Clinical Trials

Date: 2015-07-12

Type of information: Results

phase: 1

Announcement: results

Company: Epizyme (USA - MA) Eisai (Japan)

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 B cell lymphomas

Therapeutic area: Cancer - Oncology

Country: Australia, Canada, France, Italy, UK

Trial details:

• This multicenter, open-label, Phase 1/2 study will be conducted in two parts. The Phase 1 part will comprise dose escalation and establishment of the maximum tolerated dose (MTD) when E7438 is given BID (twice daily) orally on a continuous basis. Additionally, in separate cohorts in Phase 1, the effect of food on the bioavailability of E7438 will be evaluated as well as the drug-drug interaction (DDI) potential as evaluated by the effect of E7438 on the pharmacokinetics (PK) of midazolam, a CYP3A4 substrate. Once the MTD has been confirmed and a Phase 2 dose has been recommended, the protocol will be amended with updated dosing instructions and safety instructions. The Phase 2 part will determine the safety and activity of E7438 in EZH2 mutation positive subjects with histologically confirmed diffuse large B cell lymphoma (DLBCL) or Grade 3 follicular lymphomas with relapsed or refractory disease following 1) high-dose therapy (HDT) and autologous stem cell transplant (ASCT), or 2) at least one combination chemotherapy containing rituximab and an anthracycline (unless anthracycline-based therapy is contraindicated), and are ineligible or unwilling to undergo HDT and ASCT. (NCT01897571)

Latest news:

• • On December 7, 2015, Epizyme reported updated results from the ongoing phase 1 trial of tazemetostat (EPZ-6438). Data from this trial continue to show meaningful clinical activity with tazemetostat when used as an oral monotherapy in patients with either relapsed or refractory Non-Hodgkin Lymphoma (NHL). Nine of 16 response-evaluable patients with NHL have achieved an objective response, with the duration of responses lasting up to 19 months as of the data cutoff. The data were presented by Vincent Ribrag, M.D., Institut Gustave Roussy, at the 57th American Society of Hematology Annual Meeting (ASH). As of the November 7, 2015 cutoff, the following clinical data were reported: Twenty-one patients with relapsed or refractory NHL were enrolled into the phase 1 study; 16 of the 21 patients were response-evaluable as defined by the study protocol. Nine of 16 (56 percent) response-evaluable NHL patients achieved an objective response. On an intent-to-treat basis, seven of 12 (58 percent) response-evaluable NHL patients treated at or above the recommended phase 2 dose of 800 mg twice daily (BID) achieved an objective response. Four patients remained on study at data cutoff with ongoing objective responses, including three patients who had been on drug for at least 18 months. 800 mg BID showed superior tolerability, equivalent anti-tumor activity and equivalent pharmacodynamic activity as compared to the 1600 mg BID dose.
• The majority of adverse events were grade 1 or grade 2 within the 55 patients with NHL and solid tumors who were evaluable for safety. The most common adverse events, regardless of attribution, were asthenia, anorexia, thrombocytopenia, nausea, constipation, diarrhea, and vomiting. Four grade 3 or greater treatment-related adverse events have been observed including one each of: grade 3 hypertension, grade 3 liver function test elevation, grade 4 thrombocytopenia, and grade 4 neutropenia.
• • On September 26, 2015, Epizyme reported results from the ongoing phase 1 trial of tazemetostat. The data showed that tazemetostat demonstrated clinical activity in a broader group of patients with INI1-negative and SMARCA4-negative tumors than previously reported, achieved inhibition of EZH2 in tumor tissue, and had an acceptable safety profile when administered as oral monotherapy in adult patients with relapsed or refractory INI1-negative and SMARCA4-negative tumors. The data were presented at the European Cancer Congress 2015 (ECC) in Vienna, Austria by Antoine Italiano , M.D., Ph.D., of the Institut Bergonié in Bordeaux, France . Based on tazemetostat's clinical activity observed to date and other supportive research, Epizyme will initiate a global phase 2 study in adults and a global phase 1 study in children with INI1-negative tumors and synovial sarcoma in the fourth quarter of 2015. In total, 30 patients with solid tumors were enrolled into this ongoing phase 1 study, including eight patients in a food effect sub-study. Of these 30 patients, eight had INI1-negative tumors, comprised of five with malignant rhabdoid tumors and three with epithelioid sarcomas (ES). Additionally, three patients had SMARCA4-negative tumors including two patients with malignant rhabdoid tumor of the ovary, also referred to as small cell carcinoma of the ovary hypercalcemic type (SCCOHT), and one patient with thoracic sarcoma. Nineteen patients had other solid tumors that were not characterized by INI1 or SMARCA4 loss, including three patients with synovial sarcomas. In addition to the 30 patients with solid tumors, 21 patients with advanced Non-Hodgkin Lymphoma (NHL) were also enrolled into this ongoing phase 1 study, and the safety data from the ECC update presentation includes these patients. The data cutoff for this presentation was August 31, 2015 .
• Summary of Results: A total of 11 patients with INI1-negative or SMARCA4-negative tumors have been treated. The tumor histology of these patients includes MRT, MRTO, ES and thoracic sarcoma. Nine of these 11 patients have been treated at or above the recommended phase 2 dose of 800 mg twice daily. Six of the 11 patients experienced a reduction in tumor size as best response, with four patients experiencing tumor reduction of over 30%. Of five patients with an INI1-negative malignant rhabdoid tumor, one patient achieved a complete response (CR) at week eight and remains on study and in CR through week 65. Of three patients with SMARCA4-negative tumors, two patients have malignant rhabdoid tumor of the ovary. One MRTO patient achieved a PR at week 8 and remains on study through week 25. A second MRTO patient remains on study with stable disease (SD) through week 26. Of three patients with an INI1-negative epithelioid sarcoma, one patient achieved a PR of short duration and remains on study with SD through week 25. The second patient remains on study with SD through week 24. Clinical activity was not observed in the 19 patients with other tumors, including the three patients with synovial sarcomas. Inhibition of EZH2, as measured by post-treatment H3K27 trimethylation compared to baseline, was observed in tumor tissue of INI1-negative patients as assessed by immunohistochemistry.
