The open-label phase 1b portion is designed to evaluate the safety of the combination of
tazemetostat + doxorubicin, as well as to establish the maximum tolerated dose (MTD) and the
RP3D. The phase 3 portion of the clinical trial aims to compare tazemetostat + doxorubicin to
the current front-line standard treatment, single-agent doxorubicin + placebo, when used as
first-line treatment in locally advanced unresectable or metastatic ES.
1. Have voluntarily agreed to provide written informed consent and demonstrated
willingness and ability to comply with all aspects of the protocol.
2. Are aged 18 years at the time of providing voluntary written informed consent.
informed consent. 18 years at the time of providing voluntary written informed
3. Life expectancy 3 months before enrollment. 3 months before enrollment.
4. Phase 1b: Have histologically confirmed STS.
5. Phase 3: Have histologically confirmed epithelioid sarcoma, with loss of INI1 or
SMARCA4 confirmed by IHC, or molecular confirmation of tumor bi-allelic INI1 or
SMARCA4 loss or mutation when INI1 or SMARCA4 IHC is equivocal or unavailable
6. Have measurable disease as defined by the Response Evaluation Criteria in Solid
7. ECOG performance status of 0, 1, or 2.
8. Females must not be lactating or pregnant at Screening or Baseline
9. 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 final dose of study treatment, and have a male
partner who uses a condom.
10. 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 discontinuation or 30 days after oral study treatment
[tazemetostat or placebo] discontinuation, whichever is later).
11. Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to participate
in the study if they meet the following criteria:
1. No history of AIDS-defining opportunistic infections or have not had an
opportunistic infection within the past 12 months prior to enrollment.
2. No history of AIDS-defining cancers (eg Kaposi's sarcoma, aggressive B-cell
lymphoma, and invasive cervical cancer).
3. 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.
4. 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.
1. Prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2
2. Prior systemic anticancer therapy.
3. Subjects must not have any of the contraindications noted in the local doxorubicin
label (ie, Summary of Product Characteristics [SmPc] or United States Prescribing
4. Have any prior history of myeloid malignancies, including myelodysplastic syndrome
(MDS) or acute myeloid leukemia (AML).
5. Have prior history of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic
6. 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.
7. 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
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
8. Subjects taking medications that are known potent cytochrome P450 (CYP)3A4
inducers/inhibitors (including St. John's Wort)
9. 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 while on
10. Major surgery within 4 weeks before the first dose of study treatment. Subjects must
have recovered from surgery prior to enrollment to this study.
11. 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.
12. Has either a shortening fraction of <27% or an ejection fraction of ≤50% by either
echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan, and has heart failure
greater than New York Heart Association (NYHA) Class II.
13. Has cardiovascular impairment: history of congestive heart failure greater than NYHA
Class II, uncontrolled arterial hypertension (ie, systolic BP >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.
14. Prolongation of corrected QT interval using Fridericia's formula (QTcF) to > 480 msec.
15. Venous thrombosis or pulmonary embolism within the last 1 month before starting study
16. Have an active infection requiring systemic therapy.
17. Are immunocompromised (ie, has a congenital immunodeficiency), including subjects with
known history of infection with human immunodeficiency virus (HIV).
18. Have known hypersensitivity to any component of tazemetostat or doxorubicin.
19. 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), human immunodeficiency virus, OR human T-cell lymphotropic virus 1.
20. 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.
21. Female subjects who are pregnant or breastfeeding.
22. Subjects who have undergone a solid organ transplant.
23. Subjects with malignancies other than STS (phase 1b) or ES (Phase 3 only).