Table 3.

Update of HDAC inhibitors

Compound	Details
SAHA (Vorinostat) [11, 19]	Pan HDAC inhibitor
	FDA approved (CTCL)
	Developed by Merck
	Currently, SAHA is undergoing Phase 2 clinical trial in combination with pembrolimuzab and tamoxifen in patients with estrogen receptor positive breast cancer. (NCT04190056)
Romidepsin [67]	Developed by Bristol Myers Squibb
	Class 1 selective HDAC inhibitor
	FDA approved (CTCL, PTCL)
Tefinostat [192]	Developed by GlaxoSmithKline
	Monocyte/macrophage-targeted HDAC inhibitor
	A phase 1/2 study of tefinostat has been completed in patients of HCC. The results have not been published yet (NCT02759601)
	The phase 1 investigation of tefinostat (administered orally, once daily, n = 18, dose escalation—20–640 mg) in patients with R/R haematological diseases was conducted. Monocyte‐targeted increases in protein acetylation were evidenced as a result of flow cytometric assays. Maximum tolerated dose (MTD) was not identified. Grade 1/2 adverse events were observed that included nausea, anorexia, fatigue, constipation, rash and increased blood creatinine. A bone marrow response was observed in a patient with chronic monomyelocytic leukaemia. Moreover, a decrease in bone marrow blasts (50%) and clearance of peripheral blasts was observed in AML. Overall, the outcome of the study demonstrated that tefinostat was endowed with efficacy (NCT 00,820,508). [192]
CG200745 [193]	CG200745 is an intravenous hydroxamate-based pan-HDAC inhibitor
	To determine the MTD, safety and efficacy of CG200745 in subjects with MDS was completed (NCT02737462), however, the results have not published yet
	A combination study (Phase 1/2) of CG200745 with gemcitabine and erlotinib in patients with advanced pancreatic cancer has also been completed.(results not published, NCT02737228)
Ricolinostat (ACY-1215) [230]	Developed by Regenacy Pharmaceuticals
	First-in-class selective HDAC6 inhibitor
	Ricolinostat demonstrated efficacy in patients (> 250) with haematologic cancer. [230]
	In a combination study (with bortezomib and dexamethasone) in patients with R/R multiple myeloma, RP2D of ricolinostat was determined to be 160 mg daily. Moreover, the combination was found to be safe, well tolerated, and active. [231]
	A study (dose escalation, Phase 1b/2) was initiated to evaluate the combination of ACY-1215 with pomalidomide and low-dose dexamethasone in subjects with R/R multiple myeloma. (NCT01997840, status – active, not recruiting)
	In a phase 1b study, ricolinostat was administered to patients daily for 21 days of each 28-day cycle with nab-paclitaxel 100 mg/m2 on days 1, 8, and 15. The results of the study demonstrated that ricolinostat (240 mg qd) with nab-paclitaxel was safe and tolerable. In addition, majority of the patients demonstrated SD and 1 with PR. Moreover, clinical activity was also observed [NCT02632071]
Citarinostat (ACY-241)	A selective HDAC6 inhibitor Currently being investigated for the treatment of myeloma, melanoma, and NSCLC [195] A Phase 1a/b clinical investigation (ACE-MM-200) to evaluate the safety and efficacy of citarinostat alone and in combination (pomalidomide and dexamethasone) is currently ongoing in subjects (n = 85 patients) with R/R multiple myeloma. The initial results demonstrate that the drug was well tolerated (both alone and in combination) and was also found to be endowed with clinical activity (NCT02400242) Earlier, a dose escalation study to evaluate the efficacy of citarinostat in combination with paclitaxel in patients (n = 20) who failed to respond to previous treatment with advanced solid tumors revealed that the combination of citarinostat and paclitaxel is safe and demonstrated potential in heavily pretreated patients (NCT02551185) At present, a phase 1 clinical trial is currently enrolling patients to assess the efficacy of combination of citarinostat with PVX-410 and lenalidomide (NCT02886065)
CUDC-101	Quinozoline based small-molecule inhibitor (multi-targeted inhibitor) of EGFR, HER2, class I and class II HDACs [196] In a phase I study, escalating doses (75–300 mg/m2/day) of CUDC-101 was administered (1-h i.v. infusion for 5 consecutive days every 2 weeks) to 25 patients with advanced solid tumors. The results of the study indicated that CUDC-101 demonstrated clinical activity and was well tolerated. A dose of 275 mg/m2 was determined as MTD (NCT00728793). [196] The results of the phase I study revealed that the combination of CUDC-101, cisplatin, and radiation were feasible in head and neck squamous cell carcinoma. The study involved the intravenous administration of CUDC-101 for three times in a week followed by concurrent administration of cisplatin (100 mg/m2 every 3 weeks) and external beam radiation (70 Gy to gross disease) over 7 weeks. MTD was determined in the study, however, owing to DLT-independent discontinuation of CUDC-101, the results indicate that a change in the schedules or routes of administration is required (NCT01384799). [232]
Tinostamustine [197]	It is an alkylating HDAC inhibitor Chemically, it is composed by the fusion of alkylating agent bendamustine with SAHA In a phase 1 study in patients with advanced solid tumors, 60 mg/m2 tinostamustine was administered to the first cohort of patients followed by administration of maximum dose of 100 mg/m2 to the ascending 6 cohorts. A total of 22 patients were enrolled in the study. All the patients experienced ≥ 1 castration-resistant prostate cancer TAEs. Clinically significant QTC prolongation event was evidenced in only 1 patient. Overall, nostamustine demonstrated some efficacy and was well tolerated. [233] Tinostamustine is currently undergoing the below mentioned clinical stage investigations: Advanced melanoma (in combination with nivolumab, phase 1, NCT03903458, status – recruiting) R/R Hematologic Malignancies (Phase 1, NCT02576496, recruiting) Newly Diagnosed MGMT-Promoter unmethylated glioblastoma (phase 1, NCT03452930, recruiting)
Belinostat (PXD101) [69]	Developed by Onxeo, Spectrum FDA approved pan HDAC inhibitor for PTLC
Panobinostat (LBH589) [70]	Developed by Novartis Pan HDAC inhibitor approved for the treatment of multiple myeloma The combination of Panobinostat with azacitidine was evaluated in a phase 1b/2b multicenter study conducted in adults with MDS, CMML or AML. The results of the study led to the identification of the RP2D as PAN 30 mg plus AZA 75 mg/m2. [234] Panabinostat is undergoing the below mentioned clinical stage investigation: High risk AML and MDS (Phase 3, NCT04326764, recruiting) R/R Multiple Myeloma (Combination of Panobinostat and Carfilzomi, Phase 1/2, NCT01496118, status—active, not recruiting) Diffuse intrinsic pontine glioma (Phase 1, NCT02717455 recruiting)
Resminostat	An oral hydroxamate-type inhibitor of class I, IIB, and IV HDAC [200–202] A phase I/II investigation of resminostat in combination with sorafenib in patients with HCC was conducted. The study design involved the administration of sorafenib (400 mg, bid) in both phase I and II and administration of resminostat on days 1 to 5 every 14 days (dose escalation was carried in phase I from 400 mg/day to 600 mg/day). Patients were randomly subjected to sorafenib monotherapy or sorafenib/resminostat combination therapy (1:1 ratio) in phase 2 studies. In phase 1 study (n = 9 enrolled) grade 3–4 toxicities such as G4 thrombocytopenia was observed at the dose of 600 mg/day. Thus, 400 mg/day was determined as RP2D for Phase II studies. In phase II study, 170 pts were enrolled and the results demonstrated a median time to progression of 2.8 months in the combination and control arm. Significant difference was not observed in the median OS (NCT02400788) [199] Resminostat was also tested in R/R HL in a phase 2 study and the results demonstrated clear OR in R/R HL patients. Moreover, the drug was found to be endowed with excellent safety profiles in heavily pre-treated patient population (NCT01037478) [200] In a phase I/II study conducted in japanese patients with stage IIIB/IV or recurrent NSCLC and prior platinum-based chemotherapy, no DLT was observed in phase I part and the recommended dose was determined to be 600 mg/day with 75 mg/m2 of docetaxel. The results of the phase 2 part demonstrated Median PFS (95% CI—4.2 (2.8–5.7) months with docetaxel group and 4.1 (1.5–5.4) months with docetaxel—resminostat group. Overall, docetaxel resminostat therapy did not improve PFS in comparison to docetaxel alone and also increased the toxicity. [202] The results of the phase I study evaluating the combination of resminostat and S-1 (a fluoropyrimidine used as second-line treatment for BTC therapy) revealed that with resminostat (5 days on/2 days off, second dosage regimen for the combination therapy) was well tolerated. [201]
Pracinostat (SB939)	Oral HDAC inhibitor Pracinostat demonstrated clinical benefits and notable activity in phase II study conducted in patients with intermediate or high risk MF [203] In another phase II study, pracinostat was found to be well tolerated in patients with advanced solid tumours. The outcome of the investigation recommended the dose of 60 mg on a schedule of 5 consecutive days every 2 weeks. [204] In another study (Phase II), pracinostat was well tolerated in children with refractory solid tumors [205] Pracnitostat is currently undergoing the below mentioned studies: Newly diagnosed AML (Pracinostat in combination with azacitidine) (Phase 3, NCT03151408) High risk MDS (Pracinostat and Azacitidine, NCT03151304, status—unknown, Phase 2)
Givinostat	Developed by Italfarmaco Orally bioavailable hydroxamate inhibitor of HDAC [206–208] A phase 3 clinical stage evaluation of safety and efficacy of givinostat in comparison to hydroxyurea in JAK2V617F + high-risk PV Patients is planned to start in 2021. [208] In a phase 2 clinical stage evaluation, givinostat was assessed for safety and efficacy in patients with JAK2V617F positive myeloproliferative neoplasms. CR and PR were attained in the study indicating that givinostat holds enough promise for further clinical exploration in patients with MPN [206] A phase 2 study evaluating the efficacy of givinostat in JAK2V617F + patients with PV was conducted. The study results led to the determination of MTD as 100 mg twice daily. Overall response rate was found to be 80.6%. Normalization of haematological parameters was seen in majority of the patients. Grade 1/2 thrombocytopenia and gastrointenstinal disorders were observed as the common adverse effects. Overall, givinostat was well tolerated. 11% complete and 89% partial response rates were observed as the long term results of the phase II clinical trial. To add on, a lower incidence of thrombotic events in comparison to historical controls treated with hydroxyurea along with good tolerability were observed in JAK2V617F + PV patients. [NCT00928707] [207, 208]
Abexinostat	Developed by Xynomics A pan HDAC inhibitor Significantly durable responses were demonstrated by a combination of pazopanib and abexinostat in patients with clear cell renal cell carcinoma. An ongoing response of > 5 years duration was observed in one patient with previous refractory disease. In peripheral blood mononuclear cells, histone acetylation induction was associated with durable treatment response. [209] Abexinostat is undergoing phase 3 clinical investigation for advanced and metastatic renal cell carcinoma. (NCT03592472, status—active, not recruiting) Assessment study of Abexinostat for safety and efficacy in Patients with R/R FL was initiated on April 22nd, 2020 On 23rd September, Abexinostat was granted a fast track designation from the US FDA as 4L therapy treating FL. Earlier, abexinostat in combination with pazopanib, as a first- or second-line treatment of renal cell carcinoma received fast track designation from FDA. [210]
AR-42	An oral pan –HDAC inhibitor In a phase I dose escalation clinical trial, AR-42 was found to be well tolerated with no DLTs. 40 mg (three times weekly for three weeks of a 28-day cycle) was determined as the MTD. Disease control demonstrated by one patient each with MM and mantle cell lymphoma for 19 and 27 months respectively. Reduction of serum CD44 was observed in the treatment. Overall, AR-42 was found to be safe (NCT01129193) [211] In a phase 1 study, AR-42 was administered (3 dose levels (DL): AR-42 20 mg qd on d1,3,5 in DL1, 40 mg qd on d1,3,5 in DL2 and 40 mg qd on d1,3,4,5 in DL3) to thirteen patients with previously untreated or R/R AML. Decitabine was administered to the patients at the dose of 20 mg/m2 on day 6–15 of each induction cycle and 20 mg/m2 on day 6–10 of each maintenance cycle. The results of the study indicated a DLT of polymicrobial sepsis. At DL3, multi-organ failure occurred. CR was observed in two patients. CR for an ORR of 23.1% was observed in one patient. The biologic endpoint was not met in this study. [212]