• The majority of adverse events observed in the study were grade 1 or grade 2 within the entire population of 51 patients with NHL and solid tumors. The most frequent adverse events regardless of attribution were asthenia, decreased appetite, thrombocytopenia, nausea, dyspnea, anemia and constipation. Five grade 3 or greater treatment-related adverse events have been observed including one each of: thrombocytopenia, neutropenia, hypertension, liver function test elevation and decreased appetite. Solid tumor patients enrolled in this study had been heavily pre-treated, with over half of patients having received three or more prior anti-cancer therapies.
• A planned phase 2 trial studying tazemetostat in adult patients with INI1-negative solid tumors or synovial sarcoma is expected to begin in the fourth quarter of 2015. A phase 1 dose escalation study in pediatric patients with INI1-deficient solid tumors is also expected to start in the fourth quarter of 2015. The INI1-deficient tumor studies will enroll subjects in the U.S., EU and Australia . Epizyme is already enrolling patients into an international five-arm, multi-center, phase 2 study that will assess the safety and efficacy of tazemetostat in patients with relapsed or refractory NHL , stratified by cell of origin and EZH2 mutation status. The company plans to initiate additional trials of tazemetostat, including:
• A combination study of tazemetostat with R-CHOP in patients with diffuse large B-cell lymphoma (DLBCL), including higher risk front-line patients. R-CHOP, which represents the current first-line regimen for patients with DLBCL, is comprised of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.
• A combination study of tazemetostat with a B-cell signaling agent or other emerging targeted therapy for B-cell lymphomas.
• • On June 20, 2015, Epizyme, a clinical stage biopharmaceutical company creating novel epigenetic therapeutics for cancer patients, reported results from the ongoing phase 1 trial of tazemetostat (EPZ-6438), a first-in-class EZH2 inhibitor, showing meaningful clinical activity when used as an oral monotherapy in patients with advanced B-cell non-Hodgkin lymphomas (NHL) and solid tumors. In NHL, treatment with tazemetostat continues to demonstrate an encouraging profile with nine of 15 evaluable NHL patients achieving an objective response, including a partial response in the first treated patient with an EZH2 tumor mutation. The data, which include patients from the dose escalation and dose expansion cohorts of the phase 1 study, as well as a food effects sub-study, were presented by Vincent Ribrag, M.D., Institut Gustave Roussy, at the 13th International Conference on Malignant Lymphoma.
• As of June 8, 2015, the following clinical data were observed:
• • Nine of 15 evaluable NHL patients have achieved an objective response, including two patients with an ongoing complete response (CR).
• • Five of nine evaluable diffuse large B-cell lymphoma (DLBCL) patients achieved an objective response. One patient with a CR remains on study at 18 months of treatment.
• • Three of five evaluable patients with follicular lymphoma achieved an objective response. One patient with a CR remains on study at 13 months, and one patient with a PR remains on study at 13 months.
• • One patient with a marginal zone lymphoma achieved a partial response and continues on study at 11 months.
• • All treatment responses were observed between two and 10 months on therapy.
• • One of 14 patients evaluated for EZH2 status possesses a specific EZH2 tumor mutation (Y646H). This patient, who had relapsed or been refractory to six previous treatment regimens, achieved a partial response after 16 weeks of therapy and remains on study.
• • The majority of adverse events were grade 1 or grade 2 within the evaluable for safety population of 45 patients with NHL and solid tumors. The most common adverse events regardless of attribution were asthenia, anorexia, anemia, dyspnea and nausea. Five grade 3 or greater treatment-related adverse events were observed including one each of: grade 3 anorexia, grade 3 hypertension, grade 3 transaminase elevation, grade 4 thrombocytopenia, and grade 4 neutropenia.
• The NHL patients enrolled on study were heavily pre-treated, with 85 percent of patients having received three or more prior therapies and 37 percent of patients having received more than five or more prior therapies. Thirty-seven percent of patients were refractory to their last prior regimen and 26 percent of patients had received a prior autologous hematopoietic stem cell transplant.
• Drug pharmacokinetics showed rapid absorption with a mean terminal half-life of three to five hours. Cmax and AUC1-12hr were dose proportional at steady-state throughout the dosing range. Steady-state Ctrough levels were reached by day 15.
• • On March 3, 2015, Epizyme announced that updated data from the ongoing Phase 1 dose escalation study of EPZ-6438 (referred to as E7438 by Epizyme's partner Eisai) were presented by Vincent Ribrag, M.D., Institut Gustave Roussy at the 13th International Congress on Targeted Anticancer Therapies in Paris, France. In his presentation, Professor Ribrag principally reviewed the EPZ-6438 dose escalation data that were previously presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in November 2014 , including safety and efficacy data as of an October 20, 2014 data cut-off. Professor Ribrag also presented the following updates to the earlier data:
• Following a review of the data presented in November 2014 , the response in one patient with an INI1-deficient malignant rhabdoid tumor that had previously been classified and reported as a partial response was re-classified to a complete response; as of January 23, 2015 , this patient remained on study after 35 weeks
• Four of the 10 evaluable patients with NHL reported on in November 2014 continue on study, with time on study ranging from 29 weeks to 59 weeks as of January 23, 2015
• As reported in November 2014 , all of the NHL patients enrolled in the dose escalation cohorts who underwent central testing had wild-type EZH2, and responses were seen in germinal center origin and non-germinal center origin disease. Epizyme and Eisai are currently enrolling up to 12 additional patients in the expansion cohorts of this Phase 1 trial.
• • On November 20, 2014, Epizyme announced results from the Phase 1 dose escalation study of the investigational EZH2 inhibitor EPZ-6438 (referred to as E7438 by Eisai) administered orally as a single agent in patients with advanced solid tumors and B-cell non-Hodgkin lymphomas. These data have been presented by EORTC Scientific Chair Jean-Charles Soria , M.D., Ph.D., on behalf of study investigator Vincent Ribrag, M.D., both of the Institut Gustave Roussy, at the 26th Annual EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. This open-label, multicenter, Phase 1 study investigated EPZ-6438 as a single agent in patients with advanced B-cell non-Hodgkin lymphomas (diffuse large B-cell lymphoma = 6, follicular lymphoma = 5, marginal zone lymphoma = 1) or advanced solid tumors (colorectal = 4, INI1-deficient malignant rhabdoid tumor = 1, INI1-deficient synovial sarcoma = 1, other solid tumors = 6). The study objectives included establishment of the maximum tolerated or recommended Phase 2 dose, safety, tolerability, pharmacokinetics and preliminary evaluation of anti-tumor activity. Patients on study were heavily pre-treated, with fourteen patients having received between two and four prior therapies and nine having received more than four prior therapies. Five dosing cohorts were studied: 100 mg (n=6), 200 mg (n=3), 400 mg (n=3), 800 mg (n=6) and 1600 mg (n=6).
• As of October 20, 2014 , the following activity was observed in the 20 patients with advanced B-cell NHL or advanced solid tumors who were evaluable for efficacy:
• Four of 10 evaluable NHL patients achieved a partial response (PR) or better, including one complete response (CR).
• Among five evaluable DLBCL patients, three achieved a PR or better: One patient with a PR reported in August 2014 subsequently evolved to a CR upon continued treatment and remains on study at 41 weeks of treatment; one of the two patients who achieved a PR remains on study.
• Among four evaluable patients with follicular lymphoma (FL), one achieved a partial response and remains on study; three achieved stable disease (SD) and of these, two remain on study.
• Confirmatory sequencing in a central laboratory showed all 10 NHL patients evaluable for efficacy had wild-type EZH2, and responses were observed in both germinal center origin and non-germinal center origin disease.
• One patient with an INI1-deficient malignant rhabdoid tumor achieved a PR and remains on study; 10 patients with solid tumors were evaluable for efficacy, including two patients with INI1-deficient solid tumors.
• EPZ-6438 was well tolerated, and the majority of adverse events were Grade 1 or Grade 2.
• Responses were seen across a range of doses to 800 mg BID.
• All 24 patients were evaluated for safety and tolerability as of the safety data cut-off of September 24, 2014 . Twenty of 24 patients were evaluable for efficacy as of October 20, 2014 . EPZ-6438 was administered orally, twice daily in 28-day cycles to all patients.
• The majority of adverse events were Grade 1 or Grade 2. Adverse events occurring in more than 10 percent of patients were asthenia, decreased appetite and nausea. The only Grade 3 or Grade 4 treatment-related adverse event observed was Grade 4 thrombocytopenia in one patient at 1600 mg, which met the criteria for a dose-limiting toxicity. No AEs required treatment withdrawal or dose reduction; however, three AEs resulted in dose interruption.
• EPZ-6438 was rapidly absorbed and eliminated, with a terminal half-life of three to six hours. In addition, H3K27Me3 inhibition in the skin, a marker of biologic activity, was correlated to treatment exposure, with near maximal inhibition predicted by pharmacokinetic exposure at 800 mg. Among patients with non-Hodgkin lymphoma, clinical activity of EPZ-6438 did not require mutation within EZH2, as confirmatory sequencing showed all subjects evaluable for efficacy and analyzed for EZH2 were wild type. In addition, four of the five evaluable DLBCL patients had lymphoma of non-germinal center origin, and responses were observed in both germinal and non-germinal center subtypes. Currently, a Phase 2 dose of 800 mg BID is under consideration. A final recommendation for the Phase 2 dose will be approved by the Data Monitoring Committee based on efficacy, safety, and PK/PD parameters.
• • On October 1, 2014, Epizyme announced, in conjunction with its development partner Eisai, that clinical data from the ongoing Phase 1 study of EPZ-6438 (E7438), an oral, small molecule inhibitor of EZH2, will be featured in a late-breaking oral presentation at the 26th EORTC-AACR-NCI Symposium on Molecular Targets and Cancer Therapeutics, to be held November 18-21 in Barcelona, Spain.

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