E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cohort 1: Rhabdoid tumors (MRT, RTK, ATRT and selected tumors with rhabdoid features.
Cohort 2: Relapsed or refractory synovial sarcoma with SS18-SSX rearrangement
Cohort 3: Other INI1-negative tumors or any solid tumor with EZH2 GOF (gain of function) mutation
Cohort 4: Renal medullary carcinoma
Cohort 5: Epithelioid sarcoma
Cohort 6: Epithelioid sarcoma undergoing optional tumor biopsy
Cohort 7: Poorly differentiated chordoma
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E.1.1.1 | Medical condition in easily understood language |
INI1-negative tumors and synovial sarcoma |
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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 | LLT |
E.1.2 | Classification code | 10007284 |
E.1.2 | Term | Carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064886 |
E.1.2 | Term | Renal medullary carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10073134 |
E.1.2 | Term | Extraskeletal myxoid chondrosarcoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10026667 |
E.1.2 | Term | Malignant peripheral nerve sheath tumor |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10073335 |
E.1.2 | Term | Rhabdoid tumor |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10042863 |
E.1.2 | Term | Synovial sarcoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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) |
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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 | 10008747 |
E.1.2 | Term | Chordoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
To assess the Overall Response Rate (ORR) in subjects with rhabdoid tumors (Cohort 1), other INI1-negative tumors or any solid tumor with EZH2 GOF mutation (Cohort 3), renal medullary carcinoma (Cohort 4), epithelioid sarcoma (Cohort 5), epithelioid sarcoma with optional Tumor biopsy (Cohort 6) and chordoma (Cohort 7) following oral administration of tazemetostat 800 mg twice daily (BID);
To determine the progression-free survival (PFS) rate after 16 weeks of treatment with tazemetostat in subjects with relapsed/refractory synovial sarcoma (Cohort 2) following oral administration of tazemetostat 800 mg BID;
To assess the safety and tolerability of tazemetostat 1600 mg QD (cohort 8) |
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E.2.2 | Secondary objectives of the trial |
-To evaluate duration of response in subjects from Cohorts 1 -7 and in Cohorts 1, 3, 4, 5, 6 and 7 combined for subjects achieving a complete response (CR) or partial response (PR) after oral admin of tazemetostat 800 mg BID and in subjects with epithelioid sarcoma in Cohort 8 at 1600mg QD;
-To assess: disease control rate (DCR) in subjects in Cohort 5 and 6 after oral admin of tazemetostat 800 mg BID and in subjects in Cohort 8 following oral admin of tazemetostat 1600 mg QD;
-To assess the ORR in subjects in Cohort 2 after oral admin of
tazemetostat 800 mg BID and in subjects in Cohort 8 following oral admin of tazemetostat 1600 mg QD;
-To determine PFS and OS at Week 24,32&56&overall in subjects in Cohort 1-7 after oral admin of tazemetostat 800 mg BID and in subjects in Cohort 8 following oral admin of tazemetostat 1600 mg QD;
- To assess: safety and tolerability of IMP (Cohort 1-7);
-To assess PK of IMP;
-To investigate the PD effects of IMP in tumor tissue. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Age (at the time of consent/assent): ≥18 years of age
2.Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair, subject is considered to be ambulatory for the purpose of
assessing their performance status.
