Table 4.
Combination therapies of epigenetic drugs in solid tumors
| Agent(s) | Cancer type(s) | Trial details | Trial identifier/status |
|---|---|---|---|
| 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 | |||
Only select studies within the past 5 years have been included due to extent of clinical trials
AE adverse event, BET bromodomain and extra-terminal, CIMP CpG island methylator phenotype, CR complete response, CRC colorectal cancer, CRPC castrate-resistant prostate cancer, DCR disease control rate, DLT dose-limiting toxicities, DNMTi DNA methyltransferase inhibitor, EZH2 enhancer of zeste homologue 2, GBM glioblastoma multiforme, HCC hepatocellular carcinoma, HDACi histone deacetylase inhibitor, HER2 human epidermal growth factor receptor 2, HNSCC head and neck squamous cell carcinoma, HPV human papillomavirus, IDH isocitrate dehydrogenase, IDO-1 indoleamine 2,3-dioxygenase, ITT intention-to-treat, LSD1 lysine-specific demethylase 1A, MMR mismatch-repair, MSS microsatellite stable, MTD maximum tolerated dose, 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, RCC renal cell carcinoma, RP2D recommended phase 2 dose, SAE serious adverse event, SCLC small cell lung cancer, SD stable disease, SGC salivary gland cancer, TEAE treatment-emergent adverse events, TNBC triple-negative breast cancer