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Table 3 Histone modifying drugs in clinical trials for PCa

From: Epigenetic modulators as therapeutic targets in prostate cancer

Drug Clinical trial ID Phase Status Protocol Outcome Ref.
Vorinostat/SAHA NCT00330161 II Completed Metastatic PCa with disease progression on prior chemotherapy received 400 mg vorinostat/SAHA orally each day. Disease progression measured at 6 months. n = 27 Toxicity: significant toxicities including fatigue, nausea. IL-6 (Interleukin 6) was higher in patients with toxicity. 7 % patients achieved a stable disease state. No PSA decline >50 % observed. Median time to progression and overall survival were 2.8 and 11.7 months, respectively. Significant toxicities reported. [230]
Vorinostat/SAHA NCT00005634 I Completed Patients with advanced or metastatic solid tumors that have not responded to previous therapy received vorinostat/SAHA I.v. on days 1–3 every 21 days. n = 45 Determine the tolerability, pharmacokinetic profile, and biologic effects of the drug. Not available  
Vorinostat/SAHA and docetaxel NCT00565227 I Terminated due to toxicity Patients with advanced and relapsed tumors received oral vorinostat/SAHA for the first 14 days of a 21-day cycle, with docetaxel I.v. on day 4 of each cycle. n = 12 Toxicity: neutropenia, peripheral neuropathy, and gastrointestinal bleeding. The combination of vorinostat/SAHA and docetaxel was poorly tolerated. No responses were identified. [274]
Vorinostat/SAHA and doxorubicin NCT00331955 I Completed Patients receive oral vorinostat/SAHA twice daily for 5 doses on days 1–3, 8–10 and 15–17 and doxorubicin I.v. on days 3, 10, and 17 very 28 days for up to 6 courses. n = 32 Partial response was achieved in one of the two PCa patients enrolled. [275]
Vorinostat/SAHA and androgen deprivation therapy (ADT) NCT00589472 II Completed Localized PCa patients received neo-adjuvant vorinostat/SAHA with oral bicalutamide with either I.M. leuprolide or subcutaneous goserelin acetate administered for up to 8 weeks or until the day of surgery. n = 19 Determine the rate of pathologic complete response in patients with localized PCa treated with ADT and vorinostat/SAHA before radical prostatectomy measuring androgens in blood. Not available  
Vorinostat/SAHA and mTOR inhibitor temsirolimus NCT01174199 I Ongoing, not recruiting Metastatic PCa patients received oral vorinostat once daily on days 1–14 and temsirolimus intravenously on days 1, 8, and 15 of a 21-day cycle. n = 13 Determine the safety, tolerability, partial and complete objective response rates, progression-free survival and overall survival, and PSA response. Not available  
Panobinostat NCT00667862 II Completed I.v. panobinostat (20 mg/m2) was administered to CRPC patients on days 1 and 8 of a 21-day cycle. Disease progression measured at 24 weeks. n = 35 Toxicity: fatigue, thrombocytopenia, nausea
14 % patients demonstrated a decrease in PSA but none >50 %. No clinical activity.
Panobinostat (LBH589), docetaxel, and prednisone NCT00663832 I Completed CRPC patients received oral panobinostat (20 mg/m2) on days 15 for 2 consecutive weeks. On the other arm, patients received oral panobinostat (15 mg/m2) with docetaxel I.v. (75 mg/m2) every 21 days and oral prednisone (5 mg) twice every day of a 21-day cycle. n = 16 Toxicity: dyspnea and neutropenia
Panobinostat in combination with docetaxel and prednisone in patients with CRPC resulted in 63 % of patients with >50 % decline in PSA levels. No relevant anti-tumor activity.
Panobinostatbicalutamide NCT00878436 I/II Completed Men with CRPC received treatment with bicalutamide (50 mg PO) daily with oral panobinostat at 2 dose levels (20 or 40 mg). Minimum treatment was 3 weeks. n = 9 Toxicity: thrombocytopenia
In 2 patients, it was registered a >50 % PSA decline by 9 months of therapy; and 3 patients presented stable PSA levels.
Panobinostat docetaxel and prednisone NCT00493766 I Terminated because of a strategic decision In one arm, oral panobinostat alone is given to patients with progressing hormone refractory prostate cancer. In the other arm, oral panobinostat along with I.v. docetaxel and oral prednisone is administered. n = 16 Toxicity: dyspnea, neutropenia, fatigue. Exposure to oral panobinostat was similar with and without docetaxel.  
Panobinostat, docetaxel, and prednisone NCT00419536 I Terminated because of a strategic decision Not available Determine maximum tolerated dose of panobinostat and to characterize the safety, biological activity, and pharmacokinetic profile.  
Panobinostat, radiotherapy NCT00670553 I Completed Not available.
n = 7
Establish toxicity, tolerability, and safety of oral panobinostat when given in combination with radiotherapy. Not available  
Romidepsin NCT00106418 II Completed mCRPC patients received romidepsin (13 mg/m2) intravenously on days 1, 8, and 15 every 21-day cycle. Disease progression measures at 6 months. n = 35 Toxicity: nausea, fatigue
2 patients reached a confirmed radiological partial response of over 6 months, in addition to >50 % PSA decline. 11 patients had to discontinue the therapy due to toxicity. Romidepsin demonstrated minimal anti-tumor activity in chemonaive patients with CRPC.
