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

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.
Cancer (Oncology), Cancer (Oncology) - Lymphoma
John Pagel, MD, PhD

Swedish Cancer Institute

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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:

    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 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:

    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 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 have histologically confirmed FL. Subjects may have relapsed/refractory disease following at least 2 standard prior treatment regimens, including at least 1 anti-CD20-based regimen, as well as alkylating agents (eg, cyclophosphamide or bendamustine), and have no curative option with other available therapies OR have a contra-indication to their use. Subjects with prior ASCT may be included.

    2. 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.
    3. 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. Subjects taking medications that are known potent CYP3A4 inducers/inhibitors (including St. Johns Wort) (see http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm; http://medicine.iupui.edu/clinpharm/ddis/)
  4. Subjects unwilling to remove Seville oranges, grapefruit juice and grapefruit from their diet.
  5. 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.
  6. 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.

  7. 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.
  8. 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.
  9. Prolongation of corrected QT interval using Fridericia's formula (QTcF) to > 480 msec.
  10. Venous thrombosis or pulmonary embolism within the last 3 months before starting tazemetostat.
  11. Active infection requiring systemic therapy.
  12. 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).
  13. Immunocompromised patients, including patients known to be infected with human immunodeficiency virus (HIV).
  14. Any other major illness that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in this study.
  15. Females who are pregnant or breastfeeding.
  16. Subjects who have undergone an organ transplant.

     

    Phase 2 only:

  17. 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.
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