Open-Label, Multicenter, Two-Part, Phase 1 Study to Characterize Effects of a Moderate CYP3A Inhibitor on PK of Tazemetostat, Effects of Tazemetostat on PK of CYP2C8 and CYP2C19 Substrates, and Effect of Increased Gastric pH on PK of Tazemetostat in B-cell Lymphoma or Advanced Solid Tumor Patients
Condition: Diffuse Large B Cell Lymphoma; Primary Mediastinal Lymphoma; Mantle Cell Lymphoma; Advanced Solid Tumor; Marginal Zone Lymphoma
MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Mantle-Cell; Lymphoma, Large B-Cell, Diffuse
Intervention: Tazemetostat; Fluconazole; Omeprazole; Repaglinide
Intervention description: Tazemetostat is a selective oral small molecule inhibitor of EZH2; 200mg will be orally administered QD for 4 days in order to determine CYP3A4 inhibition when administered concomitantly with tazemetostat; Using omeprazole as a probe substrate, 20mg will be orally administered for a total of 5 days in order to determine the potential of tazemetostat to inhibit or induce CYP2C19. Omeprazole is also being used to determine the effect of increased gastric pH on metabolism of tazemetostat.; Using repaglinide as a probe substrate, 25mg will be orally administered for a total of 2 days in order to determine the potential of tazemetostat to inhibit or induce CYP2C8.
Intervention MeSH terms: Repaglinide; Fluconazole; Omeprazole
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a Phase 1, open-label, two-part, safety, PK, and activity study designed to
      characterize the DDI potential of tazemetostat. Tazemetostat will be taken orally BID
      continuously in 28-day cycles in both study parts.
    

Eligibility criteria:

        Inclusion criteria

          1. Male or female ≥ 18 years of age at time of consent

          2. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

          3. Has the ability to understand informed consent and provided signed written informed
             consent

             Must meet one of the following criteria:

          4. Has histologically confirmed diffuse large B-cell lymphoma (DLBCL), primary
             mediastinal B-cell lymphoma (PMBCL), marginal zone lymphoma (MZL), mantle cell
             lymphoma (MCL) and have relapsed or refractory disease following at least two lines of
             prior standard therapy, including alkylator/anthracycline (unless anthracycline-based
             chemotherapy is contraindicated)/anti-CD20-based therapy (R-CHOP; rituximab,
             doxorubicin, cyclophosphamide, vincristine, and prednisolone or prednisone, 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 one of the following criteria:

               1. Relapsed following, or refractory to, previous ASCT

               2. Did not achieve at least a partial response (PR) to a standard salvage regimen
                  (e.g., R-ICE; rituximab, ifosfamide, carboplatin, etoposide, or R-DHAP;
                  rituximab, dexamethasone, cytarabine, cisplatin)

               3. Ineligible for intensification treatment due to age or significant comorbidity

               4. Ineligible for intensification treatment due to failure to mobilize an acceptable
                  number of hematopoietic stem cells

               5. Refused intensification treatment and/or ASCT Note: Subjects with prior
                  radiotherapy will be included; however, radiotherapy alone will not be considered
                  a separate systemic treatment regimen.

             Note: Subjects with prior radiotherapy will be included; however, radiotherapy alone
             will not be considered a separate systemic treatment regimen.

             OR

          5. Has histologically confirmed FL, all grades. Subjects must have relapsed/refractory
             disease following at least 2 standard lines of systemic therapy, including at least 1
             anti-CD20-based regimen (eg, rituximab), as well as alkalating 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. Transformed disease is permitted.

             Note: Subjects with prior radiotherapy will be included; however, radiotherapy alone
             will not be considered a separate systemic treatment regimen.

             OR

          6. Histologically and/or cytologically confirmed advanced or metastatic solid tumor that
             has progressed after treatment with approved therapies or for which there are no
             standard therapies available

          7. Must have evaluable or measurable disease

          8. Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related
             clinically significant toxicities resolve to ≤ Grade 1 per NCI CTCAE, Version 4.03 or
             are clinically stable and not clinically significant, at time of consent

          9. Time required between the last dose of the latest therapy and the first dose of study
             drug:

               1. Chemotherapy: cytotoxic At least 21 days

               2. Chemotherapy: nitrosoureas At least 6 weeks

               3. Chemotherapy: non-cytotoxic (e.g., small molecule inhibitor) At least 14 days

               4. Monoclonal antibody (ies) At least 28 days

               5. Non-antibody immunotherapy (e.g., tumor vaccine) At least 42 days

               6. At least 14 days for stereotactic radiosurgery

               7. At least 12 weeks for craniospinal, ≥50% radiation of pelvis, or total body
                  irradiation prior to first dose of study drug