Romidepsin NCT00106301 II Completed Patients with CRPC were continued at the same dose of romidepsin as in the previous study, which could have been 13 mg/m2 or a reduced dose of 10 mg/m2, on days 1, 8, and 15 of each 28-day cycle. n = 2 Evaluate adverse effects and effect of romidepsin and evaluate the time of disease progression. Not available  
Romidepsin in solid tumors with liver dysfunction NCT01638533 I Currently recruiting patients Patients with recurrent prostate carcinoma receive romidepsin I.v. on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. n = 132 Establish the safety and tolerability, pharmacokinetics, and maximum tolerated dose. Not available  
Pracinostat NCT01075308 II Completed Recurrent or mCRPC patients received pracinostat orally (60 mg) 3 times a week for 3 consecutive weeks followed by 1 week off-dosing of a 28-day cycle. n = 32 Toxicity: fatigue, neutropenia
2 patients achieved a decline >50 % of PSA. In patients with measurable disease, there were no objective responses, while 7 patients had stable disease lasting 1.7 to 8 months.
Valproic acid NCT00670046 II Not provided Non-metastatic with biochemical progression PCa patients received oral valproic acid twice daily for up to 1 year in the absence of disease progression or unacceptable toxicity. n = 50 Percentage of patients exhibiting observed or predicted PSA doubling time >10 months after initiation of the study. Not available  
Valproic acid and bevacizumab NCT00530907 I Completed Bevacizumab was administered at escalating dosages of 2.5–11 mg/kg on days 1 and 15, and oral valproic acid at dosages of 5.3–10 mg/kg on days 1–28, every 28. n = 57 Toxicities: grade 3 altered mental status (n = 2), related to valproic acid. Bevacizumab 11 mg/kg given on days 1 and 15 and valproic acid 5.3 mg/kg daily were the recommended phase II dosages. Stable disease ≥6 months were reported in 4/57 of patients. Of the 39 patients evaluated for histone acetylation, 2 of 3 (67 %) patients with stable disease ≥6 months showed histone acetylation, while 8 of 36 (22 %) without stable disease ≥6 months demonstrated histone acetylation (p = 0.16). Patients with hypertension had improved overall survival. [278]
Sulforaphane NCT01228084 II Completed Patients with biochemical (PSA) recurrent PCa received 200 μmoles/day sulforaphane-rich extracts during 20 weeks. n = 20 1 patient experienced a ≥50 % PSA decline and 7 patients had PSA declines >50 %. No grade 3 events reported. [234]
Sulforaphane II Completed PCa patients with increasing PSA levels after prostatectomy orally received 60 mg of sulforaphane or placebo for 6 months. n = 78 Sulforaphane-treated patients presented 86 % longer PSA-DT than the placebo group. Increases >20 % of PSA levels higher in the placebo group (71.8 %) compared to the sulforaphane-treated group (44.4 %) [235]
MGCD-0103 and docetaxel NCT00511576 I Terminated Patients received escalating doses of oral MGCD-0103 in combination with two fixed doses of I.v. docetaxel (60 mg/m2 and 75 mg/m2). n = 54 Determine the maximum tolerated dose, dose limiting toxicitie,s and safety profile of escalating doses of oral MGCD-0103 in combination with two fixed doses of docetaxel. Not available  
Curcumin NCT02064673 II Recruiting PCa patients with localized disease who were submitted to a radical prostatectomy received oral curcumin or placebo 500 mg twice a day for 6 months. n = 600 Determine recurrence-free survival as total PSA <0.2 ng/ml. Not available  
Curcumin, prednisone, and docetaxel II   Patients with progressing CRPC and a rising PSA received docetaxel/prednisone for 6 cycles in combination with curcumin, 6000 mg/day (day −4 to day +2 of docetaxel). n = 30 Decreased PSA levels were observed in 59 % of patients and 40 % of evaluable patients presented a partial response. The regimen was well tolerated. [279]
Curcumin and radiotherapy NCT01917890 Not provided (pilot) Completed PCa patients undergo 74 Gy radiotherapy 5 times a week for 7–8 weeks and take 3 g of curcumin vs placebo. n = 40 The change in urinary symptoms across the 20-week period differed significantly between groups (p = 0.011) and patients in the curcumin group experienced much milder urinary symptoms compared with the placebo group. Curcumin could not reduce the severity of bowel symptoms or other treatment-related symptoms. PSA levels were reduced to below 0.2 ng/ml in both groups. [280]
Curcumin and taxotere NCT02095717 II Recruiting mCRCP patients receive taxotere plus curcumin capsule vs taxotere plus placebo. n = 100 Assess time to progression of metastatic disease by tumor response rate, increase in PSA levels (≥25 % and ≥2 ng/ml increase) or the appearance of new lesions metastatic. Not available  
Phenelzine NCT02217709 II Recruiting Recurrent non-metastatic PCa received phenelzine daily and orally during 12 months. n = 46 Determine biochemical recurrent prostate cancer by PSA decline to ≥50 % following at least 12 weeks of treatment. Not available  
Phenelzine and docetaxel NCT01253642 II Recruiting PCa patients with progressive disease after first-line therapy with docetaxel received phenelzine orally once a day on days −7 to −4 and twice a day on days −3 to 21 and docetaxel I.v. on day 1. Treatment repeats every 21 days for at least 12 weeks. nn = 30 Determine the proportion of patients who experience a PSA decline of at least 30 % and duration of progression-free survival. Not available  
OTX015 NCT02259114 IB Recruiting Advanced solid tumors including CRPC. Patients divided in two regimens: (1) continuous, once daily for 21 consecutive days and (2) once daily on days 1 to 7, repeated every 3 weeks (1 week on/2 weeks off). n = 98 Determine maximum tolerated dose and the number of dose limiting toxicity. Not available