Table 1.
Clinical trials of DNMTs inhibitors for urological tumors.
| Cancer | Drug | Phase (ID) | Status | Schedule | Outcome | Ref. |
|---|---|---|---|---|---|---|
| Bladder | 5-Aza-2'-deoxycytidine | I (NCT00030615) |
Completed | Advanced BlCa patients (n = 24) received daily escalating doses of 5-aza-2'-deoxycytidine for 4 weeks. Courses repeated every 6 weeks in the absence of disease progression or unacceptable toxicity. | Data not available. | ClinicalTrials.gov, 2002 |
| CC-486 | I (NCT02223052) |
Recruiting (estimated completion date: 5 September 2018) | Patients with hematologic or solid malignancies including genitourinary tumors (n = 90) have been enrolled to evaluate bioequivalence and food effect bioavailability of CC-486 (oral azacytidine). | Data not available. | ClinicalTrials.gov, 2014 | |
| CC-486 with Carboplatin or Paclitaxel protein bound particles (ABI-007) | I (NCT01478685) |
Completed | CC-486 was administered orally at doses between 100-300 mg daily for either 14 or 21 days. Carboplatin was given by intravenous (i.v.) infusion once every 21 days. ABI-007 was administered by i.v. infusion on two of every three weeks at a dosage of 100 mg/m2. | Data not available. | ClinicalTrials.gov, 2011 | |
| 5-Azacytidine and Sodium phenylbutyrate | I | Completed | 5-azacytidine subcutaneously (s.c.) and sodium phenylbutyrate (continuous i.v. infusion) were administered in refractory BlCa (n = 2), RCC (n = 3) and PCa (n = 5) patients regarding three different dose regimens during 48 cycles in 27 advanced solid tumors patients. | The results were disappointing for genitourinary malignancies, since none of the patients responded to the treatment. From all enrolled patients, only one exhibited stable disease for 5 months whereas 26 patients showed progressive disease. Grade 3 and 4 neutropenia was observed. | Lin et al., 2009 | |
| FdCyd and THU | II (NCT00978250) |
Recruiting (estimated completion date: 2 June 2020) | Both drugs will be administrated over 28-day cycles through a vein for about 3 h each day on days 1, 5, and 8, 12 of each cycle. Patients may continue to receive FdCyd and THU if their cancers does not grow, if they do not have too many side effects, and if they are willing to do so. | Data not available. | ClinicalTrials.gov, 2009b | |
| RX-3117 | I/II (NCT02030067) |
Recruiting (estimated completion date: December 2017) | Phase I study intend to determine the maximum tolerated dose of RX-3117. The enrolled subjects (n = 72) will be treated in a dose expansion followed by a 2-stage Phase 2 study for over 8 cycles of therapy. Each cycle will last 4 weeks. RX-3117 will be administered 3 times each week for 3 weeks follow by one-week rest. All subjects will be followed for at least 30 days after the last dose. | Data not available. | ClinicalTrials.gov, 2013 | |
| MG98 | I | Completed | Patients with advanced solid tumors (n = 33), including bladder and prostate cancer were treated with escalating doses of MG98 in an i.v. infusion over 7 days every 14 days. | Patients with genitourinary tumors did not respond to the treatment. Mild toxicities including fatigue, headache, and myalgia grade ≤2. | Plummer et al., 2009 | |
| 75 approved agents | II (NCT02788201) |
Recruiting (estimated completion date: 29 June 2019) | Evaluate whether the Co-expression Extrapolation (COXEN) model can chose the best therapeutic option for advanced urothelial carcinoma within 3 weeks. Patients whose BlCa has spread after at least one chemotherapy line (n = 20) are estimated to be enrolled. The subjects will take the drugs assigned by the COXEN model and will have regular visits for blood and urine tests as well as tumor scans. | Data not available. | ClinicalTrials.gov, 2016a | |
| Kidney | 5-Aza-2'-deoxycytidine | I | Completed | Refractory RCC patients (n = 3) received intravenously 5-aza-2'-deoxycytidine from 2.5 to 10 mg/m2 on days 1-5, and from 8 to 12, or 15 to 20 mg/m2 on days 1–5. Each cycle lasted four weeks. | Relative reduction of tumor size; Increased tumor apoptosis; Reduction of DNA methylation in both tumor and PBMC but without correlation between them; Increased expression of CTR1. | Stewart et al., 2009 |
| 5-Aza-2'-deoxycytidine and Interleukin-2 | I | Completed | Renal cancer patients (n = 5) received subcutaneous 5-aza-2'-deoxycytidine daily x 5 days on weeks 1 and 2 of a 12-week cycle. High-dose IL-2, consisting of two cycles of IL-2 600,000 IU/kg intravenously every 8 hours' x 14 doses separated by a 2-week break, was administered starting on week 3. Decitabine was escalated from 0.1 to 0.25 mg/kg. | Global DNA demethylation. Up-regulation of immunomodulatory genes. Three of five evaluable patients presented stable disease. Grade 4 neutropenia was observed. | Gollob et al., 2006 | |