3.Has provided signed written informed consent
4.Has a life expectancy of >3 months
5.Has a malignancy:
•For which there are no standard therapies available (Cohorts 1, 3, 4 &
5)
•That is relapsed or refractory, defined as metastatic or non-resectable, locally advanced disease that has previously been treated with and
progressed following approved therapy(ies), if therapy(ies) exists (Cohort 2)
•That has progressed within 6 months prior to study enrollment (Cohort 5 Expansion and Cohort 6 ONLY)
6.Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical Laboratory Improvement Amendments
(CLIA)/College of American Pathologists (CAP) or other Sponsor approved laboratory certification
7.For Cohort 1 (subjects with rhabdoid tumors only): The following test results must be available by local laboratory:
•Morphology and immunophenotypic panel consistent with rhabdoid tumors, and
•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
8.For Cohort 2 (subjects with relapsed/refractory synovial sarcoma only): The following test results must be available by local laboratory:
•Morphology consistent with synovial sarcoma, and •Cytogenetics or Fluorescence in situ hybridization (FISH) and/or molecular confirmation (e.g., DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11)
9.For Cohort 3,4, 5 and 7(subjects with INI1-negative tumor or any solid tumor with EZH2 GOF mutation only): The following test results must be available by local laboratory:
•Morphology and immunophenotypic panel consistent with INI1-negative tumors (not applicable for solid tumors with EZH2 GOF
mutation), and
•Loss of INI1 confirmed by IHC, or
•Molecular confirmation of tumor bi-allelic INI1 loss or mutation when INI1 IHC is equivocal or unavailable, or
•Molecular evidence of EZH2 GOF mutation
10.For Cohort 6 (subjects with epithelioid sarcoma undergoing optional tumor biopsy):
•Morphology and immunophenotypic panel consistent with epithelioid sarcoma (e.g., CD34, EMA, Keratin, and INI1)
•If providing optional biopsy: willingness to provide informed consent to undergo pre- and post-dose biopsy
11. Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤ Grade 1
per CTCAE, version 4.03 or are clinically stable and not clinically significant, at time of enrollment
12.Prior anti-cancer therapy(ies) according to the criteria described in the protocol.
13.Has sufficient tumor tissue (slides or blocks) available for central confirmatory testing of IHC and/or cytogenetics/FISH and/or DNA
mutation analysis (required for study entry but enrollment based on local results).
14.Has measurable disease based on either RECIST 1.1 for solid tumors or RANO for CNS tumors as defined in the protocol.
15.Has adequate hematologic (bone marrow and coagulation factors), renal and hepatic function as defined by criteria in the protocol.
16.For subjects with CNS tumors only: Subject must have seizures that are stable, not increasing in frequency or severity and controlled on
current anti-seizure medication(s) for a minimum of 21 days prior to the planned first dose of tazemetostat
17.Has a shortening fraction of >27% or an ejection fraction of ≥50% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan and
New York Heart Association (NYHA) Class less than or equal to 2
18.Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec
19.Female subjects of childbearing potential must:
•Have a negative beta-human chorionic gonadotropin (β-hCG) pregnancy test at time of Screening and within 14 days prior to planned
first dose of tazemetostat (urine or serum test is acceptable however, positive urine tests must be confirmed with serum testing), and
•Agree to use effective contraception, as defined in the protocol, from a minimum of 7 days prior to first Dosis until 6 months following the last dose of tazemetostat and have a male partner who uses a condom, or
•Practice true abstinence, or
•Have a male partner who is vasectomized
20.Male subjects with a female partner of childbearing potential must:
•Be vasectomized, or
•Agree to use condoms, from first dose of tazemetostat until 3 months following the last dose of tazemetostat, or
•Have a female partner who is NOT of childbearing potential
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E.4 | Principal exclusion criteria |
1.Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homolog2 (EZH2).
2.Has 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 tazemetostat.
3.Has known active CNS or any leptomeningeal metastasis of primary extra-cranial 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 drug 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 7days prior to first dose of study drug.
NOTE: Subjects with asymptomatic brain metastases found on screening 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.
4.Has had a prior malignancy other than the malignancies under study
Exception: A subject who has been disease-free for 5 years, or a subject with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma is eligible.
5.Has had major surgery within 3 weeks prior to enrollment
NOTE: Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 3 weeks prior to enrollment.
6.Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and MPN (e.g. JAK2 V617F) observed in cytogenetic testing and DNA sequencing.
NOTE: Bone marrow aspirate/biopsy will be conducted following abnormal peripheral blood smear morphology assessment conducted by central laboratory. Cytogenetic testing and DNA sequencing will be conducted following an abnormal result of bone marrow aspirate/biopsy.
7.Has a prior history of T-LBL/T-ALL.
8.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.
9.Has cardiovascular impairment, history of congestive heart failure greater than NYHA Class 2, 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.
10.Is currently taking any prohibited medication(s) as described in the protocol.
11.Has an active infection requiring systemic treatment.
12.Is immunocompromised (i.e., has a congenital immunodeficiency), including subjects with a known history of infection with human immunodeficiency virus (HIV.)
13.Has known active infection with hepatitis B virus or hepatitis C virus.
• Note - Subjects with a history of hepatitis B or C with normal ALT and undetectable HBV DNA or HCV RNA are eligible for this study
14.Has had a symptomatic venous thrombosis within the 2 weeks prior to study enrollment.
