Table 2

Inhibitors of epigenetic regulators validated in clinical trials in pancreatic cancer (terminated, completed trials and active, but not recruiting clinical trails)

Compound	Epigenetic target	Combination	Treatment	NCT number	Outcome measures	Results in PDAC	Enrolled tumour entities	No. of enrolled patients
Phase I and combined phase I/II
Vorinostat	HDAC class I/II	Marizomib	Palliative	00667082	MTD, pharmacokinetics, pharmacodynamics, toxicity and antitumour activity of the combination therapy	No antitumour activity	PDAC, NSCLC Multiple myeloma Melanoma Lymphoma	22
Vorinostat	HDAC class I/II	Radiation capecitabine	Palliative+adjuvant	00983268	MTD, tumour response, toxicity	No results yet	Periampullary adenocarcinoma PDAC	21
Vorinostat	HDAC class I/II	Radiation 5-FU	Palliative	00948688	MTD, progression-free survival 7 months after registration	No results yet	PDAC	50*
Vorinostat	HDAC class I/II	Radiation	Palliative	00831493	MTD, MOS, correlation of serum cytokine levels with symptoms and outcome	No results yet	PDAC	3
Valproate	HDAC class I	Epirubicin 5-FU cyclophosphamide	Palliative	00246103	Safety, tolerability, MTD, pharmacokinetic profile, VPA effect on histone acetylation in blood cells and tumour biopsies	Low potency, but preferable toxicity profile, might be beneficial for patients with HDAC2 overexpression	Advanced neoplasms	44
Entinostat	HDAC class I	13-cis retinoic acid	Palliative	00098891	MTD, dose-limiting toxicity, pharmacokinetics, tumour response	Stable disease in one patient with chemotherapy-resistant PDAC	Metastatic or advanced solid tumours or lymphomas	24
Entinostat	HDAC class I		Palliative	00020579	MTD and dose-limiting toxicity, pharmacokinetics, acetylation in blood cells, tumour response	No results yet	Not specified cancer	75*
Mocetinostat	HDAC classes I+IV	Gemcitabine	Palliative	00372437	Phase I: MTD, response rate, determination of recommended phase II dose Phase II: Overall response rate in combination with gemcitabine in gemcitabine-naïve patients in stage III and IV PDAC	Partial response and stabilised disease	Solid tumours where gemcitabine is considered as standards of care, phase II limited to PDAC	47
CHR-3996	HDAC class I		Palliative	00697879	Safety, tolerability, dose-limiting toxicity, MTD, pharmacokinetics, antitumour activity	Reduction of liver metastases in one patient with acinar pancreatic cancer	Solid tumours	40
Romidepsin	HDAC class I	Gemcitabine	Palliative	00379639	Dose-limiting toxicity, number of patients with adverse events, best overall response	4/9 patients showed stable disease; additive haematological side effects	Solid tumours	36
OTX015	Pan-BET		Palliative	02259114	Number of dose-limiting toxicities at cycle 1	No results yet	NUT midline carcinoma Breast cancer NSCLC, castrate-resistant prostate cancer, PDAC	98*
Bay1238097	Pan-BET		Palliative	02369029	Incidence of dose-limiting toxicity, tumour response	No results yet	Neoplasms	8
BI-2536	BRD4	Gemcitabine	Palliative	02215044	Occurrence of dose-limiting toxicity, survival, tumour response, CA19-9 levels, maximal concentration of the analytes in plasma	No results yet	Pancreatic neoplasms	12
Phase II non-radomised
Panobinostat	HDAC class I/II	Bortezomib	Palliative	01056601	PFS, number of participants with tumour response, duration of response, characterisation of quality and quantity toxicity	No treatment response and severe treatment-related toxicity, study was closed ahead of schedule	PDAC	7
Curcumin	p300, CBP	Gemcitabine	Palliative	00192842	Time to tumour progression, response rate, survival, clinical benefit, toxicity	In chemotherapy-naïve patients with advanced PDAC. Increased GI toxicity	PDAC	17
Curcumin	p300, CBP		Palliative	00094445	6 months survival, response rate, assessment of biological activity in blood mononuclear cells via signalling and apoptotic pathways, pharmacokinetics	No severe toxicity, curcumin showed biological activity with stable disease (1/22) and brief response (1/22) with 73% reduction of liver metastasis size	PDAC	50
BI-2536	BRD4		Palliative	00710710	Objective response, PFS, dose-limiting toxicity, overall survival, clinical benefit response	First-line therapy in patients with unresectable tumours, stable disease in 24.4% of patients; the second stage of the study which was supposed to test BI-2536 as a second-line therapy was not initiated	Pancreatic neoplasms	89
Phase II randomised
CI-994	HDAC class I	Gemcitabine	Palliative	00004861	Efficiency and safety of CI-994 in combination with gemcitabine	Inferior compared with gemcitabine monotherapy with decreased quality of life	PDAC	†

*Estimated enrolment.
†Enrolment not specified.
BET, bromodomain and extraterminal; FU, fluorouracil; MOS, medium overall survival; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer; PDAC, pancreatic ductal adenocarcinoma; PFS, progression-free survival; VPA, valproate.