Table 3 Co-combination of anticancer drugs with epigenetic drugs in clinical phase studies

Erlotinib/5-AZAcitidine

Tyrosine kinase inhibitor/DNMT1 inhibitor

Phase I in solid tumour

1 Patient with mCRC had PFS of 2 months

–

[161]

Valproic acid/ Bevacizumab

Phase I

Being safe for up to 6 months and creating a stable condition of the disease

Proteinuria, increased blood pressure and mental problems

[158]

Capecitabine/ Oxaliplatin /5-AZAcitidine

Thymidylate synthase inhibitor / Thymidylate synthase inhibitor /DNMT1inhibitor

Phase I/II in mCRC

–

No dose-limiting toxicities were observed for 26 patients

[211, 212]

Carboplatin/Decitabine

Alkylating agents /DNMT1 inhibitor

Preclinical and Phase I in solid tumours, including mCRC

7 Patients with mCRC who experienced PD

The main toxicity is related to myelosuppression. Dose-limiting toxicities include grade 4 long-term neutropenia, sepsis, grade 3 anorexia, and fatigue

[213]

Gefitinib/Decitabine

Tyrosine kinase inhibitor /DNMT1 inhibitor

Preclinical and Phase I in solid tumours, including mCRC

was synergistic at inducing apoptosis in colon cancer cells

Minimal toxicity to NCM460 cells

[67]

Capecitabine/ Azacitidine/Oxaliplatin

Inhibitor of DNA synthesis /DNMT1 inhibitor/

Phase I/II in mCRC

26 Patients (SD in 17 patients, median duration of 4.5 months)

No dose-limiting toxicities were observed

[214]

Panitumumab/Decitabine

Monoclonal antibody /DNMT1 inhibitor

Preclinical and Phase I in solid tumours, including mCRC

20 Patients (two had a partial response). 10 patients had stable disease (3 of them longer than 16 weeks)

Grade 1–2 (rash and hypomagnesemia) /neutropenia /neutropenic fever

[157]

Tetra-hydrouridine(THU)/5-fluoro-2-deoxycytidine

Cytidine deaminase /DNMT1 inhibitor

Phase I in solid tumours, including mCRC

35% of Patients treated with different types of solid tumours had SD

–

[161]

Irinotecan/Guadecitabine:DNMTs

Topoisomerase I inhibitor /DNMT1 inhibitor

Ongoing Phase II in mCRC

At a median follow-up of 20 months, the median OS for the 22 patients in the study is 10.7 months

Neutropenic fever / biliary drain infection / colonic obstruction / severe dehydration / Most common toxicities were neutropenia and leukopenia

[215]

Irinotecan/Disulfiram/ copper

Topoisomerase I inhibitor /DNMT1 inhibitor

Phase II in mCRC

–

severe fatigue/ headache/

cerebral confusions

[193]

Regorafenib and Hydroxy Chloroquine/ Entinostat

Kinase Inhibitor /antimalarials /HDAC inhibitors

Phase I/II in mCRC

Ongoing

Ongoing

[161]

Radiation therapy w/wo Capecitabine/Valproic Acid

Fluoropyrimidine carbamate/ anticonvulsants

Phase I /II (preoperative setting in rectal cancer)

Ongoing

Ongoing

[161]

Hydroxy Chloroquine/ Vorinostat

Antimalarials/ HDACs

Phase I/II in mCRC

Ongoing

Ongoing

[161]

Capecitabine/CI-994

Anti-metabolite /HDAC inhibitors

Phase I in advanced solid tumours, including mCRC

24 Patients (1 patient had PR and 1 had SD)

The main dose-limiting toxicity is thrombocytopenia

[216]

13-cis retinoic acid/Entinostat

Agonist at retinoic acid receptors (RARs) and retinoic X receptors (RXRs) /HDAC inhibitors

Phase I in advanced solid tumours, including mCRC

Only one patient with mCRC who experienced PD

haematological and

Skin toxicities

[217]

