HDAC inhibitors in clinical trials as single agents
| Name (Ref) | Phase | N | Tumor Type | Route of Administration/Dosing Regimen | DLT and Adverse Events | PK Results | Clinical Response/Outcome |
|---|---|---|---|---|---|---|---|
| PA (Thibault et al., 1994) | I | 17 | Solid tumors | IV bolus (60-150 mg/kg), target level 200-400 g/ml × 2 weeks | CNS depression, emesis, confusion, lethargy | Nonlinear PK, evidence of drug induction, 99% PA converted to PG and eliminated in urine, CNS penetration | 3/9 SD × 2 months in HRPC, 1/6 SD > 9 months in glioblastoma |
| PA (Thibault et al., 1995) | I | 18 | Solid tumors | IV 1-h infusion b.i.d. 125 and 150 mg/kg × 2 weeks every 4 weeks | CNS depression | PA induced own clearance (27%), MTD 125 mg/kg, Cmax 2500 g/ml | 1 PR glioblastoma, 1 hormone-refractory prostate cancer with 50% post-therapy PSA decline |
| PA (Chang et al., 1999, 2003) | II | 9 & 43 | Recurrent malignant gliomas | IV infusion 400 mg/kg/day, compared 2 schedules, 2 weeks every 2 weeks or 12-day every 2 days, max 450 mg/mg/day | Fatigue, somnolence, lethargy, disorientation, malaise, weakness, N/V & granulocytopenia | No differences in plasma concentration between 2 treatments, no apparent induction of PA metabolism | For schedule 1, PR 3/40 (7.5%), SD in 7/40 patients (17.5%), PD < 2 months 30/40 patients, For schedule 2, 1/7 SD, 6/7 PD |
| PB (Carducci et al., 2001) | I | 24 | Refractory solid tumors | IV infusion 120 h every 3 weeks, dose 150-515 mg/kg/day | Neurocortical somnolence, confusion, hypokalemia, hyponatremia, fatigue, nausea | MTD = 410 mg/kg/day, plasma CL increased continuously after 24 h, PA accumulated when Vmax was less than dosing rate | No CR, 2 SD, reduction in bone pain |
| PB (Gilbert et al., 2001) | I | 28 | Refractory solid tumors | Oral dose t.i.d. 9-45 g/day in 5 dose levels | Grade 1-2 dyspepsia, fatigue, neurocortical nausea, vomiting, hypocalcemia | MTD 27 g/day, bioavailability 78%, biologically active concentrations (0.5 mM) | No CR, PR, 7 patients (25%) with SD > 6 months |
| PB (Gore et al., 2001) | I | 27 | Myeloid dysplasia, AML | IV infusion for 7 days every 28 days | Neurocortical somnolence, confusion, slurred speech, hyperammonemia | MTD 375 mg/kg/day | No CR, PR, hematological improvements, increased neutrophils in 3, decreased blasts in 3 |
| AN-9 (Patnaik et al., 2002) | I | 28 | Advanced solid tumors | IV infusion, 6 h × 5 days every 21 days at doses 0.047-3.3 g/m2/day | No DLT, nausea, vomiting, fatigue, vision disturbance, anorexia, fever | MTD 3.3 g/m2/day based on volume of maximum lipid formulation administrable | 1 PR, no increase in fetal hemoglobin |
| AN-9 (Reid et al., 2004) | II | 47 | Refractory NSCLC | IV infusion, 2.34 g/m2/day over 6 h × 3 days every 21 days | Grade 1-2 fatigue (34%), nausea (17%), dysgeusia (11%) | 3/47 PR, 14 patients with SD > 12 weeks (30%), median survival 6.2 months, 1-year survival of 26% | |
| VA (Atmaca, 2004) | I | 26 | Progressive cancers | IV infusion 1 h split twice daily × 5 days every 2 weeks at 30-120 mg/kg/day | Grade 3/4 neurotoxicity, no severe hematological | MTD 60 mg/kg, PBMC showed hyperacetylation | Neurotoxicity is dose-limiting |
| SAHA (Kelly et al., 2003) | I | 37 | Solid tumor and hematologic malignancy (B) | IV infusion, (A) 2 h × 3 days every 3 weeks, at 75-900 mg/m2/day (B) 2 h × 5 days every 1-3 weeks 300-900 mg/m2/day for 3-15 days | (A) No DLT in 8/8, (B) Grade 3/4 thrombocytopenia and neutropenia in hematological patients | MTD on (B), 300 mg/m2/day t1/2 = 21-58 min, AUC increased with dose, accumulation of acetylated histones in PBMC after 4 h at all dose levels | 1 PR in refractory Hodgkin's disease & SD > 6 months in 2 patients with bladder cancer |
| SAHA (Garcia-Manero, 2004) | I | 15 | Advanced refractory leukemias or MDS | Orally t.i.d. × 14 days every 21 days at 100-250 mg | No DLT, nausea, vomiting, diarrhea, anorexia, headache, fatigue, dyspepsia | Histone hyperacetylation at all dose levels | 1 CR at dose level 3 after 2 courses, 2 AML, 1 MDS patient had decrease in marrow blasts to <10% |
| SAHA (Kelly, 2002) | I | 39 | Advanced cancers | Oral, daily or BID at 200-600 mg | Thrombocytopenia, fatigue | Prolonged plasma concentrations <10 h with single dose | Prolonged duration of acetylated histones in peripheral blood mononuclear cells (>10 h), objective response in patients with larynx, renal cancer and lymphoma |
