E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Atypical teratoid rhabdoid tumor (ATRT), Malignant rhabdoid tumor (MRT), Rhabdoid tumor of kidney (RTK).
Outside of Germany :
- selected tumors with rhabdoid features;
- INI-negative tumors or synovial sarcoma: Epithelioid sarcoma, Epithelioid malignant peripheral nerve sheath tumor, Extraskeletal myxoid chondrosarcoma, Myoepithelial carcinoma, Renal medullary carcinoma, other INI1-negative malignant tumors (like dedifferentiated chordoma), Synovial Sarcoma with a SS18-SSX rearrangement. |
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E.1.1.1 | Medical condition in easily understood language |
Relapsed/refractory rhabdoid tumors and central nervous system (CNS) tumors. |
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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 | 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 | LLT |
E.1.2 | Classification code | 10065870 |
E.1.2 | Term | Atypical teratoid/rhabdoid tumor of CNS |
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 | 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 | LLT |
E.1.2 | Classification code | 10074121 |
E.1.2 | Term | Rhabdoid tumor of the kidney |
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.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Dose Escalation:
To determine the maximum tolerated dose (MTD) or the recommended Phase 2 dose (RP2D) of tazemetostat when administered as an oral suspension twice daily (BID) in pediatric subjects with relapsed/refractory rhabdoid tumors, (outside of Germany to include integrase interactor 1 (INI1)-negative tumors or synovial sarcoma).
Dose Expansion:
To evaluate the antitumor activity of tazemetostat as assessed by overall response rate (ORR) in pediatric subjects with relapsed/refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1), non-ATRT rhabdoid tumors (Cohort 2), INI1-negative tumors (Cohort 3)(outside of Germany ) and tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Cohort 4 [outside of Germany]) using disease appropriate standardized response criteria.
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E.2.2 | Secondary objectives of the trial |
Dose Escalation: To evaluate the preliminary antitumor activity of tazemetostat as assessed by ORR using disease appropriate standardized response criteria.
Dose Expansion: To determine the progression-free survival (PFS) & overall survival (OS) at 24 and 56 weeks & overall pediatric subjects with relapsed/refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1), non-ATRT rhabdoid tumors (Cohort 2), INI1-negative tumors or synovial sarcoma ((Cohort 3) outside of Germany),& tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Cohort 4 [outside of Germany]) using disease-appropriate standardized response criteria.
ALL subjects:
- To assess safety&tolerability and PK parameters of tazemetostat administered as an oral suspension BID in pediatric subjects;
-To evaluate the duration of response in subjects achieving a PR or CR according to disease appropriate standardized response criteria.
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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): ≥6 months to <18 years of age Cohort 4 only: ≥10 y to <18 y
2.Performance Status:If <12 y: Lansky Performance Status >50% ,If ≥ 12 y of age: Karnofsky Performance Status >50%
3.Has provided signed written ICF 4. Has a life expectancy of >3 months. 5.Has relapsed or refractory disease and no standard treatment
options. 6.Is ineligible for other treatment regimens. 7.Has a documented local diagnostic pathology of original biopsy. 8.Has all prior treatment related
clinically significant toxicities resolve to ≤ Grade 1 per CTCAE, version 4.03 or are clinically stable& not clinically significant. 9.Prior therapies
must be completed according to the protocol. 10.Has adequate hemat. BM & coagulation factors, renal&hepatic function as defined by criteria in
the protocol 11.Specific requirements for subjects with CNS involvement eg: stable deficits within certain timeframe, stable seizure, treated brain
metastases without evidence of progression. 12.Has a LV fractional shortening of >27% or an LV ejection fraction of ≥50% by ECHO or
MUGA scan & NYHAC ≤2. 13. Has a QT interval corrected by Fridericia's formula (QTcF) ≤450 msec. 14.Is able to swallow and retain orally administered medication and does not have any uncontrolled GI condition that may alter absorption. 15.Has sufficient tumor tissue for central confirmatory
testing of IHC and/or cytogenetics/FISH and/or DNA mutation analysis. 16.Is willing and able to comply with all aspects of the protocol. 17.18.
