Clinical Trials

Inclusion Criteria:

• Have voluntarily agreed to provide written informed consent and demonstrated willingness and ability to comply with all aspects of the protocol. Study related activities will not start until written consent is obtained.
• Phase 1b dose escalation cohort patients must be 18 – 65 years old at the time of providing voluntary written informed consent.
• Phase 3 or any Phase1b dose expansion patients must be ≥ 18 years old.
• Life expectancy ≥ 3 months before enrollment.
• Phase 1b: Have histologically confirmed STS.
• Phase 3: Morphology and immunophenotypic panel consistent with ES (eg, CD34, epithelial membrane antigen [EMA], Keratin, and integrase interactor 1 [INI1]). Subjects must have unresectable locally advanced or metastatic ES.
• Phase 3: Have sufficient tumor tissue (approximately 10 to 20 unstained slides, each with 5- micron thick tissue sections or an equivalent tumor block) available for central confirmatory testing of immunohistochemistry (IHC) and/or cytogenetics/fluorescence in situ hybridization (FISH) and/or DNA mutation analysis (required for study entry but enrollment based on local results).
• Have measurable disease as defined by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).
• ECOG performance status of 0, 1, or 2.
• Have adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function as defined by criteria below:
• Hematologic function (BM Function)
  • Hemoglobin* ≥ 9 g/dL
  • Platelets** ≥ 100 000/mm^3 (≥ 100 × 10^9 /L)
  • ANC*** ≥ 1000/mm^3 (≥ 1.0 × 10^9 /L)
• Hematologic function (Coagulation Factors)
  • INR/PT**** < 1.5 ULN
  • PTT < 1.5 ULN
• Renal function
  • Serum creatinine***** ≤ 1.5 × ULN
• Hepatic function
  • Total bilirubin****** < 1× ULN
  • AST******* < 3 × ULN
  • ALT******* < 3 × ULN

Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BM = bone marrow; INR = international normalized ratio; PT = prothrombin time; PTT = partial thromboplastin time; ULN = upper limit of normal.

*    May receive transfusion.
**   Should be evaluated after at least 7 days since last platelet transfusion.
***  Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days.
**** INR is the preferred value to be measured. However, if only PT can be performed in the testing laboratory that is acceptable.
***** If creatinine is not ≤ 1.5×ULN, then creatinine clearance must be > 50 mL/min/1.73 m^2 (as calculated by CockcroftGault methods or local institutional standard).
****** If attributed to documented Gilbert’s disease, total bilirubin < 2.5 × ULN. Eligibility can be determined by total or conjugated bilirubin.
****** If attributed to tumor involvement, AST and ALT < 5 × ULN.

• Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin [β-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of β-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 treatment. All females will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months consecutively amenorrheic, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
• 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 screening, during treatment cycles, and for 6 months after the final dose of study treatment and have a male partner who uses a condom. Highly effective contraception includes:
  • Placement of an intrauterine device;
  • 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 while enrolled on trial and must continue to use the same contraceptive during the study and for 6 months after doxorubicin or tazemetostat discontinuation.
• Male subjects must have had either 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 6 months after doxorubicin or tazemetostat discontinuation.
• Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to participate in the study if they meet the following criteria:
  • No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections or have not had an opportunistic infection within the past 12 months prior to enrollment;
  • No history of AIDS-defining cancers (e.g., Kaposi’s sarcoma, aggressive B-cell lymphoma, and invasive cervical cancer);
  • Subjects may take prophylactic antimicrobials, however subjects that are taking specific antimicrobial drugs where there may be drug-drug interaction or overlapping toxicities should be excluded from study participation;
  • Subjects should be on established anti-retroviral therapy for at least 4 weeks and have an HIV viral load of < 400 copies/mL prior to enrollment.

Exclusion Criteria:

• Prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2).
• Prior systemic anticancer therapy.
• Subjects must not have any of the contraindications noted in the local doxorubicin label (i.e., Summary of Product Characteristics [SmPc] or United States Prescribing Information [USPI]).
• Have any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
• Have prior history of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (TLBL/T-ALL).
• Have participated in another interventional clinical study and received investigational drug within 30 days or 5 half-lives, whichever is longer, prior to the planned first dose of study treatment.
• Have known active central nervous system (CNS) or any leptomeningeal metastasis of primary extracranial tumor. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging 4 weeks prior to the first dose of study treatment and any neurologic symptoms have stabilized), have no evidence of new or enlarging brain metastases, and are on stable or tapering doses of steroids for at least 7 days prior to first dose of study treatment.
  • NOTE:  Subjects with asymptomatic brain metastases found on screening magnetic resonance imaging (MRI) may be entered into the study without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy in the opinion of the treating Investigator and in the opinion of a radiation therapy or neurosurgical consultant.
• Subjects taking medications that are known potent cytochrome P450 (CYP)3A4 inducers/inhibitors (including St. John’s Wort) http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio nsLabeling/ucm080499.htm; https://drug-interactions.medicine.iu.edu/MainTable.aspx.
• Are unwilling to exclude Seville oranges, grapefruit juice, AND grapefruit from the diet and all foods that contain those fruits from time of enrollment to through the duration of study participation.
• Major surgery within 4 weeks before the first dose of study treatment. Subjects must have recovered from surgery prior to enrollment to this study.
• Are unable to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, vomiting) that might impair the bioavailability of study treatment.
• Has either a shortening fraction of 150 mm Hg and/or diastolic BP > 110 mm Hg), unstable angina, myocardial infarction, or stroke within 6 months prior to the planned first dose of tazemetostat; or ventricular cardiac arrhythmia requiring medical treatment.
• Prolongation of corrected QT interval using Fridericia’s formula (QTcF) to > 480 msec.
• Have an active infection requiring systemic therapy.
• Are immunocompromised (i.e., has a congenital immunodeficiency).
• Have known hypersensitivity to any component of tazemetostat or doxorubicin.
• Have a known active infection with hepatitis B virus (HBV, as measured by positive hepatitis B surface antigen), hepatitis C virus (HCV, as measured by positive hepatitis C antibody). EXCEPTIONS: Subjects with a history of hepatitis B or C who have normal alanine aminotransferase (ALT) AND are hepatitis B surface antigen negative and/or have undetectable HCV RNA are eligible.
• Any other major illness that, in the Investigator’s judgment, will substantially increase the risk associated with the subject’s participation in this study OR interfere with their ability to receive study treatment or complete the study.
• Female subjects who are pregnant or breastfeeding.
• Subjects who have undergone a solid organ transplant.
• Subjects with malignancies other than STS (phase 1b) or ES (Phase 3 only).
  • EXCEPTIONS: 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.
• Subjects housed in an institution by order of the authorities or courts.

Eligibility last updated 1/11/22. Questions regarding updates should be directed to the study team contact.