NOTE: Subjects with a history of a deep vein thrombosis >2 weeks prior to study enrollment who are on anticoagulation therapy with low molecular weight heparin are eligible for this study.
15.For subjects with CNS involvement (primary tumor or metastatic disease): Have any active bleeding, or new intra-tumoral hemorrhage of more than punctate size on screening MRI obtained within 14 days of starting study drug or known bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents.
16.Has known hypersensitivity to any of the components of tazemetostat or other inhibitor(s) of EZH2.
17.Is unable to take oral medications, or has malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea or vomiting) that might impair the bioavailability of tazemetostat.
18.Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements.
19.For female subjects of childbearing potential: Is pregnant or nursing.
20.For male subjects: Is unwilling to adhere to contraception criteria from time of enrollment in study to at least 3 months after last dose of tazemetostat as defined in the protocol.
21.Has been committed to an institution by official or judicial order.
22.Is dependent upon the Sponsor, the trial site, the investigator, or the CRO trial site, the investigator or the CRO. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Cohorts 1 , 3, 4, 5,6 and 7 ORR (confirmed CR+PR) for tazemetostat in subjects with INI1-negative tumors using disease-appropriate standardized response criteria (primary CNS tumors: Response Assessment for Neuro-Oncology [RANO] and all others: RECIST 1.1).
Cohort 2: PFS rate after 16 weeks of treatment with tazemetostat. This is the number of subjects with confirmed CR or PR, or stable disease (SD) at the Week 16 assessment.
Cohort 8: Assessment of safety and tolerability of tazemetostat following 1600 mg oral administration QD |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Cohorts 1 (rhabdoid tumors), 3 (other INI1-negative tumors), 4 (renal medullary carcinoma), 5 (epithelioid sarcoma), 6 (epithelioid sarcoma undergoing optional tumor biopsy and 7- ORR: every 8 weeks for Tumor response until disease progression;
- Cohort 2 (synovial sarcoma) – PFS: every 8 weeks until disease progression;
- Cohort 8 assessment of AEs and clinical laboratory tests. |
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E.5.2 | Secondary end point(s) |
Duration of response for each cohort and for Cohorts 1, 3, 4, 5, 6, and 7 combined and Cohort 8. Duration of response, for the subset of subjects with a
confirmed CR or PR, is defined as the time from the first documented evidence of confirmed CR or PR to the time of first documented disease progression or death due to any cause, whichever comes first using disease-appropriate standardized response criteria; Cohorts 5 and 6: DCR for tazemetostat. This is defined as the number of subjects who achieve confirmed response (CR+PR) or who have SD lasting at least 32 weeks; Cohorts 2 and 8: ORR (confirmed CR+PR, RECIST 1.1) for tazemetostat ; PFS at Weeks 24, 32, and 56 and overall for each cohort. PFS is defined as the time from the date of first dose of study treatment to the earlier of the date of first documented disease progression or date of death due to any cause; OS at Weeks 24, 32, and 56 and overall for each cohort. OS is defined as the time from the date of the first dose of study treatment to the date of death due to any cause; Safety and tolerability of tazemetostat; Population PK parameters oral clearance (CL/F), oral volume of distribution (Vd/F), and first-order absorption rate constant (Ka) for tazemetostat; PD effects of tazemetostat in tumor tissue in IHC assessments of changes in the level of H3K27-Me3 following tazemetostat dosing. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Cohort 2 (synovial sarcoma) – ORR: every 8 weeks until disease progression All Cohorts -
•PFS: every 8 weeks until disease progression and analyzed at 24 and 56
weeks. OS: continuously throughout the treatment period and then
every 16 weeks until death or study completion
•Response duration: every 8 weeks from the time of confirmed response (CR or PR) until disease progression or death.
•Safety: At each visit or required timepoint during treatment and until for 30 days after last treatment or until new anti-cancer therapy
•PK: Days 1, 15, 29, 43 and 57
•PD: Any time after week 8 |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
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 |
France |
Germany |
Italy |
Taiwan |
United Kingdom |
United States |
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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
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The end of study will occur when the last subject discontinues the study treatment and has had to opportunity to complete the safety follow-up visit or the long-term survival follow-up period, whichever is later. The study may end prior to this if 80% of enrolled subjects are deceased prior to the collection of the last survival follow-up. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |