Table 1.
Selected Recent Clinical Trials with DNMT Inhibitors.
| Drug(s) | Indication(s) | Author (Year) | Total Patients | Results | Comments | Ref. |
|---|---|---|---|---|---|---|
| Azacitidine | MDS | Silverman (2002/2006) | 191 | 7% CR, 16% PR, 37% HI | Low dose treatment improved quality of life and survival rate; delayed progression time to AML( CALGB9221). | [102,104] |
| MDS | Fenaux (2009) | 358 | 17% CR, 12% PR, 42% SD | Improved OS compared to CCR in high risk MDS patients (AZA-001). | [105] | |
| MDS | Lyons (2009) | 151 | 44%, 45%, 56% HI | RBC transfusion independence achieved in 3 alternative dosing regimens. | [109] | |
| MDS | Martin (2009) | 25 | 27% ORR | Response rates are comparable to CALGB 9221 and AZA-001 trials but shorter OS in this 5 days treatment regimen. | [110] | |
| MDS/AML | Muller-Thomas (2009) | 32 | 15.6% CR, 25% HI, 34.4% SD | Survival advantage in responder group of high-risk MDS | [111] | |
| MDS | Musto (2010) | 74 | 10.8% CR, 9.5% PR, 20.3% HI | Survival benefits in responder group. | [108] | |
| Decitabine | MDS | Kantarjian (2006) | 170 | 9% CR, 13% HI, 17% ORR | RBC transfusion independence and delayed progression time toward AML (D-0007). | [112] |
| MDS | Kantarjian (2007) | 95 | 34% CR | Better response rate at low dose. | [114] | |
| MDS | Steensma (2009) | 99 | 17% CR, 18% HI, 32% ORR | Alternative dosing and significant difference in ORR compared to single-center trial by Kantarjian et al, (ADOPT). | [115] | |
| Refractory Solid Tumor | Stewart (2009) | 31 | Relative reduction of tumor size but no correlation between PBMC DNA methylation and tumor DNA methylation. | [117] | ||
| MG98 | MDS/AML | Klisovic (2009) | 23 | 26% SD | No clinical benefits observed in administered doses and no correlation between DNMT1 downregulation with SD. | [119] |
| Advanced Solid Malignancies | Plummer (2009) | 33 | Suppression of DNMT1 expression in PBMC in all doses with mild toxicity observed. | [121] | ||
| Azacitidine in Combination | ||||||
| Azacitidine + Valproic Acid + all-trans-Retinoic Acid | AML/MDS | Soriano (2007) | 53 | 22% CR, 42% ORR | The increase of histone acetylation level is not correlated with VPA dose level. | [122] |
| Azacitidine + Thalidomide | MDS/AML | Raza (2008) | 40 | 42% HI, 14% SD | High expression of cellular proliferation genes was observed in non-responders. | [135] |
| Azacitidine + Valproic Acid | Advanced cancer | Braiteh (2008) | 55 | 25%SD | Safe dosage of azacitidine up to 75mg/m2 in advanced malignancies. | [124] |
| Azacitidine + Sodium Phenylbutyrate | Refractory Solid Tumor | Lin (2009) | 27 | No clear benefits seen in the three dosing regimens tested. | [126] | |
| Azacitidine + Valproic Acid | MDS | Voso (2009) | 62 | 30.7% CR/PR, 15.4% HI, 38.5% SD | Increasing therapeutic level of VPA promoted efficacy of azacitidine | [123] |
| Azacitidine + Entinostat | MDS/AML | Fandy (2009) | 30 | 42%ORR | Lack of association between reversal of DNA methylation and clinical response. | [125] |
| Azacitidine + Allogeneic SCT | MDS/AML | Jabbour (2009) | 17 | High response rate in patients with recurrent disease after HSCT. | [136] | |
| Azacitidine + Lenalidomide | MDS | Sekeres (2010) | 18 | 44% CR, 17% HI, 67% ORR | Higher CR is associated with normal cytogenetics and lower methylation levels | [129] |
| Azacitidine + Cytarabine | MDS/AML | Borthakur (2010) | 34 | Limited clinical activity in patients with relapsed, refractory AML. | [137] | |
| Azacitidine + Etanercept | MDS/CMML | Scott (2010) | 32 | 72% ORR | Increased response rate and duration of response observed. | [138] |
| Decitabine in Combination | ||||||
| Decitabine + Valproic Acid | Advanced leukemia | Garcia-Manero (2006) | 54 | 19% CR | Lower pretreatment CDKN2B methylation level correlates with higher response rate. | [127] |
| Decitabine +Carboplatin | Solid Tumor | Appleton (2007) | 33 | A correlation between different doses of decitabine with PBC DNA demethylation. | [132] | |
| Decitabine + Valproic Acid | AML | Blum (2007) | 25 | 44% ORR | VPA increased treatment-related toxicity; Re-expression of ER associated with clinical response. | [128] |
| Decitabine + Gemtuzumab ozogamicin | AML | Chowdhury (2009) | 12 | 42% CR | Treatment facilitated subsequent HSCT. | [131] |
| Decitabine + Allogeneic SCT | MDS | De Padua Silva (2009) | 17 | No increased toxicity due to decitabine. | [139] | |
| Decitabine + Imatinib Mesylate | CML | Oki (2007) | 28 | 32% CR, 4% PR, 7% HI | Higher activity in patients without BCR-ABL mutations. | [130] |
| Decitabine + IL-2 | Metastatic Melanoma; Renal Carcinoma | Gollob (2006) | 21 | Reexpreesion of immunomodulatory genes. | [133] | |
Abbreviations: CR, complete remission; PR, partial response; HI, hematologic improvement; ORR, overall response rate; SD, stable disease. CCR, conventional care regimens; RBC, red blood cells; HSCT, hematopoietic stem cells transplantation; PBMC, peripheral blood mononuclear cell; PBC, peripheral-blood cells.