| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Phase 1b: Have histologically confirmed Soft tissue sarcoma (STS).
Phase 3: Morphology and immunophenotypic panel consistent with epithelioid sarcoma (eg, CD34, epithelial membrane antigen [EMA], Keratin, and INI1). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Soft tissue sarcoma and epithelioid sarcoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10015100 |
| E.1.2 | Term | Epithelioid sarcomas |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075333 |
| E.1.2 | Term | Soft tissue sarcoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1b: Evaluate the safety and tolerability of tazemetostat in combination with doxorubicin in subjects with advanced STS and select a dose for further evaluation in phase 3 (the RP3D)
Phase 3: Evaluate and compare the PFS by independent review committee in subjects with advanced ES treated with tazemetostat + doxorubicin versus placebo + doxorubicin |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b: Assess the PK of tazemetostat when administered in combination with doxorubicin in subjects with STS
Phase 3:
Key secondary objective: 1. Evaluate and compare the OS of tazemetostat + doxorubicin versus placebo + doxorubicin in subjects with advanced ES 2.Evaluate and compare the DCR in subjects with advanced ES treated with tazemetostat + doxorubicin or placebo + doxorubicin 3. Evaluate and compare the ORR of tazemetostat + doxorubicin versus placebo + doxorubicin in subjects with advanced ES 4. Evaluate and compare the DOR in subjects with advanced ES treated with tazemetostat + doxorubicin or placebo + doxorubicin 5. Assess health-related QoL as measured by EORTC-QLQ-C30 instrument in subjects with locally advanced ES treated with tazemetostat+doxorubicin vs placebo+doxorubicin.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have voluntarily agreed to provide written informed consent and demonstrated willingness and ability to comply with all aspects of the protocol.
2. Phase 1b dose escalation cohort patients must be 18 – 65 years old at the time of providing voluntary written informed consent.
3. Phase 3 or any Phase1b dose expansion patients must be ≥18 years old.
4. Life expectancy ≥ 3 months before enrollment.
5. Phase 1b: Have histologically confirmed STS.
6. Phase 3: Morphology and immunophenotypic panel consistent with epithelioid sarcoma (eg, CD34, epithelial membrane antigen [EMA], Keratin, and INI1).
7. 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).
8. Have measurable disease as defined by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).
9. ECOG performance status of 0, 1, or 2.
10. Have adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function as defined in the protocol
11. 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 (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
12. 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.
13. 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.
14. Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to participate in the study if they meet the following criteria:
a. No history of AIDS-defining opportunistic infections or have not had an opportunistic infection within the past 12 months prior to enrollment.
b. No history of AIDS-defining cancers (eg Kaposi’s sarcoma, aggressive B-cell lymphoma, and invasive cervical cancer).
c. 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.
d. 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. |
|
| E.4 | Principal exclusion criteria |
1. Prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2).
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 Information [USPI]).
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 leukemia (T-LBL/T-ALL).
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 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.
8. 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/DrugInteractionsLabeling/ucm080499.htm; https://druginteractions.medicine.iu.edu/MainTable.aspx.
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 study.
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.
NOTE: Minor surgery (eg, minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 3 weeks prior to enrollment.
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 treatment.
16. Have an active infection requiring systemic therapy.
17. Are immunocompromised (ie, has a congenital immunodeficiency).
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).
EXCEPTIONS: Subjects with a history of hepatitis B or C who have normal alanine aminotransferase (ALT) (Inclusion Criterion #10) AND are hepatitis B surface antigen negative and/or have undetectable HCV RNA.
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).
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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b: DLTs as determined by AEs and clinical laboratory tests
Phase 3: Independent Review Committee-assessed PFS |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Phase 1b: Safety PK parameters: AUC0-24, AUC0-last, Cmax
Phase 3:
• OS
• AEs and clinical laboratory tests
• Investigator-assessed PFS
• DCR (defined as the number of subjects who achieve confirmed response [CR+PR] or who have SD for 24 weeks).
• ORR (confirmed CR+PR; RECIST 1.1)
• Duration of response: Time from first documented evidence of CR or PR to the time of first documented disease progression or death, whichever occurs first
• Change from baseline in EORTC-QLQ-C30 symptom, function, and global health status domains
• PFS2 (defined as time from randomization to objective tumor progression on next-line treatment or death, whichever occurs first)
• TFST: the time from randomization to the time of start second line of treatment
• Population PK parameters: CL/F, oral Vss, AUCss, Ctrough, Cmax
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the trial
PK:
Phase 1b: Cycle 1 Day -1, Day 1, Day 8, Day 21, Cycle 2 Day 1, Day 2, Cycle 3 and 5 Day 1
Phase 3: Cycle 1 Day 1, Day 8, Cycle 2, 3 and 5 Day 1 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Germany |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Singapore |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
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