Date: 2018-04-09
Type of
information: Publication of results in a medical journal
phase: 1
Announcement: publication of results in The Lancet Oncology
Company: Epizyme (USA - MA)
Product: tazemetostat - EPZ-6438 (E7438)
Action
mechanism:
- enzyme inhibitor/histone methyltransferase inhibitor. EZH2 is a histone methyltransferase (HMT) that is increasingly understood to play a potentially oncogenic role in a number of cancers. These include germinal center (GC) non-Hodgkin lymphomas, INI1-deficient cancers such as synovial sarcoma and malignant rhabdoid tumors, and a range of other solid tumors. EPZ-6438 is a first-in-class oral EZH2 inhibitor created with Epizyme’s proprietary product platform, for the treatment of non-Hodgkin lymphoma patients. In many human cancers, misregulated EZH2 enzyme activity results in misregulation of genes that control cell proliferation — without these control mechanisms, cancer cells are free to grow rapidly.
- Epizyme granted Eisai a worldwide license to EPZ-6438 (Eisai refers to this therapeutic candidate as E7438), subject to Epizyme's right to opt in for co-development, co-commercialization and profit share arrangement with Eisai in the United States. Epizyme is working with Roche and Eisai to develop a companion diagnostic to identify patients with non-wild type EZH2, where EZH2 contains point mutations.
Disease: advanced solid tumors and B-cell non-Hodgkin lymphoma (NHL)
Therapeutic
area: Cancer - Oncology
Country:
Trial
details:
- The open-label Phase 1 study was designed to evaluate the maximally tolerated dose and supported defining the recommended Phase 2 dose (RP2D) of tazemetostat. Tazemetostat was dosed twice daily as a single agent in patients with relapsed or refractory B-cell NHL (n=21) or with advanced solid tumors (n=43) including molecularly defined INI1- or SMARCA4-negative tumors. Additional study objectives were to evaluate the adverse events (AE), pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of the agent.
Latest
news:
- • On April 9, 2018, Epizyme announced its first-in-human data on the effects of EZH2 inhibition in patients with advanced solid tumors and B-cell non-Hodgkin lymphoma (NHL) was published in The LancetOncology. The objectives of the Phase 1 dose-escalation portion of the study were to evaluate the safety and tolerability of orally dosed tazemetostat, a first-in-class selective inhibitor of EZH2. The study established the recommended dose for the Phase 2 expansion study and demonstrated favorable safety findings and anti-tumor activity.
- The results of the safety, PK and PD analyses helped determine the RP2D of 800 mg twice daily. The most common treatment-related adverse events, regardless of attribution, were grade 1 or 2 asthenia, anorexia, anemia, muscle spasms, nausea and vomiting. One single dose-limiting toxicity of grade 4 thrombocytopenia was identified at the highest dose of 1600 mg, but no other grade 3 or 4 toxicities were observed at a frequency greater than five percent.
- Anti-tumor activity was seen across several tumor types. In B-cell NHL, durable objective responses were observed in eight patients. Three patients had a complete response (CR), one with diffuse large B-cell lymphoma (DLBCL) and two with follicular lymphoma (FL). Five additional patients experienced a partial response (PR): three with DLBCL, one with FL and one with marginal zone lymphoma.
- Of the patients with solid tumors enrolled in this study, 13 had INI1- or SMARCA4-negative tumors. Activity was observed in five of these patients, including a CR in one patient with a malignant rhabdoid tumor, and a PR in one patient with SMARCA4-negative malignant rhabdoid tumor of the ovary (MRTO). Prolonged stable disease was observed in a patient with MRTO and two patients with epithelioid sarcoma (ES) experienced prolonged stable disease greater than 20 months.
- The results from this early phase study laid the groundwork for further exploration of tazemetostat in larger trials as a targeted approach to treat molecularly defined tumors predicted to be dependent on EZH2 activity, such as ES and NHL. Phase 2 studies in adults and a Phase 1 study for children, adolescents and young adults are currently enrolling patients living with these types of cancer.
Is
general: Yes