| SAHA (Blumenschein, 2004) | II | 13 | SCCHN (metastatic head and neck cancers) | Oral, daily at 400 mg | No DLT, grade 3-4 thrombocytopenia, anemia, anorexia | No PR or CR, 1 MR based on tumor shrinkage, | |
| FK-228 (Marshall et al., 2002) | I | 33 | Advanced cancers | IV infusion 4 h, weekly × 3 every with 1 week off at 1-17.7 mg/m2 | Grade 3 thrombocytopenia, fatigue, nausea, vomiting, anorexia at dose above 5 mg/m2, subtle electrocardiographic changes | MTD 13.3 mg/m2/day | |
| FK-228 (Piekarz et al., 2001; Sandor et al., 2002) | I | 37 | Advanced or refractory cancers | IV infusion 4 h on days 1 and 5 every 21 days at dose 1-24.9 mg/m2 | Grade 3 fatigue, nausea, vomiting, grade 4 thrombocytopenia, cardiac arrhythmia | MTD 17.8 mg/m2 over 4 h over 4 h t1/2 (a) =0.42 h; elimination t1/2 (b) =8.1 h, mean CL = 11.6 L/h/m2, inhibition of cell cycle in PC-3 cells | Increased acetylation of histones in Sezary cells, variable effect on histones after 7 h, 1 PR in colon cancer × 6 months, 1 CR in peripheral T-cell lymphoma, 3 PR in CTCL |
| FK-228 (Byrd et al., 2004) | I | 20 | CLL and AML | IV infusion on days 1, 8, 15 at 13 mg/m2 | Fatigue, nausea, progressive constitutional symptoms | Increases in histone acetylation by 100%, p21 promoter H4 acetylation, p21 protein | No cardiotoxicity, need to explore other schedules due to progressive toxicity |
| CI-994 (Prakash et al., 2001) | I | 53 | Solid tumors | Orally on schedule (A) × 2 weeks, (B) × 8 weeks followed by 2 weeks' rest | Schedule (A) thrombocytopenia, neutropenia, increased liver function tests, creatinine, (B) thrombocytopenia, nausea, vomiting | Schedule (A) MTD 15 mg/m2/day, no cumulative toxicities, (B) MTD 8 mg/m2/day, t1/2 = 7.4-14.1 h, inverse relationship between platelet nadir and AUC, low effect of food on absorption | Both schedules, 1 PR in NSCLS × 2 years, 3 SD in NSCLC, colorectal and renal cancer |
| MS-275 (Ryan, 2003) | I | 30 | Solid tumors and lymphomas | Orally on schedule (A) daily × 28 days every 6 weeks, (B) weekly × 4, every 6 weeks at 2-12 mg/m2 | Schedule (A) severe GI toxicity, (B) and (C) fatigue, nausea, vomiting, anxiety thrombocytopenia, headache | MTD on (A) 2 mg/m2, (B) 10 mg/m2, histone acetylation at all dose levels | Schedule (A) intolerable, 15 SD on (B), |
| MS-275 | I | Hematologic malignancy | Orally every 7 days for 4 weeks at 4-10 mg/m2 | Severe infections at 10 mg/m2, thrombocytopenia, gastrointestinal toxicity | MTD at 8 mg/m2 | ||
| MS-275 (Gore, 2004) | I | 17 | Solid tumors and lymphomas | Orally on schedule (A) 2-6 mg/m2 biweekly, (B) 2 mg/m2 twice weekly × 3 weeks with 1 week off, (C) 4 mg/m2 weekly for 3 weeks with 1 week off | No drug related DLT, grade 1-3 hypophosphatemia, asthenia, nausea, anorexia | MTD not reached on (A), (B) not pursued, rapid absorption with Tmax 0.5-2 h, dose-dependent increase in exposure, biphasic elimination with t1/2 = 100 h | 1 PR on (A) in melanoma, 3 SD in Ewing's sarcoma, rectal carcinoma and melanoma |
| LAQ824 (Ottmann, 2004) | I | 21 | ALL, AML, CLL, CML, MDS | IV infusion, 3 h on days 1-3 of 21-day cycle at 6-80 mg/m2 in 6 dose levels | Thrombocytopenia (cerebral bleeding), grade 2 hyperbilirubinemia | MTD 36 mg/m2, dose-proportional increase in exposure, t1/2 = 9-18 h, 1.5 fold accumulation at day 3, Cmax after 1.5 h, not at end of infusion in >50% patients, indicates nonlinear PK | No QTc prolongation, ECG <400 ms, 1 CR in M1 AML, 6 SD, histone acetylation at >12 mg/m2 doses |
| LAQ824 (Rowinsky, 2004) | I | 28 | Advanced solid tumors | IV infusion, 3 h on days 1-3 of 21-day cycle at 6-100 mg/m2 in 7 dose levels | Grade 3/4 transient transaminitis, fatigue, hyperbilirubinemia, nausea, thrombocytopenia, | Dose-proportional increase in exposure, t1/2 = 8-14 h, Cmax after 1.5 h, not at end of infusion in >50% patients, indicates nonlinear PK | 1 ECG > 500 ms, 3 SD, histone acetylation at >12 mg/m2 doses FK-228 (Piekarz et al., 2001; Sandor et al., 2002) |
| LBH589 (Beck, 2004) | I | 13 | Advanced solid tumors | IV infusion, 30 min either on (A) days 1-3 and 8-10 of 21-day cycle at 1.2 - 7.2 mg/m2, (B) days 1-3 or 15-17 of 28 day cycle at 2.4-4.8 mg/m2 | Prolonged grade 2 thrombocytopenia in (A), grade 3 neutropenia, anemia, hypoglycemia | Exposure increased proportionally with dose, t1/2 = 15-20 h | 6 SD, increased histone acetylation after first dose |
MTD, maximum tolerated dose; DLT, dose limiting toxicity; PK, pharmacokinetics.