Table 3.
Clinical trials in BC using DNMT inhibitors.
| Drug | Phase (ID) | Status | Enrollment | Schedule | Results | Period | Reference |
|---|---|---|---|---|---|---|---|
| 5-Aza and sodium phenylbutyrate | I (NCT00005639) |
Completed | Patients with diagnosis of a refractory solid tumor malignancy with no curative options including BC (n = 34) | Regimen A: Low-dose of 5-aza with intermittent phenylbutyrate 400 mg/m2/day over 24 h on days 6 and 13. Regiment B: 5-aza 75 mg/m2/day for 7 days, followed by two different doses of phenylbutyrate starting on day 8 and continuing for 7 days. Each cycle lasts 35 days for A and B. Regiment C: 2 different daily doses of 5-AC for 21 days and phenylbutyrate 400 mg/m2/day over 24 h once per week. Each cycle lasts 42 days. |
Three doses were well tolerated. Common toxicities included bone marrow suppression-related neutropenia and anemia. One patient showed stable disease; the remaining did not show any clinical response. | 2000–2005 | [163] |
| DAC | I (NCT00030615) |
Completed | Advanced metastatic solid tumor patients after other standard therapies fail including BC (n = 24) | DAC intravenous (IV) over 30 min on days 1–5 weekly for 4 weeks. Course repeated every 6 weeks in the absence of disease progression or unacceptable toxicity. | Not available | 2001–2008 | [168] |
| FdCyd and THU | II (NCT00978250) |
Completed | Metastatic or unresectable solid tumors including urothelial transitional cell carcinoma (n = 18), whose disease progressed after at least one line of standard therapy. | FdCyd (100 mg/m2/day) by 3 h intravenous infusion and THU (350 mg/m2/day) 20% as a bolus, with the remaining co-administered with FdCyd over 3-h infusion on days 1–5 and 8–12 of each 28-day cycle. | Co-administration with THU was shown to increase the area under the curve of FdCyd more than 4-fold. Combination was well tolerated. ORR of 5.6%, PFS of 3.6 months, and 42% of 4-month PFS probability for urothelial cancer patients. |
2009–2019 | [162,169] |
| CC-486, carboplatin, and paclitaxel protein-bound particles (ABI-007) | I (NCT01478685) |
Completed | Patients with relapsed or refractory solid tumors including urinary bladder neoplasms (n = 169) | Arm A: CC-486 (doses between 100–300 mg) was administered orally daily either 14 or 21 days. Carboplatin was given by intravenous (IV) infusion once every 21 days Arm B: CC-486 (doses between 100–300 mg) was administered orally daily for either 14 or 21 days ABI-007 was administered by intravenous (IV) infusion on two of every three weeks Arm C: CC-486 (doses between 100–300 mg) was administered orally daily for either 14 or 21 days. |
CC-486 dosed 14/21 days was tolerated as a priming agent with carboplatin and ABI-007. Both combinations show evidence of clinical activity. | 2011–2015 | [164,165] |
| RX-3317 | I (NCT02030067) |
Completed | Patients with advanced or metastatic solid tumors including advanced BC (n = 124) | A cycle was 4 weeks, with up to 8 cycles. RX-3117 dosing was given 3 times each week for 3 weeks followed by 1 week off treatment. All subjects were followed for at least 30 days after the last dose of RX-3117. | Not available | 2013–2019 | [170] |
| CC-486 | I (NCT02223052) |
Completed | Subjects with hematologic or solid tumor malignancies including BC patients (n = 89) | Arm 1: Two 150-mg tablets of CC-486 on day 1 and 1 × 300 mg CC-486 on day 2 Arm 2: 1 × 300 mg tablet of CC-486 on day 1 and 2 × 150 mg CC-486 on day 2. | Not available | 2014–2018 | [171] |
| SGI-110, gemcitabine, and cisplatin | Ib/IIa (2015-004062-29) |
Recruiting | Urothelial BC patients with stages T2-4aN0M0 (n = 20) | Arm 1: SGI-110 days 1–5 at the determined dose, gemcitabine 1000 mg/m2 days 8 + 15, cisplatin 70 mg/m2 day 8. 3–4 cycles of 21 days each. Arm 2: Gemcitabine 1000 mg/m2 days 8 + 15, cisplatin 70 mg/m2 day 8 3–4 cycles of 21 days each for both arms. 3–4 cycles of 21 days each. |
Not available | 2015–present | [172] |
| 75 approved agents | II (NCT02788201) |
Completed | Patients with a diagnosis of metastatic, progressive urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis (n = 8) | COXEN algorithm was used to determine the best therapy from among 75 FDA-approved agents (single agent or combination). Patients had regular visits for blood, urine, and tumor scans. | Not available | 2017–2019 | [173] |
| Azacitidine, pembrolizumab, and epacadostat | I (NCT02959437) |
Completed | Subjects with advanced or metastatic solid tumors including BC patients (n = 70) | Five doses of azacitidine were administered by subcutaneous injection or intravenously (IV) over days 1 to 7 in cycles 1 through 6. Pembrolizumab was administered in a 30-min IV infusion every 3 weeks on day 1 of each 21-day cycle. Epacadostat tablets were administered orally twice daily. |
Not available | 2017–2020 | [166] |
| Atezolizumab and guadecitabine | II (NCT03179943) |
Suspended | Recurrent/advanced urothelial carcinoma (stage IV) patients who previously progressed on checkpoint inhibitor therapy with anti- PD-1 or PD-L1 therapy (n = 53) | Atezolizumab is administered intravenously on day 1 and day 22 of a 6-week cycle for a period of 8 cycles. Guadecitabine is administered subcutaneously on days 1 through 5 of the 6-week cycle for a period of 4 cycles. | Not available | 2017–estimated end 2022 | [167] |
Abbreviations: 5-aza—5-azacytidine; DAC—decitabine.