Histone deacetylase inhibitors and pancreatic cancer: Are there any promising clinical trials?

Table 1 Clinical studies on histone deacetylase inhibitors for treatment of patients with pancreatic cancer

HDACI	Patients total number	Patients with PC number	Time schedule	Dosage schedule (HDACI)	MTD (HDACI)	Responses (for patients with pancreatic cancer treated with HDACI)			Main toxicities	Ref.
						PR	SD	PD
VPA + epirubicin phase I	48	1	q21 d	15-160 mg/kg per day iv/po d1, d2	140 mg/kg per day	1	-	-	Neutropenia, thrombocyto-penia, hypocalcaemia, fatigue, QTc prolongation	[33]
4-PB phase I	21	1	q28 d	60-360 mg/kg iv 2 × daily d1-d5, d8-d12	300 mg/kg per day	-	-	1	Fatigue, headache, nausea, vomiting, confusion	[36]
MS-275 + 13-cis retinoic acid phase I	Not defined	1	q28 d	4-5 mg/m2po, once weekly	5 mg/m2	-	1	-	Hyponatremia, neutropenia, anemia, fatigue	[39]
MS-275 phase I	27	1	a: q14 d b: q28 d c: q28 d	2-6 mg/m2po a: one dose 1st wk b: 2 × weekly for 3 wk c: 1 × weekly for 3 wk	a: 6 mg/m2 b: not defined c: 4 mg/m2	-	-	1	Hypophospha-temia, hyponatremia, nausea, asthenia, fatigue, anorexia1	[40]
CI-994 phase II	17	17	Continues	8 mg/m2 per day po	-	-	2	N/D	Thrombocyto-penia, fatigue, anorexia, nausea, vomiting, bruising, hematuria	[42]
CI-994 phase I	53	1	a: acute q21 d b: chronic q10 wk	a: 10-15 mg/m2 per day po d1-d14 b: 5-12.5 mg/m2 per day po d1-d56	a: 15 mg/m2 b: 8 mg/m2	-	-	1	Thrombocyto-penia, neutropenia, nausea, vomiting, diarrhea, fatigue, hoarseness, paresthesias, alopecia	[43]
CI-994 + capecita-bine phase I	54	4 sch. c	a: q21 d b: q42 d c: q21 d	a: 4-10 mg/m2 per day po d1-d14 b: 6 mg/m2 per day po d1-d35 c: 4-8 mg/m2 per day po d1-d14	a: 10 mg/m2 b: (abandoned) c: 8 mg/m2	-	-	4	Thrombocyto-penia, anemia, anorexia, diarrhea, nausea, vomiting, fatigue	[44]
CI-994 + carboplatin paclitaxel phase I	30	2	q21 d	4-6 mg/m2 per day po d1-d14 or d1-d7	6 mg/m2 (d1-d7)	-	-	2	Thrombocyto-penia, neutropenia, fatigue, alopecia, nausea	[45]
CI-994 + gemcita-bine vs gemcita-bine alone phase II	174	174 (86 + 88)	q28 d	6 mg/m2 per day po d1-d21	-	8/68	-	60/68	Thrombocyto-penia, neutropenia, anemia, nausea, vomiting, anorexia, diarrhea	[46]
MGCD-0103 phase I	38	2	q21 d	12.5-56 mg/m2 per day po d1, 3, 5, 8, 10, 12	56 mg/m2 RPTD: 45 mg/m2	-	-	2	Fatigue, anorexia, nausea, vomiting, diarrhea, abdominal pain, dehydration	[48]
LAQ824 phase I	39	3	q21 d	6-100 mg/m2 per day iv d1-d3	72 mg/m2 RPTD: < 72 mg/m2	-	-	3	Thrombocyto-penia, fatigue, anorexia, nausea, vomiting, diarrhea, nonspecific ST-segment, hyperbiliru-binemia, transaminitis2	[50]

¹The patient with pancreatic cancer experienced grade 3 hypophosphatemia as DLT and was finally excluded from study after cycle 2 due to PD;

²At 100 mg/m² one patient with advanced pancreatic cancer, developed grade 4 hyperbilirubinemia associated with febrile neutropenia on day 3. The patient developed thrombocytopenia on day 8 of treatment and anemia, necessitating platelet and blood transfusions. This was followed by an episode of atrial fibrillation on day 13 and then acute renal failure. The patient finally died on d18. PC: Pancreatic cancer; PD: Progressive disease; PR: Partial response; RPTD: Recommended dose for phase II; SD: Stable disease.