Sorafenib/Entinostat

Tyrosine kinase inhibitors /HDAC inhibitors

Phase I in advanced solid tumours, including mCRC

5 Out of 10 patients with mCRC had SD

grade 3–4 toxicities were muscle weakness (13%), skin rash (10%), fatigue (6%), diarrhoea (6%), and hand-foot syndrome (3%)

[218]

Bevacizumab/Panobinostat

Angiogenesis inhibitors /HDAC inhibitors

Phase I in advanced solid tumours, including mCRC

9 Patients with mCRC, 3 had SD

–

[219]

Lapatinib/Panobinostat

GFR/HER2 kinase inhibitor/HDAC inhibitors

Colorectal Cancer Models

–

–

[150]

5-FU/Phenylbutyrate

Inhibition of thymidylate synthase /HDAC inhibitors

Phase I in mCRC

9 patients with mCRC (4 patients evaluable, 3 SD lasting 12, 25 and 54 weeks, respectively)

Fatigue, confusion, hearing loss, triglyceridemia, and hyperuricema

[220]

Modified FOLFOX6 or Bortezomib/Vorinostat

Proteasome inhibitors/HDAC inhibitors

PhaseI/II in solid tumours, including mCRC

23% of 21 patients had SD

Thrombocytopenia, gastrointestinal toxicities, neutropenia, and fatigue increased at higher doses

[221]

Pazopanib/ Vorinostat

VEGFR-PDGFR inhibitor /HDAC inhibitors

PhaseI/II in solid tumours, including mCRC

Long PFS and OS in patients, especially in patients with mutation TP53

-

[222, 223]

FOLFOX/ Vorinostat

HDAC inhibitors

PhaseI in solid tumours, including mCRC

–

Thrombocytopenia, neutropenia, GIT toxicities,

Fatigue

[221]

Doxorubicin/ Vorinostat

Anthracycline group of chemotherapeutic agents (Antineoplastics)/HDAC inhibitors

PhaseI/II in solid tumours, including mCRC

–

Venous thromboembolism and

haematological

[224]

Hydroxychloroquine or Regorafenib/ Vorinostat: HDAC,HDAC1,HDAC3

/Multi-targeting kinase inhibitor /HDAC inhibitors

PhaseI/II in solid tumours, including mCRC

Median PFS (1.8 months) and OS (5.2 months)

grade 3 fatigue/ rapid weight loss

[225]

Oxaliplatin/ACY-1215:HDAC6

Alkylating agent /HDAC inhibitors

Preclinical in CRC cells and mouse xenografts

Improve overall survival

It had profound side effects, including fatigue, nausea, vomiting, diarrhoea, thrombocytopenia, and neutropenia

[222]

Oxaliplatin/ 5-FU Irinotecan/CG2:HDAC

Alkylating agent/ alkylating agent/ DNA topoisomerase I inhibitor /HDAC inhibitors

Preclinical in CRC cells and mouse xenografts

CG2, in combination with irinotecan, shows promising anti-tumour effects both in vitro and in vivo

In vitro, results showed increased cytotoxicity when CG2 was combined with oxaliplatin

[223]

Bortezomib /Vorinostat

Proteasome Inhibitors /HDAC inhibitors

Phase I

Potential clinical efficacy of the combination therapy with primary concern of late-cycle toxicities that precluded long-term administration

Thrombocytopenia, increased alanine transaminase (ALT) and fatigue

[225]

Bevacizumab /Valproic Acid

Kinase Inhibitors/ HDAC inhibitors

Phase I

–

Grade 3 altered mental status/ Grade 3 proteinuria/Grade 3 hypertension

[158]

5-fluorouracil (5-FU) /vorinostat

Inhibition of thymidylate synthase /HDAC inhibitors

phase I/II clinical trials in (mCRC)

10 Metastatic colorectal cancer patients who failed to all standard therapeutic options

Grade 3 and 4 toxicities were fatigue, mucositis, and thrombocytopenia

[226]