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. | |
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] |