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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

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ClinicalTrials.gov Identifier: NCT01897571
Recruitment Status : Active, not recruiting
First Posted : July 12, 2013
Last Update Posted : January 7, 2021
Sponsor:
Information provided by (Responsible Party):
Epizyme, Inc.

Tracking Information
First Submitted Date  ICMJE June 21, 2013
First Posted Date  ICMJE July 12, 2013
Last Update Posted Date January 7, 2021
Study Start Date  ICMJE June 2013
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 28, 2017)
  • Maximum tolerated dose (MTD) (Phase 1 only) [ Time Frame: 28 day cycle of therapy ]
    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
  • Objective response rate (ORR; complete response + partial response [CR + PR]) (Phase 2) [ Time Frame: Every 8 weeks or sooner, if clinically indicated, until documentation of disease. ]
    To determine the objective response rate (ORR; complete response + partial response [CR + PR]) of tazemetostat in subjects with enhancer of zeste homolog 2 (EZH2) gene mutation positive or negative (wild-type) with histologically confirmed diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL), with relapsed or refractory disease and the ORR of tazemetostat in combination with prednisolone in subjects with EZH2 wild-type DLBCL
Original Primary Outcome Measures  ICMJE
 (submitted: July 9, 2013)
  • Maximum tolerated dose (MTD) [ Time Frame: 28 day cycle of therapy ]
    The MTD will be determined based on the incidence of Dose-Limiting Toxicities (DLT) in Cycle 1, although toxicities occurring during subsequent cycles will also be reviewed. If serious toxicities are observed at this dose level in later cycles, a reduction of the MTD may be considered.
  • Objective response rate (ORR; complete response + partial response [CR + PR]) [ Time Frame: From date of randomization until the date of first documented progression of disease, date of death from any cause, or a minimum of 6 cycles. Subjects were followed for an average of 5 years. ]
    Every 8 weeks or sooner, if clinically indicated, until documentation of disease progression, development of unacceptable toxicity that leads to E7438 treatment withdrawal, or withdrawal of consent either for treatment or the entire study. Subjects who discontinue study treatment for reasons other than disease progression will be followed until disease progression, death, or initiation of another anticancer therapy.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 5, 2021)
  • The effect of a high fat meal on the bioavailability of tazemetostat (Phase 1) [ Time Frame: 28 day cycle of therapy ]
  • The effect of tazemetostat on exposure of midazolam, a CYP3A4 substrate [ Time Frame: 28 day cycle of therapy ]
  • To assess the preliminary activity of tazemetostat (Phase 1) [ Time Frame: 28 day cycle of therapy ]
  • 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 ]
  • 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 ]
  • The effect of tazemetostat monotherapy on overall survival (Cohorts 4 and 5 only) [ Time Frame: From the date of first dose until the date of death from any cause. ]
  • 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 ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: July 9, 2013)
  • Food effect of a high fat meal on the bioavailability of E7438 [ Time Frame: Day -8 and -1, Cycle 1 (Day 1 and 15), Cycle 2 (Day 1) ]
    PK profile, after MTD is identified.
  • Effect of E7438 on exposure of midazolam, a CYP3A4 substrate [ Time Frame: Day -1, Cycle 1 (Day 15), Cycle 2 (Day 1) ]
    PK profile, after enrollment into the Food Effect Cohort is completed.
  • Progression-free survival (PFS) [ Time Frame: From date of randomization until the date of first documented progression of disease, date of death from any cause, or a minimum of 6 cycles. Subjects were followed for an average of 5 years. ]
    Every 8 weeks or sooner, if clinically indicated, until documentation of disease progression, development of unacceptable toxicity that leads to E7438 treatment withdrawal, or withdrawal of consent either for treatment or the entire study. Subjects who discontinue study treatment for reasons other than disease progression will be followed until disease progression, death, or initiation of another anticancer therapy.
  • Disease Control Rate (DCR: complete response [CR] + partial response [PR] + stable disease[SD]) [ Time Frame: From date of randomization until the date of first documented progression of disease, date of death from any cause, or a minimum of 6 cycles. Subjects were followed for an average of 5 years. ]
    Every 8 weeks or sooner, if clinically indicated, until documentation of disease progression, development of unacceptable toxicity that leads to E7438 treatment withdrawal, or withdrawal of consent either for treatment or the entire study. Subjects who discontinue study treatment for reasons other than disease progression will be followed until disease progression, death, or initiation of another anticancer therapy.
  • Clinical Benefit Rate (CBR: CR or PR or durable SD) [ Time Frame: From date of randomization until the date of first documented progression of disease, date of death from any cause, or a minimum of 6 cycles. Subjects were followed for an average of 5 years. ]
    Durable SD is considered greater than or equal to 23 weeks. Every 8 weeks or sooner, if clinically indicated, until documentation of disease progression, development of unacceptable toxicity that leads to E7438 treatment withdrawal, or withdrawal of consent either for treatment or the entire study. Subjects who discontinue study treatment for reasons other than disease progression will be followed until disease progression, death, or initiation of another anticancer therapy.
  • Pharmacokinetics (PK) profile of E7438 characterizing the absorption, distribution, metabolism, and elimination properties of the drug [ Time Frame: Cycle 1 (Day 1 and 15), Cycle 2 (Day 1) ]
    Plasma and urine concentrations of E7438 will be tabulated and summarized by dose level, day and time. E7438 PK parameters will be derived from plasma concentrations by noncompartmental analysis using actual times.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
Brief Summary 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) comprised dose escalation and expansion parts to establish the MTD and/or the recommended Phase 2 dose (RP2D) when tazemetostat was 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 were 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 1-5and of tazemetostat in combination with prednisolone (Cohort 6) with placement determined by centrally confirmed histology, cell of origin (COO), and EZH2 mutation status.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE Drug: Tazemetostat
Other Names:
  • EPZ-6438
  • E7438
Study Arms  ICMJE
  • Experimental: Tazemetostat (formerly known as EPZ-6438 and E7438): Phase 1
    This 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
    Intervention: Drug: Tazemetostat
  • Experimental: Tazemetostat (formerly known as EPZ-6438 and E7438): Phase 2
    This 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.
    Intervention: Drug: Tazemetostat
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: March 28, 2017)
420
Original Estimated Enrollment  ICMJE
 (submitted: July 9, 2013)
154
Estimated Study Completion Date  ICMJE May 2021
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 ≥40 mL/min per the Cockcroft and Gault formula or the local institutional standard formula.
  5. Adequate bone marrow function:

