Table 4 Combination therapies of epigenetic drugs in solid tumors

Combination of epigenetic agents

Azacitidine (DNMTi) + entinostat (HDACi)

Advanced breast cancer

Phase II trial

NCT01349959

Enrollment: 58 patients

Active, not recruiting

Results: Combination therapy was well tolerated but primary endpoint (ORR) was not met [193]

Azacitidine + entinostat

Recurrent advanced NSCLC

Phase I/II

NCT00387465

Enrollment: 94 patients

Completed 11/2014

Results: Combined low-dose azacitidine and entinostat was well tolerated and resulted in objective, durable responses in pretreated patients with recurrent advanced NSCLC. Median survival in the entire cohort was 6.4 months [135]

CC-486 + romidepsin (HDACi)

Advanced solid tumors, HPV + NPC, HPV + cervical cancer, liposarcoma

Phase I trial

NCT01537744

Enrollment: 18 patients

Completed 9/2016

Results: Although the recommended combination was tolerable, no significant anticancer activity was observed [194]

Azacitidine + vorinostat (HDACi)

Locally recurrent and metastatic NPC and nasal natural killer T-cell lymphoma

Phase I trial

NCT00336063

Enrollment: 18 patients

Active, not recruiting

Results: Eleven patients were treated at 3 dose levels. This combination appeared tolerable at dose level 3 (azacitidine 25 mg/m² + vorinostat 100 mg twice daily). DLTs include grade 4 thrombocytopenia, grade 3 nausea, vomiting and fatigue and grade 5 hepatic failure, and worsening of pre-existing Sweet’s Syndrome. Common grade 1/2 AEs were fatigue (73%), cough (64%), anorexia (55%) and injection site reaction (45%). One minor response was seen and 5 patients had prolonged stable disease (> 16 weeks) [195]

Combination with Chemotherapy or Other Agents

Azacitidine + capecitabine and oxaliplatin

Metastatic CRC

Phase I/II trial

NCT01193517

Enrollment: 26 patients

Completed 11/2016

Results: Fifteen patients in phase I and 11 in phase II were evaluable. No DLTs observed. Combination azacitidine, capecitabine and oxaliplatin was well tolerated with high rates of SD in CIMP-high patients but no objective responses seen [196]

Azacitidine + nab-paclitaxel

Advanced or metastatic solid tumors, including HER2-negative breast cancer

Phase I/II trial

NCT00748553

Enrollment: 30 patients

Completed 10/2015

Results: In the phase I cohort (16 patients, with at least one prior therapy): Response rate was 61.5%. In the phase II cohort (14 patients without prior therapy): ORR 53.8% and PFS data not collected. Most common AEs were leukopenia (43.33%), nausea (36.67%), fatigue (60%) and neuropathy (46.67%) [197]

CC-486 + nab-paclitaxel

Advanced NSCLC

Phase II trial

NCT02250326

Enrollment: 240 patients

Active, not recruiting

Results: Median PFS 3.2 months vs. 2.2 months, DCR 65.4% (CR/PR 13.6%) vs. 67.5% (CR/PR 16.3%) and median OS 8.1 months vs. 17.0 months for nab-paclitaxel + CC-486 arm vs. nab-paclitaxel only arm. Grade 3 or higher TEAEs occurred at 40.5% in the combination arm and 31.6% in the nab-paclitaxel alone arm. There was no survival benefit from the addition of CC-486 to nab-paclitaxel [198]

Decitabine + temozolomide

Metastatic melanoma

Phase I/II trial

NCT00715793

Enrollment: 39 patients

Completed 8/2015

Results: ORR 18%, DCR 61%, median PFS 3.4 months, median OS 12.4 months and 1-year OS rate 56%. DLT was neutropenia in 6 patients. Common non-hematologic toxicities were fatigue and nausea. The combination of decitabine and temozolomide was safe and suggested possible superiority over the historical 1-year OS rate [199]

Decitabine + tetrahydrouridine/THU-DAC

Advanced pancreatic cancer

Phase I trial

NCT02847000

Enrollment: 13 patients

Completed 10/2017

Results: Eight patients underwent evaluation scans at 8 weeks with SD in 1 patient and PD in 7. Common reasons for treatment discontinuation were PD (n = 6), physician discretion (n = 3) and AEs (n = 2). THU-DAC was deemed to be safe [200]

Guadecitabine/SGI-110 (DNMTi) + carboplatin

Recurrent ovarian cancer

Phase II trial

NCT01696032

Enrollment: 120 patients

Completed 8/2016

Results: Overall response rate 16% in guadecitabine + carboplatin (G + C) arm versus 8% in the TC (treatment of choice) arm. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G + C and TC groups). However, the 6-month PFS rate was significantly higher in the G + C group. There was no difference between the two arms in OS [140]

Guadecitabine + cisplatin

Refractory germ cell tumor

Phase I trial

NCT02429466

Planned enrollment: 14 patients

Completed

Results: MTD was guadecitabine 30 mg/m² × 5 days and cisplatin 100 mg/m² (with growth factor support). DLT was neutropenic fever. Most common toxicities were neutropenia (82% any grade), thrombocytopenia (42%), anemia (33%), neutropenic fever (8%) and diarrhea (8%). There were 2/14 CR lasting > 6 months, 2 PR and 1 SD. ORR 28.5%. Guadecitabine + cisplatin at MTD showed promising antitumor activity in this refractory germ cell population [201]

Guadecitabine + irinotecan

Metastatic CRC

Phase I/II trial

NCT01896856

Enrollment: 118 patients

Completed 8/2019

Results: 22 patients were treated across four dose levels. DLTs were neutropenic fever, biliary drain infection, colonic obstruction and severe dehydration. Most common toxicities were neutropenia (82% any grade, 77% grade 3/4), neutropenic fever (23%), leukopenia (73% any grade, 50% grade 3/4) and injection site reactions (64% total, 0% Grade 3/4). 12/17 evaluable patients had SD as best response [202]

Belinostat + cisplatin and etoposide

SCLC and other cancers of neuroendocrine origin

Phase I trial

NCT00926640

Enrollment: 28 patients

Completed 4/2018

Results: Hematologic toxicities were most common. Objective responses were seen in 11 (39%) of 28 patients; 13/28 (46%) had SD and 4 (14%) had PD. Among patients with neuroendocrine tumors, including SCLC, 7 (47%) of 15 patients achieved PR, 7 (47%) had SD and 1 (7%) had PD. There were no CR. The combination was safe, although some patients were more susceptible to AEs, and showed clinical activity in SCLC and other neuroendocrine cancers [203]

Mocetinostat (HDACi) + gemcitabine

Metastatic leiomyosarcoma

Phase II trial

NCT02303262

Enrollment: 20 patients

Completed 12/2016

Results: Best responses included 1 PR and 12 SD in 18 evaluable patients. Median duration of response 2 months and median PFS 2 months. Although mocetinostat can be safely combined with gemcitabine in this population, the study could not demonstrate that mocetinostat can reverse chemoresistance in patients with previously established gemcitabine-resistant leiomyosarcoma [204]

Panobinostat + bevacizumab

Recurrent high grade glioma

Phase I/II trial

NCT00859222

Enrollment: 51 patients

Completed 12/2015

Results: Although reasonably well tolerated, adding panobinostat to bevacizumab did not significantly improve 6-month PFS compared with historical controls of bevacizumab monotherapy in either cohort [205, 206]

Vorinostat + sorafenib

Advanced HCC

Phase I trial

NCT01075113

Enrollment: 16 patients

Completed 7/2019

Results: Although some patients had durable disease control, the addition of vorinostat to sorafenib led to toxicities in most patients [207]

Vorinostat + capecitabine and cisplatin

Metastatic or recurrent gastric cancer

Phase I/II trial

NCT01045538

Enrollment: 45 patients

Completed 4/2016

Results: ORR 42%, median PFS 5.9 months, 6-month PFS rate 44.4% and median OS 12.7 months. Did not meet primary end point (6-month PFS rate) and more AEs were observed in comparison with historical data from fluoropyrimidine–platinum doublet regimens [208]

ZEN003694 + enzalutamide

Metastatic CRPC

Phase Ib/IIa trial

NCT02711956

Planned enrollment: 75 patients

Completed

Results: The most common treatment-related AEs of any grade included transient photophobia (66%), nausea (40%), fatigue (31%), decreased appetite (22%) and dysgeusia (16%). The overall median time to progression was 44.4 weeks (similar in subgroups with prior abiraterone or enzalutamide resistance) and durable responses were observed. ZEN003694 in combination with enzalutamide had acceptable toxicity profile and promising activity in metastatic CRPC refractory to enzalutamide or abiraterone [209]

Molibresib/GSK525762 (BET inhibitor) + fulvestrant

Advanced breast cancer

Phase I/II trial

NCT02964507

Planned enrollment: 294 patients

Active, not recruiting

Results: N/A

Molibresib + abiraterone or enzalutamide

CRPC

Phase Ib trial

NCT03150056

Planned enrollment: 130 patients

Active, not recruiting

Results: N/A

Combination with Immune Checkpoint Inhibitor (ICI)

Decitabine + durvalumab and tremelimumab

Recurrent and/or metastatic HNSCC

Phase Ib/II trial

NCT03019003

Planned enrollment: 59 patients

Recruiting

Results: N/A

Azacitidine + pembrolizumab

Advanced pancreatic cancer

Phase II trial

NCT03264404

Planned enrollment: 31 patients

Recruiting

Results: N/A

Azacitidine + pembrolizumab

Metastatic CRC (microsatellite stable, MSS)

Phase II trial

NCT02260440

Enrollment: 31 patients

Completed 9/2017

Results: ORR was 3% (1/30). Median PFS was 2.1 months and median OS was 6.2 months. Treatment-related AEs were reported in 63% of patients but most were grade 1/2 (96%). Azacitidine + pembrolizumab demonstrated tolerable safety profile but minimal antitumor activity in MSS metastatic CRC [210]

CC-486 + pembrolizumab

Metastatic NSCLC

Phase II trial

NCT02546986

Enrollment: 100 patients

Active, not recruiting

Results: PFS 2.9 months versus 4.0 months, DCR 25.5% versus 38.8%, OS 11.9 months versus NA for azacitidine + pembrolizumab arm versus placebo + pembrolizumab arm. For the azacitidine + pembrolizumab arm, 49% of patients experienced any grade 3/4 TEAE related to study drug (vs. 20.4%) [211]

CC-486 + pembrolizumab

Platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer

Phase II trial

NCT02900560

Enrollment: 34 patients

Active, not recruiting

Results: None available

CC-486 + pembrolizumab

Metastatic melanoma

Phase II trial

NCT02816021

Planned enrollment: 71 patients

Recruiting

Results: N/A

THU-DAC + pembrolizumab

Unresectable locally advanced or metastatic NSCLC and esophageal carcinomas

Phase I/II trial

NCT03233724

Planned enrollment: 85 patients

Recruiting

Results: N/A

Decitabine + pembrolizumab (followed by standard neoadjuvant chemotherapy)

Locally advanced HER2-negative breast cancer

Phase II trial

NCT02957968

Planned enrollment: 32 patients

Recruiting

Results: N/A

Guadecitabine + durvalumab

Advanced RCC

Phase Ib/II trial

NCT03308396

Planned enrollment: 58 patients

Recruiting

Results: N/A

Guadecitabine + durvalumab and tremelimumab

Extensive-stage SCLC

Phase I trial

NCT03085849

Enrollment: 2 patients

Completed 11/2018

Results: None available

Guadecitabine + durvalumab

Advanced HCC, pancreatic adenocarcinoma, cholangiocarcinoma

Phase Ib trial

NCT03257761

Planned enrollment: 90 patients

Recruiting

Results: N/A

Guadecitabine + pembrolizumab

Recurrent ovarian, primary peritoneal, or fallopian tube cancer

Phase II trial

NCT02901899

Enrollment: 35 patients

Active, not recruiting

Results: None available

Guadecitabine + atezolizumab

Recurrent/advanced urothelial carcinoma

Phase II trial

NCT03179943

Planned enrollment: 53 patients

Active, not recruiting

Results: N/A

Entinostat + atezolizumab

Advanced TNBC

Phase Ib/II trial

NCT02708680

Planned enrollment: 88 patients

Status unknown

Results: None available

Entinostat + avelumab

Advanced epithelial ovarian cancer

Phase Ib/II trial

NCT02915523

Enrollment: 140 patients

Active, not recruiting

Results: N/A

Entinostat + pembrolizumab

Advanced metastatic or recurrent NSCLC, melanoma, MMR-proficient CRC

Phase Ib/II trial

NCT02437136

Planned enrollment: 202 patients

Status unknown

Results: 76 patients with NSCLC who progressed on prior anti-PD/PD-L1 therapy had been enrolled (72 evaluable for response). ORR 10%, which did not meet pre-specified target, but may represent clinically meaningful activity. Reponses were independent of baseline PD-L1 expression. Median duration of response was 5.3 months and median PFS 2.8 months. An additional 50% of patients achieved disease stabilization. Most patients tolerated the therapy well [212]

Entinostat + ipilimumab and nivolumab

Metastatic or unresectable HER2-negative breast cancer

Phase I trial

NCT02453620

Enrollment: 45 patients

Active, not recruiting

Results: None available

Entinostat + bevacizumab and atezolizumab

Advanced RCC

Phase I/II trial

NCT03024437

Planned enrollment: 62 patients

Recruiting

Results: N/A

Entinostat + nivolumab

Unresectable or metastatic cholangiocarcinoma and pancreatic adenocarcinoma

Phase II trial

NCT03250273

Planned enrollment: 54 patients

Recruiting

Results: N/A

Entinostat + nivolumab and ipilimumab

Metastatic RCC

Phase II trial

NCT03552380

Planned enrollment: 53 patients

Active, not recruiting

Results: N/A

Mocetinostat (HDACi) + guadecitabine and pembrolizumab

NSCLC

Phase I/Ib trial

NCT03220477

Planned enrollment: 40 patients

Recruiting

Results: N/A

Mocetinostat + ipilimumab and nivolumab

Melanoma

Phase Ib trial

NCT03565406

Planned enrollment: 12 patients

Terminated

Results: N/A

Panobinostat + ipilimumab

Unresectable stage III/IV melanoma

Phase 1 trial

NCT02032810

Enrollment: 17 patients

Active, not recruiting

Results: Three patients had previous anti-PD1 therapy. Response rate was 12% (2 PR) with 35% SD. Median PFS 2.23 months (95% CI, 1.57—5.8) and median OS 20.97 months (95% CI, 8.97—NR). At tolerated doses, the addition of panobinostat does not appear to increase response to ipilimumab in advanced melanoma [213]

Romidepsin + pembrolizumab ± azacitidine

Advanced MSS CRC

Phase I trial

NCT02512172

Enrollment: 27 patients

Active, not recruiting

Results: None available

Vorinostat + pembrolizumab

Stage IV NSCLC

Phase I/II trial

NCT02638090

Planned enrollment: 100 patients

Recruiting

Results: None available

Vorinostat + pembrolizumab

Recurrent metastatic HNSCC or salivary gland cancer

Phase I/II trial

NCT02538510

Enrollment: 50 patients

Active, not recruiting

Results: There were 25 patients with HNSCC (52% were p16 + oropharynx) and 25 with salivary gland cancers (SGC). Most common AEs were renal insufficiency (14%), fatigue (12%) and nausea (6%). There were 3 deaths on study. HNSCC group had 0 CR, 8 PR, and 5 SD while SGC group had 0 CR, 4 PR, and 14 SD. This combination demonstrated activity in HNSCC, with fewer responses in SGC [214]

Vorinostat + pembrolizumab

Advanced renal or urothelial cell carcinoma

Phase I/Ib trial

NCT02619253

Planned enrollment: 57 patients

Active, not recruiting

Results: None available

INCB057643 (BET inhibitor) + pembrolizumab and epacadostat (IDO1 inhibitor)

Advanced solid tumors, including stage IIIB or stage IV NSCLC, stage IV microsatellite-stable CRC, HNSCC, urothelial carcinoma, and melanoma

Phase I/II trial

NCT02959437

Enrollment: 70 patients

Completed

Azacitidine + pembrolizumab is assessed in group A; INCB057643 + Pembrolizumab + Epacadostat is assessed in group B; INCB059872 + Pembrolizumab + Epacadostat is assessed in group C

Results: None available

Tazemetostat (EZH2 inhibitor) + pembrolizumab

Advanced urothelial carcinoma

Phase I/II trial

NCT03854474

Planned enrollment: 30 patients

Recruiting

Results: N/A

INCB059872 (LSD1 inhibitor) + epacadostat and pembrolizumab

Advanced solid tumors, including stage IIIB or stage IV NSCLC, stage IV microsatellite-stable CRC, HNSCC, urothelial carcinoma, and melanoma

Phase I/II trial

NCT02959437

Enrollment: 70 patients

Active, not recruiting

Results: None available