| 5-Aza-2'-deoxycytidine and Interferon alfa-2β | II (NCT00561912) |
Terminated | Patients with advanced RCC (n = 2) received 5-aza-2'-deoxycytidine 15 mg/m2 intravenously daily over 1h for 5 days plus Interferon Alfa-2b 0.5 million units subcutaneously twice daily continuously, on day 1 cycle 3. Each cycle was 28 days long. | Terminated due to low accrual. | ClinicalTrials. ClinicalTrials.gov, 2007 |
|
| 5-Aza-2'-deoxycytidine and Anti-PD-1 | I/II (NCT02961101) |
Recruiting (estimated completion date: May 2019) | Patients with relapsed or refractory malignancies, including RCC, will be enrolled to evaluate the feasibility, safety and efficacy of an anti-programmed cell death protein 1 (PD-1) antibody combined with low-dose 5-aza-2'-deoxycytidine every 3 weeks. | Data not available. | ClinicalTrials.gov, 2016b | |
| 5-Azacytidine and Valproic Acid | I | Terminated | 5-Azacytidine was administered subcutaneously daily for 10 days in patients with advanced cancers (n = 55), two of them with RCC. Cycles were 28 days long and 5-azacytidine was administered at 75 mg/m2. | One of the two treated RCC patients achieved a 6 months' stable disease. Data not available for decrease in methylation but it was observed histone acetylation. Grade 3 and 4 toxicities were observed. | Braiteh et al., 2008 | |
| 5-Azacytidine and Interferon-α-2β | I (NCT00217542) |
Completed | Patients (n = 42) received azacytidine subcutaneously once daily on days 1–4 and 15–17 and recombinant interferon alfa-2b subcutaneously on specific days during course 1. Beginning in course 2 and for all subsequent courses, patients received azacytidine subcutaneously once daily on days 1–3 and 15–17 and interferon alfa-2b subcutaneously on specific days. Treatment repeated every 28 days for up to 12 total courses in the absence of disease progression or unacceptable toxicity. | Data not available. | ClinicalTrials.gov, 2005 | |
| 5-Azacytidine and Bevacizumab | I/II (NCT00934440) |
Terminated | All patients with advanced RCC (n = 23) in phase I and II received bevacizumab at the standard dose of 10 mg/kg every 2 weeks and the doses were administered at specific times. 5-azacytidine was administered in different dose levels for each study phase (I/II). | Data not available. | ClinicalTrials.gov, 2009a | |
| MG98 | I/II (NCT00003890) |
Completed | Untreated patients (n = 17) with measurable metastatic renal carcinoma received MG98 360 mg/m2 intravenous over 2 h twice weekly for 3 weeks. Courses were repeated every 4 weeks. | No conclusive pattern of decreased DNMT1 activity was detected after MG98 treatment. Toxicities was experienced including rigors, fatigue, fever, and nausea. | Winquist et al., 2006 | |
| MG98 and Interferon-α-2β | Study phase not provided | Completed | Patients with advanced RCC (n = 19) were divided in 2 groups: 10 received a continuous regimen and 9 received an intermittent regimen twice weekly. In the first group, patients received MG98 in two 7-day continuous infusions every treatment week followed by a week of rest in each cycle. In the intermittent group, patients were treated with a 2h intravenous infusion of MG98 twice per week for three weeks with the last cycle week of rest. Additionally, both groups received interferon-α-2β subcutaneously three days per week with an initial dose of 12 MIU/day or 9 MIU/day. | Interferon-α-2β 9 MIU plus MG98 125 mg/m2 for a continuous schedule and interferon-α-2β 9 MIU plus MG98 200 mg/m2 for an intermittent schedule were considered the maximum tolerable doses. The first showed 2 out of 7 dose-limiting grade 3 toxicities, including fever and thrombocytopenia. One partial response and eight stable disease were achieved. | Amato et al., 2012 | |
| Prostate | 5-Azacytidine, docetaxel and prednisone | I/II (NCT00503984) |
Terminated | mCRPC cancer patients who progressed during or within 6 months of docetaxel chemotherapy, were eligible (n = 22). In phase I, patients received the highest dose of azacytidine 150 mg/m2 daily for 5 days + Docetaxel 75 mg/m2 on day 6. In phase II, it was used the combination of azacytidine 75 mg/m2 daily for 5 days followed by docetaxel 75 mg/m2 on day 6 along with growth factor support and fixed prednisone 5 mg since day 1 to 21. | In phase I, grade 4 neutropenia was frequent. In phase II, 10 of 19 evaluable patients showed PSA response and 3 of 10 achieved an objective response. Significant demethylation of GADD45A was observed. | Singal et al., 2015 |
| 5-Azacytidine and Combined Androgen Blockade (CAB) | II (NCT00384839) |
Completed | Chemonaïve patients with CRPC on CAB and PSA-doubling time (DT) < 3 months were eligible (n = 36). CAB was continued and 5-azacytidine 75 mg/m2 was administered for 5 consecutive days of each 28-day cycle up to 12 cycles or until clinical progression or intolerable toxicities. | 19 patients attained a PSA-DT ≥3 months. Overall median PSA-DT was significantly prolonged with 2.8 months. The obtained median clinical progression-free survival was 12.4 weeks. Grade 3 toxicities of fatigue and neutropenia were observed. | Sonpavde et al., 2011 | |
| 5-Azacytidine and Valproic Acid | I | Completed | 5-Azacytidine was administered subcutaneously daily for 10 days in patients with advanced cancers (n = 55), in which two of them with PCa. Cycles were 28 days long and 5-azacytidine was administered at 75 mg/m2. | One of the two treated PCa patients achieved a 6 months' stable disease. | Braiteh et al., 2008 | |
| 5-Azacytidine and Sodium Phenylbutyrate | II (NCT00006019) |
Completed | Patients (n = 20) received 5-azacytidine on days 1–7 and phenylbutyrate i.v. over 1–2 h on days 8–12. Additional courses in these patients were repeated every 21–28 days in the absence of disease progression or unacceptable toxicity. | Data not available. | ClinicalTrials.gov, 2000 | |
| 5-Aza-2'-deoxycytidine | II | Completed | Patients with metastatic recurrent PCa after total androgen blockade and flutamide withdrawal (n = 14) received an infusion of 3 doses of 5-aza-2'-deoxycytidine 75 mg/m2. Cycles of therapy were repeated every 5–8 weeks to allow for resolution of toxicity. | Two of 12 patients evaluable for response had stable disease with a time to progression of > 10 weeks. 5-Aza-2'-deoxycytidine was well tolerated with modest clinical activity against CRPC. | Thibault et al., 1998 | |
| SGI-110 and Pembrolizumab | I (NCT02998567) |
Not yet recruiting | Patients with refractory solid tumors (n = 35), including CRPC, will receive s.c. SGI-110 daily on days 1–4 of each 21-day cycle. Pembrolizumab will be administered i.v. once per 21-day cycle on specific days. | Data not available. | ClinicalTrials.gov, 2016c | |
| Curcumin and Radiotherapy | Study phase not provided (NCT01917890) | Completed | PCa patients (n = 40) treated with external beam radiotherapy were separated in two groups 20 of them received 3 g/day curcumin orally and 20 received placebo. | Patients treated with curcumin presented reduced urinary symptoms, showing possible radioprotective effects. | Hejazi et al., 2013 | |
| Disulfiram | I (NCT01118741) |
Completed | Eligible patients (n = 19) were ≥18 years old, previously treated with local therapy and subsequently developed biochemically recurrent disease. Cohort 1 (n = 9) and 2 (n = 10) received disulfiram treatment 250 mg and 500 mg daily, respectively. The primary endpoint was the proportion of subjects with a demethylation response. Secondary endpoints included rate of PSA progression at 6 months, changes in PSA doubling time and safety/tolerability. | Only five of the evaluable subjects were on trial for ≥ 6 months from cohort 1 and obtained a PSA progression by 6 months. Three of the responders displayed pretreatment instability in their 5-mC content. Six patients experienced grade 3 toxicities. | Schweizer et al., 2013 | |
| Testicular | 5-Azacytidine | II | Completed | Patients with solid tumors (n = 214) were enrolled and four of them were testicular cancer patients. 5-azacytidine doses varied from 225 mg/m2 to 150 mg/m2. | Two of the four testicular cancer patients presented partial responses. | Quagliana et al., 1976 |
| II | Completed | Patients (n = 17) received 5-azacytidine at a dosage of 150 mg/m2/day at days 1 to 5 by continuous infusion every three weeks. | It was not observed any 5-azacytidine activity. Grade 3 and 4 toxicities were reported. | Roth et al., 1993 | ||
| SGI-110 and cisplatin | I (NCT02429466) |
Recruiting (estimated completion date: 31 December 2018) | TGCT patients (n = 15) who relapsed after several chemotherapy lines will be enrolled. SGI-110 will be given subcutaneously, daily, 30 mg/m2 on days 1–5 followed by cisplatin 100 mg/m2 on day 8, every 4 weeks. Treatment will be continued for a maximum of 6 cycles or until disease progression or unacceptable toxicity. | Data not available. | ClinicalTrials.gov, 2015 | |
| Hydralazine and Magnesium Valproate | II (NCT00404508) |
Completed | Patients with refractory solid tumors (n = 15) received hydralazine at 182 mg for rapid, or 83 mg for slow, acetylators, and magnesium valproate at 40 mg/kg, beginning a week before chemotherapy. | A decrease in chemotherapy resistance was observed. A clinical benefit was reported, namely stable clinical response a 5.6 months progression-free survival and an overall survival of 5.7 months | Candelaria et al., 2007 |