    a. Absolute neutrophil count (ANC) ≥750/mm^3 (≥0.75 x 10^9/L) - Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days

    b. Platelets greater ≥ 75,000/mm^3 (≥75 x 10^9/L) - Evaluated after at least 7 days since last platelet transfusion

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

  6. Adequate liver function:

    1. Total bilirubin ≤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) ≤3 x ULN (≤5 x ULN if subject has liver metastases)
  7. Time between prior anticancer therapy and first dose of tazemetostat as below:

    1. Cytotoxic chemotherapy - At least 21 days
    2. Non-cytotoxic chemotherapy (eg. Small molecule inhibitor) - At least 14 days
    3. Nitrosoureas - At least 6 weeks
    4. Monoclonal antibody (ies) - At least 28 days
    5. 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
    6. High dose therapy with autologous hematopoietic cell infusion - At least 60 days
    7. 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 or 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 6 months after the last final dose of study drug; any male partner must use a condom. Highly effective contraception is one that results in a failure rate of <1% per year when used consistently and correctly and includes:

    1. Double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide.
    2. Placement of an intrauterine device.
    3. 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 6 months 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 6 months after study drug discontinuation.

  10. Male subjects must have had a successful vasectomy (with confirmed azoospermia) 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 3 months after study drug discontinuation). Nonvasectomized male subjects must also agree to refrain from donating sperm from first dose of tazemetostat until 3 months following the last dose of tazemetostat.
  11. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.
  12. Phase 1 only: 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.
  13. Phase 2, Cohorts 1-6 only: 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 strong CYP3A inhibitors and strong or moderate CYP3A inducers (including St. Johns Wort) (see http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/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 that have not resolved to ≤ Grade 1 per CTCAE version 4.03 or prior treatment-related toxicities that 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.
  19. Phase 2 only: 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   France,   Germany,   Italy,   Poland,   Taiwan,   Ukraine,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01897571
Other Study ID Numbers  ICMJE E7438-G000-101
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Epizyme, Inc.
Study Sponsor  ICMJE Epizyme, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Epizyme, Inc.
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP