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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
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
5-azacytidine Ovarian cancer, platinum insensitive (30 pts) Toxicity: fatigue, myelosuppression
DR4 methylation in PBMC related to activity
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.
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
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
1000 mg/m2, 48 h c.i.
Thymic epithelial (26 pts)
Cisplatin, doxorubicin, cyclophosphamide
Toxicity: nausea, diarrhea, neutropenia, thrombocytopenia,
Immunomodulatory effect observed
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]
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
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
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
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
0.15 mg/kg i.v. daily × 5 days/wk for 2 wks
Phase I-II
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)
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
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.
01–0.2 mg/kg 3 days weekly
10-30mg q 4 days
Temozolomide 150–200 mg/m2/day
Resistant melanoma
Toxicity: myelosuppression, fatigue, nausea
No antitumour acitivity.
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
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
5 mg/week
Breast (64pts)
Examestane 25 mg/day
Randomised phase II. Patients had progressed with AI.
Protein lysine hyperacetylation associated with prolonged PFS
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
(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.
(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.
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
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]
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
30 mg days 1 and 4
Erlotinib 100 mg/day
DLT: cardiac, nausea. Fatigue.
PK and PD data.
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]
RD 300 mg
GI carcinoma (14 pts)
30 Gy in 3 Gy/day over 2 weeks
Toxicity: fatigue
Diarrhoea proportional to the volume of intestine irradiated.
[41, 138]
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
days 1–3 q 14 days 600–2000 mg/day
RD 1700 mg once 600 mg tid
Phase I
Refractory colorectal (43 pts)
toxicity: neutropenia, thrombocytopenia, fatigue, nausea or vomiting, anorexia, mucositis.
No consistent effect on biopsies.
400 mg/day
Tamoxifen (43 pts)
Hormone-resistant breast
Histone hyperacetylation and higher baseline HDAC2 levels that correlated with response [84]
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]
400 mg/day
Randomised Phase II
vs. placebo
NSCLC 94 pts
Paclitaxel Carboplatin
Toxicity thrombocytopenia, nausea, emesis, fatigue.
RR 34% vs. 12%
400 mg/day
Phase I-II
resistant colorectal
Failed to establish an MTD
Toxicity: fatigue, thrombocytopenia and mucositis.
Intratumoral TS downregulation in one patient. Acetylation of H3 in PBMCs
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
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
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
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
300 mg/day for 16 days q 28 days
Phase I
Mixed tumours (22pts)
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
300 mg for days 1–3 q 8 days
1.3 mg/m2 days1,8 and 15 q 21 days
NSCLC (21 pts)
Preoperative treatment.
Toxicity: fatigue and hypophosphatemia
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]
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.
300–400 mg/day for days 1-14
Gastric (30 pts)
Capecitabine, Cisplatin
Toxicity: thrombocytopenia, fatigue, stomatitis, anorexia
H3Ac correlated with SAHA dose
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.
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.
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
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
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
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
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”.
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
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
  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