               8. Autologous hematopoietic cell infusion after high dose therapy At least 60 days

               9. Hematopoietic growth factor At least 14 days

         10. Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic
             function

               1. Hemoglobin ≥9 g/dL

               2. Platelets ≥75,000/mm3 (≥75 × 10^9/L)

               3. ANC: for patients with lymphoma ≥750/mm3 (≥0.75 × 10^9/L), for patients with
                  advanced solid tumors ≥1,000/mm3 (≥1.0 × 10^9/L),

               4. PT <1.5 ULN

               5. PTT <1.5 ULN

               6. eGFR ≥ 50 mL/min/1.73 m2

               7. Conjugated bilirubin <1.5 × ULN

               8. AST <3 × ULN

               9. ALT <3 × ULN

             NOTE: Laboratory results obtained during screening should be used to determine
             eligibility criteria. In situations where laboratory results are outside the permitted
             range, the investigator may retest the subject and the subsequent within range
             screening result may be used to determine the subject's eligibility.

         11. Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec

         12. Subjects with a history of Hepatitis B or C are eligible on the condition that
             subjects have adequate liver function as defined by the protocol and are hepatitis B
             surface antigen negative and/or have undetectable HCV RNA.

         13. Male subjects must refrain from donating sperm starting at the planned first dose of
             investigational product (IP) until 30 days following the last dose of IP

         14. Male subjects with a female partner of childbearing potential must:

               1. Be vasectomized, or

               2. Remain abstinent or use a condom as defined in Section 8.3.8.4.2, starting at the
                  planned first dose of IP until 30 days following the last dose of IP. The
                  reliability of sexual abstinence should be evaluated in relation to the duration
                  of the clinical trial and the preferred and usual lifestyle of the subject.
                  Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, or post-ovulation
                  methods) and withdrawal are not acceptable methods of contraception.

         15. Female partners of male subjects who are of childbearing potential must also adhere to
             one of the following:

               1. Placement of an intrauterine device or intrauterine system.

               2. Established use of oral, injected, or implanted hormonal methods of contraception
                  or use of a barrier method of contraception.

               3. Progesterone only oral contraception, where inhibition of ovulation is not the
                  primary mode of action.

         16. Women of childbearing potential or female partners of male subjects must abide by the
             contraception measures defined by the protocol

        Exclusion criteria:

          1. Is pregnant or nursing

          2. Has active central nervous system (CNS) or leptomeningeal metastasis

          3. Has had a prior malignancy other than the malignancies under study Exception: Subject
             who has been disease-free for 3 years, or a subject with a history of a completely
             resected non-melanoma skin cancer or successfully treated in situ carcinoma are
             eligible.

          4. Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) and
             any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS).

             NOTE: Bone marrow aspirate/biopsy will be conducted following abnormal peripheral
             blood smear morphology assessment conducted by the local laboratory. Cytogenetic
             testing and DNA sequencing will be conducted following an abnormal result of bone
             marrow aspirate/biopsy.

          5. Has a prior history of T-LBL/T-ALL.

          6. Has had major surgery within 3 weeks prior to enrollment NOTE: Minor surgery (e.g.,
             minor biopsy, central venous catheter placement) is permitted within 3 weeks prior to
             enrollment.

          7. Is unwilling to exclude grapefruit juice, Seville oranges, and grapefruit from the
             diet and all foods that contain those fruits from time of enrollment to while on study

          8. Has cardiovascular impairment, history of congestive heart failure greater than NYHA
             Class II uncontrolled arterial hypertension, unstable angina, myocardial infarction,
             or stroke within 6 months prior to the planned first dose of tazemetostat; or
             ventricular cardiac arrhythmia requiring medical treatment

          9. Subjects taking medications that are known potent or moderate inducers/ inhibitors of
             CYP3A4 (including St. John's Wort)

         10. Has an active infection or recent history (<30 days before study drug administration)
             requiring systemic treatment

         11. Is immunocompromised, including subjects with known human immunodeficiency virus (HIV)
             infection

         12. Has known hypersensitivity to any of the components of IP.

         13. Is unable to take oral medications, has a history of surgery that would interfere with
             the administration or absorption of oral medication, has malabsorption syndrome or any
             other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea or vomiting)
             that might impair the bioavailability of IP

         14. Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled
             infection, or psychiatric illness/social situations that would limit compliance with
             study requirements.

         15. Is unwilling to adhere to contraception criteria from time of enrollment in study to
             at least 30 days after last dose of IP.

         16. A history of bleeding (i.e., hemoptysis, hematuria, gastrointestinal blood loss,
             epistaxis, or others with greater than Grade 1 according to NCI CTCAE Version 4.03)
             within 1 month prior to beginning therapy or any clinical indications of current
             active bleeding.

         17. Clinical history, current alcohol (ethanol), or illicit drug use which, in the
             judgment of the investigator, will interfere with the subject's ability to comply with
             the dosing schedule and protocol-specified evaluations.

         18. Regular alcohol consumption averaging more than seven drinks/week for women and 14
             drinks/week for men within 6 months of screening.