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Table 2 Clinical trials of single agent DNMT inhibitors and HDAC inhibitors in solid tumors

From: Advances in epigenetic therapeutics with focus on solid tumors

Agent(s)

Cancer type(s)

Trial details

Trial identifier/status

DNMT inhibitors

CC-486 (oral form of azacitidine)

Locally advanced or metastatic NPC

Phase II trial

NCT02269943

Enrollment: 36 patients

Completed 4/2017

Results: ORR 12%; median PFS and OS were 4.7 and 18.0 months, respectively. CC-486 as monotherapy did not show sufficient clinical activity in this patient population. The most common grade 3/4 TEAEs were neutropenia (33%) and febrile neutropenia (11%) [182]

Guadecitabine (SGI-110)

Advanced HCC

Phase II trial

NCT01752933

Enrollment: 52 patients

Completed 9/2015

Results: DCR 25% and 24.4%, median duration of response 262 days and 144 days, median PFS 55 days and 82.5 days, median OS 294 days and 245 days in the 60 mg/m2 group and 45 mg/m2 group, respectively. The most common being febrile neutropenia in both groups (25% vs. 11%) [183]

ASTX727 (cedazuridine and decitabine)

Recurrent or progressive non-enhancing IDH mutant gliomas

Phase I trial

NCT03922555

Enrollment: 18 patients

Recruiting

Results: pending

HDAC Inhibitors

Entinostat (SNDX-275, MS-275)

Relapsed or refractory abdominal neuroendocrine tumors

Phase II trial

NCT03211988

Planned enrollment: 40 patients

Recruiting

Results: N/A

Mocetinostat (MGCD0103)

Locally advanced or metastatic urothelial carcinoma

Phase II trial

NCT02236195

Enrollment: 17 patients

Completed 7/2016

Results: Eligible patients received oral mocetinostat at a dose of 70 mg thrice weekly (TIW) escalating to 90 mg TIW in 28-day cycles in a planned 3-stage study. Single agent mocetinostat was not efficacious in this setting and significant toxicities impacted drug exposure and possibly contributed to modest clinical activity in these pretreated patients [184]

Panobinostat (LBH589)

Locally recurrent or metastatic HER2-negative breast cancer

Phase II trial

NCT00777049

Enrollment: 54 patients

Completed 4/2015

Results: In HR + group (n = 33) there were 1 PR, 13 SD, 14 PD and 5 missing data; most common SAE was thrombocytopenia (12.5%). In HR-group (n = 21) there was 1 CR, 4 SD, 14 PD, 2 missing data; most common SAE was constipation (10%)

Metastatic medullary thyroid cancer and radioactive iodine resistant differentiated thyroid cancer

Phase II trial

NCT01013597

Enrollment: 13 patients

Completed 2/2016

Results: Patients received LBH589 20 mg by mouth three times weekly for 28-day cycles. No responses seen, median time to progression 3.6 months, median OS 18.4 months (5.8 to NA). Most common toxicities were lymphopenia, thrombocytopenia and fatigue (8 patients each). There were 3 deaths “not otherwise specified”

Metastatic melanoma

Phase I trial

NCT01065467

Enrollment: 16 patients

Completed 3/2017

Results: 6 patients were treated on Arm A (oral panobinostat 30 mg daily on MWF) and 10 patients were enrolled to Arm B (oral panobinostat 30 mg three times a week every other week) with 9 patients treated. DLT in arm A included clinically significant thrombocytopenia requiring dose interruption. Among all 15 treated patients, ORR was 0% and DCR was 27%. Panobinostat monotherapy was not active in melanoma and there was a high toxicity rate [185]

Valproic acid (VPA)

Uveal melanoma

Phase II trial

NCT02068586

Planned enrollment: 150 patients

Recruiting

Results: N/A

Advanced thyroid cancers of follicular origin

Phase II trial

NCT01182285

Enrollment: 13 patients

Completed 4/2016

Results: No responses were seen and 6 patients had PD. Zero of 10 patients had increased radioiodine uptake at their tumor sites. Valproic acid did not increase radioiodine uptake and did not have anticancer activity in patients with advanced, radioiodine-negative thyroid cancer of follicular cell origin [186]

Vorinostat (SAHA)

Locally advanced, recurrent or metastatic adenoid cystic carcinoma

Phase II trial

NCT01175980

Enrollment: 30 patients

Completed 6/2018

Results: Stable disease was the best response in 27 patients. Median PFS and stable disease duration were both 11.4 months and median OS has not been reached. Grade 3 AEs that occurred in more than 1 patient included lymphopenia (n = 5), hypertension (n = 3), oral pain (n = 2), thromboembolic event (n = 2) and fatigue (n = 2). Eleven patients required dose reduction due to drug related AEs [187]

  1. Only select studies within the past 5 years have been included due to extent of clinical trials
  2. AE adverse events, CRC colorectal cancer, CRPC castrate-resistant prostate cancer, DCR disease control rate, DNMT DNA methyltransferase, HCC hepatocellular carcinoma, HDAC histone deacetylase, HR hormone receptor, ITT intention-to-treat, NPC nasopharyngeal carcinoma, NSCLC non-small cell lung cancer, ORR objective response rate, OS overall survival, PD progressive disease, PFS progression-free survival, PR partial response, SAE serious adverse event, SCLC small cell lung cancer, SD stable disease, TEAE treatment-emergent adverse event