Table 2.

Epigenetic treatment associated with a conventional anticancer agent

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]

References are included at the end of the text

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