pts)
Toxicity: diarrhea, fatigue, and vomiting [137]
SAHA
100-400mg/day
RD 300 mg
GI carcinoma (14 pts)
Radiotherapy
30 Gy in 3 Gy/day over 2 weeks
Toxicity: fatigue
Diarrhoea proportional to the volume of intestine irradiated.
[41, 138]
SAHA
200–800 mg/day 1week q 2 weeks
RD 600 mg/day
Refractory colorectal
FolFOx (21 pts)
Toxicity: fatigue, anorexia, dehydration
no consistent modulation of TS expression
[88]
SAHA
days 1–3 q 14 days 600–2000 mg/day
RD 1700 mg once 600 mg tid
Phase I
Refractory colorectal (43 pts)
FU-LV
toxicity: neutropenia, thrombocytopenia, fatigue, nausea or vomiting, anorexia, mucositis.
No consistent effect on biopsies.
[139]
SAHA
400 mg/day
Tamoxifen (43 pts)
Hormone-resistant breast
Histone hyperacetylation and higher baseline HDAC2 levels that correlated with response [84]
SAHA
RD 400 mg/day 14 days q 21 days
600 mg/day bid q 21days
Phase I (28 pts)
Mixed tumours
Paclitaxel (200 mg/m2) (Carboplatin (AUC 6)
Toxicity: emesis, neutropaenia, fatigue [140]
SAHA
400 mg/day
Randomised Phase II
vs. placebo
NSCLC 94 pts
Paclitaxel Carboplatin
Toxicity thrombocytopenia, nausea, emesis, fatigue.
RR 34% vs. 12%
[85]
SAHA
400 mg/day
Phase I-II
resistant colorectal
5FU-leucovorin
Failed to establish an MTD
Toxicity: fatigue, thrombocytopenia and mucositis.
Intratumoral TS downregulation in one patient. Acetylation of H3 in PBMCs
[141]
SAHA
200–300 mg bid days 1–3 q 7 days
Phase I-II
Breast (54 untreated pts)
Paclitaxel 90 mg/m2/week Bevacizumab 10 mg/kg
Increased diarrhoea with the addition of SAHA
Increased acetylation of Hsp90 and α-tubulin
[66]
SAHA
400 mg/day 14 days
Phase II
Glioblastoma (37 pts)
Bortezomib 1.3 mg/m2/day days 1,4,8 and 11 q 21days
Toxicity: Fatigue.
No therapeutic advantage
[142]
SAHA
100–200 mg/day for days 1–14 q 21 days
Phase I
Mixed tumours
12 patients
Docetaxel 50–75 mg/m2 day 4 q 21 days
Excessive toxicity: neutropenic fever, cardiac, bleeding
No PK interaction
[143]
SAHA + VPA
for days 1–2 400–100 mg/day
RD 800 mg/day
Phase I (32 pts)
Mixed tumours
Doxorubicin on day 3
20 mg/m2 weekly
Toxicity: fatigue, nausea
HDAC2 expression in PBMC similar to tumours
no correlation of SAHA levels with acetylation
[144]
SAHA
300 mg/day for 16 days q 28 days
Phase I
Mixed tumours (22pts)
Marizomib
0.15-0.7 mg/m2 i.v.
days 1, 8 and 15 q 28 days
Toxicity: Fatigue, nausea, diarrhea, vomiting,
PK data. Data on proteasome inhibition in PBMC
[76]
SAHA
300 mg for days 1–3 q 8 days
Bortezomib
1.3 mg/m2 days1,8 and 15 q 21 days
NSCLC (21 pts)
Preoperative treatment.
Toxicity: fatigue and hypophosphatemia
[145]
SAHA
200–300 mg tid for days 1–4 and 8-11
Bortezomib 1–1.3 mg/m2 for day 9
Phase I (60 pts)
Comparison in PBMC and biopsies after SAHA and SAHA-Bort. Dcreased Nur77 expression. [146]
SAHA
400 mg p.o.
for days 1–7 and 15–21 q 28 days
NSCLC (33 pts) Erlotinib-resistant
Erlotinib 150 mg/day
No clinical activity
Toxicity: anemia, fatigue and diarrhoea.
[147]
SAHA
300–400 mg/day for days 1-14
Gastric (30 pts)
Capecitabine, Cisplatin
Toxicity: thrombocytopenia, fatigue, stomatitis, anorexia
H3Ac correlated with SAHA dose
[148]
SAHA
200–400 mg p.o. for days 1–14 q 21 days
Mixed tumours (35 pts)
Sorafenib 400 mg p.o. bid
Recommended dose for SAHA 300 mg/die, but not tolerated.
Toxicity: hand-foot syndrome. No tumour response.
[149]
SAHA
tid for days 1–4 and 8–11 q 21 days
Mixed tumours (29 pts)
Bortezomib 1.3 mg/m2 i.v. for days 1, 4, 8 and 11
Toxicity thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea.
PK data provided.
[150]
SAHA
p.o. for days 1–14
MTD 400 mg
Mixed tumours (23 pts)
Bortezomib i.v. for days 1, 4, 8 and 11 q 21 days.
MTD 1.3 mg/m2
Toxicity: fatigue, hyponatremia, nausea, anorexia
Some PK data
[151]
SAHA
300 mg daily
Mixed tumours (78 pts)
Pazopanib 600 mg daily
Toxicity: thrombocytopenia, neutropenia, fatigue, hypertension, diarrhea, vomiting [152]
SAHA 400 mg daily Gefitinib 250 mg
NSCLC pretreated (52 pts)
No clinical benefit
Toxicity: anorexia, diarrhea, fatigue, anemia
[153]
Valproate
30–90 mg/kg/day
for days 1–5 q 21 days
MTD 75 mg/kg/day
Karenitecin i.v. 0.8-1 mg/m2/day
for days 3–7 q 21 days
Melanoma: xenografts
Phase I-II (39 pts)
Toxicity: somnolence, fatigue
VPA levels at MTD 1.28 mMol
Histone hyperacetylation was observed in PBMC. No effect of valproate on Karenitecin PK
[154]
Valproate
15–160 mg/kg/day for days 1–3
RD 120 mg/kg/day
Phase I (44 pts)
Mostly breast
FEC day 3
Toxicity: somnolence, myelosuppression
Histone acetylation in tumour samples and in PBMCs correlated with valproic acid levels and was further linked to baseline HDAC2 but not to HDAC6 expression
[43]
Valproate
10–90 mg/kg/day
Melanoma (32 pts)
Dacarbazine 800 mg/m2 q 21 days,
interferon-α 600.000 IU twice daily
Toxicity: neurological, myelosuppression
Acetylation in PBMC measured.
“casting some doubts on the clinical use of VPA in this setting”.
[155]
Valproate
Dose escalated to obtain active plasma concentration
Mesothelioma resistant to cisplatin (45 pts)
Doxorubicin 60 mg/m2 q 21 days
Toxicity: myelosuppression
16% partial response rate
[156]
Valproate
15–160 mg/kg/day for days 1–3
MTD 140
Phase I
Mixed tumours (48pts)
Epirubicin 100 mg/m2 for day 3
Toxicity: somnolence, confusion, neutropenia
VPA levels correlate with acetylation in PBMC
Plasma VPA higher than in vitro effective concentrations
[44]
  1. References are included at the end of the text
  2. A.I. aromatase inhibitor, 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, GIST gastrointestinal stromal tumour, HNC head-and-neck carcinoma, 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