Bisthianostat	A novel orally available bisthiazole-based HDAC inhibitor Comprises of thiazole-thiazoline as the capping unit in natural product largazole [213] A phase 1 study conducted in patients (8 patients 8 patients enrolled at 3 dose levels) from 100 to 400 mg with R/R multiple myeloma. In the study, hematological TAAEs were observed in 4 of 8 patients (50%). Grade 3/4 hematological as well as non-haematological AEs were not observed. There was no discontinuation in the treatment of patients due to AEs except one of the patient who experienced grade 2 nausea. Overall, the outcome of the investigation indicates that the drug is well tolerated and is endowed with modest efficacy. Stable disease (SD) was evidenced 50% patients. [214] (NCT03618602)
Quisinostat	Orally available potent HDAC inhibitor [215–217] In a phase II study, the combination of quisinostat with paclitaxel and carboplatin in subjects with recurrent platinum resistant ovarian cancer demonstrated high efficacy and good tolerability. [NCT02948075] [216] Quisinostat was evaluated in patients with previously treated CTCL in a phase II multicentre trial. In the study, quisinostat (8 mg or 12 mg on days 1, 3 and 5 of each week in 21-day treatment cycles) was administered to the patients. The results of the study demonstrated that quisinostat 12 mg three times weekly was found to be effective and safe for the treatment of patients with R/R CTCL [217] A phase 1 study involving the administration of quisinostat (orally, once daily in three weekly cycles) to patients with advanced malignancies demonstrated better toleration of intermittent schedules than the continuous schedules. Overall, quisinostat displayed an adverse event profile similar to other HDAC inhibitor and the RP2D was determined to be 12 mg [215] (NCT00677105)
Nanatinostat	An oral HDAC inhibitor selective for specific isoforms of Class I HDACs Induces latent viral genes in EBV-associated malignancies A combination of nantinostat with antiviral valganciclovir for the treatment of EBV-associated R/R lymphomas was evaluated in a Phase 1b/2a study. The results of the study are mentioned below: ORR—56% (Phase 1b portion), Complete response—28%, clinical benefit rate—78%, Median duration of treatment for responders—6.5 months In HIV-negative patients, ORR—67%, CR—33% and CBR—93% Overall, the combination was well tolerated at 5 mg (Nanatinostat) and 450 mg (valganciclovir) BID. Hematological adverse events were observed that were resolved without sequalae or bleeding events. [218], NCT03397706] Fast Track designation has been granted to the combination of nantinostat and valganciclovir by FDA for the treatment of patients with R/R EBV-positive lymphomas. [219]
Fimepinostat	A synthetic, orally-available, small molecule inhibitor of HDAC and PI3K In a phase 1 clinical study of fimepinostat conducted in patients with R/R/ lymphomas or multiple myeloma, OR was observed in 9 patients in 21 response-evaluable patients out of 25 patients with R/R DLBCL enrolled in the study. 60 mg dose of fimepinostat (administered orally) using a 5 days on and 2 days off schedule in a 21-day cycle was determined as the RP2D. At the RP2D, no DLTs were observed Orphan drug designation was granted to Fimepinostat by FDA for the treatment of patients with DLBCL in 2015 In 2018, Fast track designation was granted to by US FDA for the development of fimepinostat in adult patients with R/R DLBCL. [220]
Etinostat, (SNDX-275 and MS-275) [222]	Developed by—Syndax Is an orally administered selective class I HDAC inhibitor Belongs to the benzamide class of HDAC inhibitors A combination study (Phase 3) of Exemestane and Entinostat in Chinese subjects with Hormone Receptor-Positive, Locally Advanced or Metastatic Breast Cancer is also ongoing (NCT03538171) The effects of entinostat addition to exemestane in patients with HR-positive advanced breast cancer were evaluated. The results of this phase II clinical study (ENCORE 301) revealed remarkable advantages attained with this combination in terms of improvement of OS as well as PFS. In light of these favourable trends, a phase III trial (E2112) was initiated for the evaluation of this combination in patients with locally advanced and metastatic breast cancer (NCT02115282). [222] The combination studies of etinostat with pembrolizumab (ENCORE601, phase 2 trial) conducted in subjects with NSCLC demonstrated better outcomes attained with this combination in patients with higher levels of a circulating cell called a classical monocyte [223] An assessment study of High Dose Interleukin 2 vs High Dose Interleukin 2 in combination with Entinostat in Advanced Renal Cell Carcinoma is ongoing. (NCT03501381, Recruiting)
Mocetinostat,	Recently, first clinical trial for mocetinostat using genomic-based selection to identify patients with urothelial cancer was conducted. The results of the study demonstrated that administration of mocetinostat led to significant toxicities and displayed limited efficacy. Owing to this, mocetinostat monotherapy is not recommended for further investigation in this setting [224] Mocenitostat was evaluated in a phase 2 study in patients (n = 72 with R/R DLBCL and FL). The study design involved the administration of mocetinostat (starting doses: 70–110 mg TIW, 4-week cycles). The results of the study demonstrated that 54.1% and 73.1% of patients showed clinical benefit (response or stable disease) from mocetinostat in the DLBCL and FL cohorts and PFS was 1.8–2.8 months (DLBCL) and 11.8–26.3 (FL). Fatigue, nausea and diarrhoea (61.1%) were found to most frequent TAAEs. Overall, mocenitostat was found to be safe as single agent, however, was endowed with limited efficacy. [225] Mocetinostat is undergoing the below mentioned studies: Metastatic Solid Tumors and NSCLC (combination with PD-L1 Inhibitor, Durvaluma, Phase 2, NCT02805660, status—completed, results not posted) Advanced NSCLC (combination with nivolumab, NCT02954991, Phase 2, status—recruiting) In children, Adolescents and young adults with Refractory and/or Recurrent Rhabdomyosarcoma (NCT04299113, status—recruiting, Phase 1) Advanced NSCLC (combination with pembrolizumab plus guadecitabine, Phase 1, NCT03220477 status—recruiting)
Tucidinostat (Chidamide)	Developed by chipscreen Is an orally bioavailable HDAC inhibitor belongs to benzamide class of HDAC and inhibits HDAC isoenzymes 1, 2, 3 and 10 CFDA approved (for PTCL) [226] Currently, tucidinostat is undergoing phase III clinical evaluation in combination with R-CHOP in patients with newly diagnosed MYC/BCL2 double-expressor DLBCL (NCT04231448, status—recruiting) In a Phase III study, combination of exemestane with tucidinostat for post-menopausal patients with advanced, hormone receptor-positive breast cancer was assessed for safety and efficacy. In the study, 365 patients were enrolled (244 tucidinostat and 121- placebo). In the tucidinostat group, the median duration of follow-up was 13.9 months (IQR 9·8–17·5) and investigator-assessed median PFS was 7·4 months (95% CI 5.5–9.2). Overall, the combination improved the PFS in comparison to placebo plus exemestane. Haematological adverse events (Grade 3–4) were more common with the combination than the placebo plus exemestane group [227] Tucidinostat in combination with R-CHOP is also undergoing phase III evaluation in patients with newly diagnosed MYC/BCL2 Double-Expressor DLBCL (NCT04231448) and phase II evaluation in combination with toripalimab in subjects with refractory and advanced soft-tissue sarcoma (NCT04025931, Phase, recruiting) The combination of tucidinostat with exemestane has been approved by NMPA for breast cancer [235]
Domatinostat	Is an orally administered, selective inhibitor of LSD1 and class 1 HDAC inhibitor In a phase 2 studies of domatinostat in patients with patients with advanced hematological malignancies, domatinostat (monotherapy) demonstrated clinical activity and was found to be safe, well tolerated and the RP2D was determined to be 400 mg TDD in a 200 mg BID schedule (14 + 7) [228] Domantinostat is currently undergoing phase 2 evaluation (combination studies with avelumab) in GI cancer (NCT03812796)
CXD1	Developed by celleron therapeutics CXD101, is a dual mechanism HDAC inhibitor Is a novel epigenetic immune-regulator endowed with potential to enhance immune recognition of tumour cells CXD-101 has been found to be effective in lung and colon xenograft models in preclinical studies CXD-101 is undergoing phase 2 clinical studies in NSCLC (NCT03833440, status—recruiting) Clinically important tumour remissions have been displayed by CXD101 in the phase I trials. [229]