Clinical Trials /

Open-Label, Multicenter, Phase 1/2 Study of Tazemetostat (EZH2 Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects With Adv. Solid Tumors or With B-cell Lymphomas and Tazemetostat in Combination With Prednisolone in Subjects With DLBCL

NCT01897571

Description:

This is a multicenter, open-label, Phase 1/2 study that is being conducted in two parts. The Phase 1 part (closed to accrual as of January 25, 2016) is comprised of dose escalation and expansion parts to establish the MTD and/or the recommended Phase 2 dose (RP2D) when tazemetostat 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 tazemetostat as well as the drug-drug interaction (DDI) potential of tazemetostat are being evaluated. The Phase 2 part was initiated once the MTD and /or RP2D was established. Phase 2 enrolls subjects with DLBCL (Cohorts 1-3 and 6) and FL (Cohorts 4 and 5) for the determination of efficacy and safety of tazemetostat monotherapy (Cohorts 1-5) and of tazemetostat in combination with prednisolone (Cohort 6) with placement determined by centrally confirmed histology, cell of origin (COO), and EZH2 mutation status.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Open-Label, Multicenter, Phase 1/2 Study of Tazemetostat (EZH2 Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects With Adv. Solid Tumors or With B-cell Lymphomas and Tazemetostat in Combination With Prednisolone in Subjects With DLBCL
  • Official Title: An Open-Label, Multicenter, Phase 1/2 Study of Tazemetostat (EZH2 Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects With Advanced Solid Tumors or With B-cell Lymphomas and Tazemetostat in Combination With Prednisolone in Subjects With Diffuse Large B Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: E7438-G000-101
  • NCT ID: NCT01897571

Conditions

  • B-cell Lymphomas (Phase 1)
  • Advanced Solid Tumors (Phase 1)
  • Diffuse Large B-cell Lymphoma (Phase 2)
  • Follicular Lymphoma (Phase 2)
  • Transformed Follicular Lymphoma
  • Primary Mediastinal Large B-Cell Lymphoma

Interventions

DrugSynonymsArms
TazemetostatEPZ-6438, E7438Tazemetostat (formerly known as EPZ-6438 and E7438): Phase 1

Purpose

This is a multicenter, open-label, Phase 1/2 study that is being conducted in two parts. The Phase 1 part (closed to accrual as of January 25, 2016) is comprised of dose escalation and expansion parts to establish the MTD and/or the recommended Phase 2 dose (RP2D) when tazemetostat 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 tazemetostat as well as the drug-drug interaction (DDI) potential of tazemetostat are being evaluated. The Phase 2 part was initiated once the MTD and /or RP2D was established. Phase 2 enrolls subjects with DLBCL (Cohorts 1-3 and 6) and FL (Cohorts 4 and 5) for the determination of efficacy and safety of tazemetostat monotherapy (Cohorts 1-5) and of tazemetostat in combination with prednisolone (Cohort 6) with placement determined by centrally confirmed histology, cell of origin (COO), and EZH2 mutation status.

Trial Arms

NameTypeDescriptionInterventions
Tazemetostat (formerly known as EPZ-6438 and E7438): Phase 1ExperimentalThis portion comprises dose escalation and dose expansion to establish the recommended Phase 2 dose (RP2D) when tazemetostat 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 tazemetostat as well as the drug-drug interaction (DDI) potential of tazemetostat are evaluated. CLOSED TO ENROLLMENT
  • Tazemetostat
Tazemetostat (formerly known as EPZ-6438 and E7438): Phase 2ExperimentalThis portion is restricted to subjects with DLBCL or FL for the determination of efficacy and safety of tazemetostat monotherapy and tazemetostat in combination with prednisolone as defined by histology, cell of origin and EZH2 mutation status.
  • Tazemetostat

Eligibility Criteria

        Inclusion Criteria

        All Subjects:

          1. Phase 1: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

             Phase 2: ECOG performance status of 0 to 2.

          2. Life expectancy ≥ 3 months before starting tazemetostat.

          3. Subjects with Hepatitis B or C are eligible on the condition that subjects have
             adequate liver function as defined by Inclusion Criterion #6 and are hepatitis B
             surface antigen negative and/or have undetectable hepatitis C virus (HCV) RNA.

          4. Adequate renal function defined as calculated creatinine clearance greater than or
             equal to 40 mL/min per the Cockcroft and Gault formula or the local institutional
             standard formula.

          5. Adequate bone marrow function:

               1. Absolute neutrophil count (ANC) ≥750/mm3 (≥0.75 x 10^9/L) - Without growth factor
                  support (filgrastim or pegfilgrastim) for at least 14 days

               2. Platelets greater ≥ 75,000/mm3 (≥75 x 10^9/L) - Evaluated after at least 7 days
                  since last platelet transfusion

               3. Hemoglobin greater than or equal to 9.0 g/dL - May receive transfusion

          6. Adequate liver function:

               1. Total bilirubin less than or equal to 1.5 x the upper limit of normal (ULN)
                  except for unconjugated hyperbilirubinemia of Gilbert's syndrome

               2. Alkaline phosphatase (ALP) (in the absence of bone disease), alanine
                  aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal
                  to 3 x ULN (less than or equal to 5 x ULN if subject has liver metastases)

          7. Time between prior anticancer therapy and first dose of tazemetostat as below:

             a. Cytotoxic chemotherapy - At least 21 days b. Non-cytotoxic chemotherapy (eg. Small
             molecule inhibitor) - At least 14 days c. Nitrosoureas - At least 6 weeks d.
             Monoclonal antibody (ies) - At least 28 days e. Radiotherapy- At least 14 days from
             local site radiation therapy/At least 6 weeks from prior radioisotope therapy/At least
             12 weeks from 50% pelvic or total body irradiation f. High dose therapy with
             autologous hematopoietic cell infusion - At least 60 days g. High dose therapy with
             allogeneic transplant - At least 90 days (if graft versus host disease [GVHD] is
             present, must be < Grade 2) and no prohibited medications per Exclusion Criteria #3)

             Note: Starting at Cycle 1 Day 1, subjects may receive no more than 10 mg of prednisone
             daily (or equivalent corticosteroid, excluding protocol-defined prednisolone dosing
             for subjects enrolled in Cohort 6) when used for treatment of lymphoma related
             symptoms, with the intent to taper by the end of Cycle 1.

          8. Males or females aged ≥ 18 years at the time of informed consent (Phase 2). Males and
             females aged ≥ 16 years at time of informed consent (Phase 1).

          9. Females must not be lactating or pregnant at screening or baseline (as documented by a
             negative beta-human chorionic gonadotropin [beta-hCG] test with a minimum sensitivity
             of 25 IU/L or equivalent units of beta-hCG). A separate baseline assessment is
             required if a negative screening pregnancy test was obtained more than 72 hours before
             the first dose of study drug. All females will be considered to be of childbearing
             potential unless they are postmenopausal (at least 12 months consecutive amenorrheic,
             in the appropriate age group, and without other known or suspected cause) or have been
             sterilized surgically (ie, bilateral tubal ligation, total hysterectomy or bilateral
             oophorectomy, all with surgery at least 1 month before dose). Females of childbearing
             potential must not have had unprotected sexual intercourse within 30 days prior to
             study entry and must agree to use a highly effective method of contraception, from the
             last menstrual period prior to randomization, during Treatment Cycles, and for 30 days
             after the last final dose of study treatment, and have a male partner who uses a
             condom. Highly effective contraception includes:

             a. Double barrier methods of contraception such as condom plus diaphragm or
             cervical/vault cap with spermicide.

             b. Placement of an intrauterine device. c. Established hormonal contraceptive methods:
             oral, injectable, or implant. Females who are using hormonal contraceptives must have
             been on a stable dose of the same hormonal contraceptive product for at least 4 weeks
             prior to dosing and must continue to use the same contraceptive during the study and
             for 30 days after study drug discontinuation.

             Female subjects exempt from this requirement are subjects who practice total
             abstinence or have a male partner who is vasectomized. If currently abstinent, the
             subject must agree to use a highly effective method of contraception as described
             above if they become sexually active during the Treatment Cycles, and for 30 days
             after study drug discontinuation.

         10. Male subjects must have had a successful vasectomy or they and their female partner
             must meet the criteria above (ie, not of childbearing potential or practicing highly
             effective contraception and use a condom throughout the study period and for 30 days
             after study drug discontinuation).

         11. Voluntary agreement to provide written informed consent and the willingness and
             ability to comply with all aspects of the protocol.

             Phase 1 only:

         12. Histologically and/or cytologically confirmed advanced or metastatic solid tumor or
             B-cell lymphomas that have progressed after treatment with approved therapies or for
             which there are no standard therapies available.

             Phase 2 only:

         13. Subjects must satisfy all of the following criteria:

               1. Have histologically confirmed DLBCL (including primary mediastinal B-cell
                  lymphoma), with relapsed or refractory disease following at least 2 lines of
                  prior standard therapy, including alkylator/anthracycline (unless
                  anthracycline-based chemotherapy is contraindicated)/anti-CD20-based therapy
                  (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone
                  [R-CHOP] or equivalent) AND must be considered unable to benefit from
                  intensification treatment with autologous hematopoietic stem cell transplantation
                  (ASCT) as defined by meeting at least 1 of the following criteria:

                    -  Relapsed following, or refractory to, previous ASCT

                    -  Did not achieve at least a partial response to a standard salvage regimen
                       (eg, rituximab, ifosfamide, carboplatin, and etoposide phosphate [R-ICE] or
                       rituximab, dexamethasone, cytarabine, and cisplatin [R-DHAP])

                    -  Ineligible for intensification treatment due to age or significant
                       comorbidity

                    -  Ineligible for intensification treatment due to failure to mobilize an
                       acceptable number of hematopoietic stem cells

                    -  Refused intensification treatment and/or ASCT or b .Have histologically
                       confirmed FL, all grades. Subjects may have relapsed/refractory disease
                       following at least 2 standard prior systemic treatment regimens where at
                       least 1 anti-CD20-based regimen was used. Subjects with prior radiotherapy
                       will be included; however, radiotherapy alone will not be considered a
                       systemic treatment regimen.

             c. Have provided sufficient archival tumor tissue that has been successfully tested
             for EZH2 mutation status and cell of origin (DLBCL only) at study specific
             laboratories allowing for allocation into an open cohort.

             d. Have measurable disease as defined by International Working Group-Non-Hodgkin's
             Lymphoma (IWG-NHL [Cheson, 2007]).

        Exclusion Criteria

        All Subjects:

          1. Prior exposure to tazemetostat or other inhibitor(s) of EZH2.

          2. Subjects with leptomeningeal metastases or brain metastases or history of previously
             treated brain metastases.

          3. Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) and
             any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS).

          4. Has a prior history of T-cell lymphoblastic lymphoma(T-LBL) or T-cell lymphoblastic
             leukemia (T-ALL).

          5. Subjects taking medications that are known potent CYP3A4 inducers/inhibitors
             (including St. Johns Wort) (see
             http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
             onsLabeling/ucm080499.htm; http://medicine.iupui.edu/clinpharm/ddis/)

          6. Subjects unwilling to remove Seville oranges, grapefruit juice and grapefruit from
             their diet.

          7. Any prior treatment-related (i.e. chemotherapy, immunotherapy, radiotherapy)
             clinically significant toxicities have not resolved to ≤ Grade 1 per CTCAE version
             4.03 or prior treatment-related toxicities are clinically unstable and clinically
             significant at time of enrollment.

          8. Major surgery within 4 weeks before the first dose of study drug.

             Note: Minor surgery (eg. minor biopsy of extracranial site, central venous catheter
             placement, shunt revision) is permitted within 3 weeks prior to enrollment.

          9. Inability to take oral medication, or malabsorption syndrome or any other uncontrolled
             gastrointestinal condition (e.g., nausea, diarrhea, or vomiting) that might impair the
             bioavailability of tazemetostat.

         10. Significant cardiovascular impairment: history of congestive heart failure greater
             than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension,
             unstable angina, myocardial infarction, or stroke within 6 months of the first dose of
             study drug; or cardiac ventricular arrhythmia.

         11. Prolongation of corrected QT interval using Fridericia's formula (QTcF) to > 480 msec.

         12. Venous thrombosis or pulmonary embolism within the last 3 months before starting
             tazemetostat.

         13. Active infection requiring systemic therapy.

         14. Known hypersensitivity to any component of tazemetostat, prednisolone/prednisone
             (combination cohort only), or inability to be treated with a Pneumocystis prophylaxis
             medication (combination cohort only).

         15. Immunocompromised patients, including patients known to be infected with human
             immunodeficiency virus (HIV).

         16. Any other major illness that, in the investigator's judgment, will substantially
             increase the risk associated with the subject's participation in this study.

         17. Females who are pregnant or breastfeeding.

         18. Subjects who have undergone an organ transplant.

             Phase 2 only:

         19. Subjects with noncutaneous malignancies other than B-cell lymphomas. Exception:
             Subjects with another malignancy who have been disease-free for 5 years, or subjects
             with a history of a completely resected non-melanoma skin cancer or successfully
             treated in situ carcinoma are eligible.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) (Phase 1 only)
Time Frame:28 day cycle of therapy
Safety Issue:
Description:To determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of tazemetostat as a single agent administered orally twice daily (BID), continuously in 28-day cycles in subjects with advanced solid tumors or with relapsed and/or refractory B cell lymphomas

Secondary Outcome Measures

Measure:The effect of a high fat meal on the bioavailability of tazemetostat (Phase 1)
Time Frame:28 day cycle of therapy
Safety Issue:
Description:
Measure:The effect of tazemetostat on exposure of midazolam, a CYP3A4 substrate
Time Frame:28 day cycle of therapy
Safety Issue:
Description:
Measure:To assess the preliminary activity of tazemetostat (Phase 1)
Time Frame:28 day cycle of therapy
Safety Issue:
Description:
Measure:The effect of tazemetostat monotherapy and tazemetostat in combination with prednisolone on progression-free survival (PFS) (Phase 2)
Time Frame:From date of enrollment until the date of first documented progression of disease, or date of death from any cause
Safety Issue:
Description:
Measure:The effect of tazemetostat monotherapy and tazemetostat in combination with prednisolone on duration of response (DOR) (Phase 2)
Time Frame:From date of enrollment until the date of first documented progression of disease, or date of death from any cause
Safety Issue:
Description:
Measure:The safety and tolerability of tazemetostat monotherapy and tazemetostat in combination with prenisolone (Phase 1 and Phase 2)
Time Frame:28 day cycle of therapy
Safety Issue:
Description:
Measure:The pharmacokinetic (PK) profile of tazemetostat monotherapy and tazemetostat in combination with prednisolone (Phase 1 and Phase 2)
Time Frame:28 day cycle of therapy
Safety Issue:
Description:
Measure:The effect of tazemetostat monotherapy and tazemetostat in combination with prednisolone on overall survival (OS)
Time Frame:From the date of first dose until the date of death from any cause.
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Epizyme, Inc.

Last Updated