Table 3.
Clinical trials of newer epigenetic agents in solid tumors
| Agent(s) | Cancer type(s) | Trial details | Trial identifier/status |
|---|---|---|---|
| IDH inhibitors | |||
| Enasidenib (AG-221) | Advanced solid tumors, AITL | Phase I/II trial | NCT02273739 |
| Enrollment: 21 patients | Completed 6/2016 | ||
| Results: None available | |||
| Ivosidenib (AG-120) | Advanced solid tumors, including cholangiocarcinoma, chondrosarcoma, and glioma | Phase I trial | NCT02073994 |
| Planned enrollment: 170 patients | Active, not recruiting | ||
| Results: Ivosidenib demonstrated good oral exposure and a long half-life. Ivosidenib 500 mg once daily was an appropriate dose irrespective of intrinsic and extrinsic factors, including patient/disease characteristics and concomitant administration of weak CYP3A4 inhibitors/inducers. Persistent plasma 2-HG inhibition was observed in IDH1-mutant cholangiocarcinoma and chondrosarcoma [188] | |||
| Glioma | Phase I trial | NCT03343197 | |
| Enrollment: 49 patients | Active, not recruiting | ||
| Results: In cohort 1 (patients randomized 2:2:1 to AG-120 500 mg daily, AG-881 50 mg daily, or no treatment for 4 weeks preoperatively), AG-120 and AG-881 were CNS penetrant and lowered 2-HG compared to untreated samples. Cohort 2 is open and will evaluate AG-120 250 mg twice daily and AG-881 10 mg daily [189] | |||
| Advanced cholangiocarcinoma | Phase III trial | NCT02989857 | |
| Planned enrollment: 186 patients | Active, not recruiting | ||
| Results: Ivosidenib resulted in significant improvement in PFS and favorable OS trend versus placebo in IDH1-mutated advanced cholangiocarcinoma [130] | |||
| BET Inhibitors | |||
| AZD5153 | Solid tumors, lymphomas | Phase I trial | NCT03205176 |
| Planned enrollment: 60 patients | Not recruiting | ||
| Results: AZD5153 monotherapy appeared to be safe and tolerated at doses up to 30 mg once daily and 15 mg twice daily. Linear increase in PK was observed [190] | |||
| Birabresib (OTX015, MK-8628) | Selected advanced solid tumors, including NMC, NSCLC, CRPC | Phase 1b trial | NCT02259114 |
| Enrollment: 47 patients | Completed 3/2017 | ||
| Results: The RP2D of birabresib was 80 mg once daily with continuous dosing. Clinical activity was observed in NMC (3 of 10 patients had PR). Birabresib has dose-proportional exposure based on PK analysis and a favorable safety profile [128] | |||
| Selected advanced solid tumors | Phase Ib trial | NCT02698176 | |
| Enrollment: 13 patients | Terminated due to futility | ||
| Summary: Dose escalation trial of MK-8628 in TNBC (1 patient), CRPC (9 patients), or NMC (3 patients) | |||
| GBM | Phase IIa trial | NCT02296476 | |
| Enrollment:12 patients | Terminated due to futility | ||
| Summary: Dose escalation and expansion cohort study to evaluate single-agent MK-8628 in recurrent GBM after failing standard front-line therapy | |||
| BMS-986158 | Selected advanced solid tumors, hematologic malignancies | Phase I/IIa trial: | NCT02419417 |
| Planned enrollment: 417 patients | Recruiting | ||
| Results: N/A | |||
| INCB054329 | Advanced malignancies | Phase I/II trial | NCT02431260 |
| Enrollment: 69 patients | Terminated due to PK variability | ||
| Summary: Open-label dose escalation and expansion study of INCB054329 | |||
| INCB057643 | Advanced malignancies | Phase I/II trial | NCT02711137 |
| Enrollment: 136 patients | Terminated due to safety issues | ||
| Summary: Open-label, dose escalation and dose expansion study of INCB057643 as monotherapy and in combination with standard-of-care agents in patients with advanced malignancies | |||
| Molibresib (GSK525762) | NMC, other solid tumors | Phase I/II trial | NCT01587703 |
| Enrollment: 196 patients | Completed | ||
| Results: RP2D was selected as 80 mg once daily. The most frequent treatment-related AEs of any grade were thrombocytopenia (51%), gastrointestinal events (22–42%), anemia (22%) and fatigue (20%). Among 19 patients with NUT carcinoma-4 achieved either confirmed or unconfirmed PR, 8 had SD as best response and 4 were progression-free for > 6 months [191] | |||
| RO6870810 | Advanced solid tumors | Phase I trial | NCT01987362 |
| ZEN003694 | Enrollment: 52 patients | Completed 10/2017 | |
| Results: None available | |||
| Metastatic CRPC | Phase I trial | NCT02705469 | |
| Enrollment: 44 patients | Completed 10/2017 | ||
| Results: None available | |||
| EZH2 Inhibitors | |||
| Tazemetostat (EPZ-6438) | Advanced solid tumors, B-cell lymphoma | Phase I trial | NCT03028103 |
| Planned enrollment: 28 patients | Active, not recruiting | ||
| Results: None available | |||
| Advanced solid tumors, B-cell lymphomas | Phase I/II trial | NCT01897571 | |
| Planned enrollment: 420 patients | Active, not recruiting | ||
| Results: 64 patients [21 with B-cell non-Hodgkin lymphoma (NHL) and 43 with advanced solid tumors] received doses of tazemetostat. No treatment-related deaths occurred; 7 (11%) patients had non-treatment-related deaths (1 at 200 mg twice daily, 4 at 400 mg twice daily and 2 at 1600 mg twice daily). The RP2D was determined to be 800 mg twice daily. Durable objective responses, including CR, were observed in 8/21 (38%) patients with B-cell NHL and 2/43 (5%) patients with solid tumors. Tazemetostat showed a favorable safety profile and anti-tumor activity in patients with refractory B-cell NHL and advanced solid tumors. Phase 2 is ongoing [191) | |||
| Mesothelioma | Phase II trial | NCT02860286 | |
| Enrollment: 74 patients | Completed 5/2019 | ||
| Results: Efficacy was assessed in 61 patients with deficient BRCA1 associated protein 1 (BAP1). Primary endpoint was met with 31 (51%) patients achieving disease control at 12 weeks and 15 patients sustained disease control at 24 weeks. Most frequent AEs of any grade include fatigue (32%), decreased appetite (28%), dyspnea (28%), and nausea (27%). Tazemetostat monotherapy had favorable toxicity profile and showed promising antitumor activity with confirmed responses and durable disease control in malignant mesothelioma [192] | |||
| INI1-negative tumors, relapsed/refractory synovial sarcoma | Phase II trial | NCT02601950 | |
| Planned enrollment: 250 patients | Recruiting | ||
| Results: 62 INI1-negative epithelioid sarcoma patients were enrolled and treated with tazemetostat 800 mg BID. ORR 15% (1.6% CR, 13% PR). There were 9/62 (15%) confirmed PR, with ORR 15% and DCR 26%. Median OS was 82.4 weeks. Most common AEs include fatigue (24/62; 39%), nausea (35%) and cancer pain (32%). Grade ≥ 3 TEAEs in ≥ 2 pts included anemia (6%) and decreased weight (3%). There were no drug-related deaths and a low discontinuation rate (1.7%). Tazemetostat was generally well tolerated and showed durable clinical response [127]. On January 23, 2020, FDA granted accelerated approval to tazemetostat (EZH2) for the treatment of adults and pediatric patients > 16 years old with metastatic or locally advanced epithelioid sarcoma who were not eligible for complete resection [107] | |||
| LSD1 Inhibitors | |||
| INCB059872 | Relapsed or refractory Ewing sarcoma | Phase Ib trial | NCT03514407 |
| Planned enrollment: 21 patients | Terminated | ||
| Results: N/A | |||
| Advanced malignancies | Phase I/II trial | NCT02712905 | |
| Planned enrollment: 215 patients | Terminated | ||
| Results: N/A | |||
| Seclidemstat (SP-2577) | Advanced solid tumors | Phase I trial | NCT03895684 |
| Planned enrollment: 50 patients | Recruiting | ||
| Results: N/A | |||
| Relapsed or refractory Ewing sarcoma | Phase I trial | NCT03600649 | |
| Planned enrollment: 50 patients | Recruiting | ||
| Results: N/A | |||
AE adverse events, AITL angioimmunoblastic T-cell lymphoma, ALK anaplastic lymphoma kinase, AML acute myeloid leukemia, BET bromodomain and extra-terminal, CR complete response, CRC colorectal cancer, CRPC castrate-resistant prostate cancer, DLT dose-limiting toxicities, ER estrogen receptor, EZH2 enhancer of zeste homologue 2, GBM glioblastoma multiforme, HMT histone methyltransferase, IDH isocitrate dehydrogenase, IDO-1 indoleamine 2,3-dioxygenase, INI1 integrase interactor or INI1/SNF5/SMARCB1, LSD1 lysine-specific demethylase 1A, MDS myelodysplastic syndrome, MTD maximum tolerated dose, NSCLC non-small cell lung cancer, NMC nuclear protein in testis (NUT) midline carcinoma, PK/PD pharmacokinetics/pharmacodynamics, RP2D recommended phase 2 dose, SCLC small cell lung cancer, TNBC triple-negative breast cancer