For female subjects of childbearing potential and for male subjects with a female partner of childbearing potential Subject must adhere to
contraception methods described in the protocol. For Dose Escalation Only:ALL criteria above and the following:1.Has evaluable disease as defined as lesions that can be accurately measured at least in one dimension by radiographic examination or physical examination or and other lesions such as bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis or hepatosplenomegaly from disease2.Has one of the
following histologically confirmed tumors: Rhabdoid tumor: ATRT (closed to enrollment), MRT, RTK, selected tumors with rhabdoid features, INI1-
negative tumor: (Epithelioid sarcoma, Epithelioid malignant peripheral nerve sheath tumor, EMC, Myoepithelial carcinoma, Renal medullary
carcinoma), other INI1-negative malignant tumors, Synovial sarcoma with SS18-SSX rearrangement (closed to enrollment).
3. For subjects with ATRT, MRT, and RTK or tumors with rhabdoid features only: the following test results must be available:
•Morphology and immunophenotypic panel consistent with rhabdoid tumor, and •Loss of INI1 or SMARCA 4 confirmed by IHC, or
•Molecular confirmation of tumor bi-allelic INI1 or SMARCA 4 loss or mutation when INI1 or SMARCA4 IHC is equivocal or unavailable
4. For subjects with INI1 negative tumor only the following test results must be available:
•Morphology and immunophenotypic panel consistent with INI1 negative tumors, 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 5.For subjects with synovial sarcoma with SS18-SSX rearangement only the following test results must be available:
•Morphology consistent with synovial sarcoma, and
•Cytogenetics or FISH and/or molecular confirmation (e.g.DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11) For Dose Expansion Only: ALL listed above for All subjects and in addition:
1. Has measurable disease 2.Has one of the following tumors: Cohort 1: ATRT-(enrollment closed), Cohort 2: MRT, RTK, Selected tumors with
rhabdoid features, Cohort 3:INI1-negative tumors or synovial sarcoma: ES, Epithelioid malignant peripheral nerve sheath tumor, EMC,
Myoepithelial carcinoma, Renal medullary carcinoma, Chordoma (poorly differentiated or de-differentiated), other INI1-negative malignant
tumors, Cohort 4 (enrollment closed):one of the tumor types defined in Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement.
3.For subjects with ATRT/MRT/RTK only -have test results available:
•Morphology and immunophenotypic panel consistent with rhabdoid tumor, and •Loss of INI1 or SMARCA4 confirmed by IHC, or •Molecular
confirmation of tumor bi-allelic INI1 or SMARCA4 loss or mutation. 4. For subjects with INI1-negative tumors only – test results available: •
Morphology and immunophenotypic panel consistent with INI1-negative tumors, and •Loss of INI1 confirmed by IHC, or •Molecular confirmation
of tumor bi-allelic INI1 loss/mutation. 5.For subjects with synovial sarcoma with SS18-SSX rearrangement (in Cohort 4 only- closed to enrollment): Morphology consistent with synovial sarcoma & Cytogenetics or FISH &/or molecular confirmation of SS18 rearrangement t(X;18)(p11;q11) 6.For subjects Cohort 4-(closed to enrollment): Able to swallow&retain orally taken tablets |
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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.Is being actively treated for another concurrent malignancy or is less than five years from completion of treatment for another malignancy
3.Has participated in another interventional clinical study and received investigational drug within 30 days or five half-lives, whichever is longer, prior to the planned first dose of tazemetostat
4.Has had major surgery within 2 weeks prior to enrollment
5.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 at Screening.
Cytogenetic testing and DNA sequencing will be conducted by a central laboratory following an abnormal result of bone marrow aspirate/biopsy.
6.Has a prior history of T-cell lymphoblastic lymphoma/T-cell acute
lymphoblastic lymphoma (T-LBL/T-ALL).
7.Has clinically active heart disease including prolonged QTcF (>450 msec)
8.Is currently taking any prohibited medication(s) as described in section 7.3
9.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
10.Has an active infection requiring systemic treatment
11.Is immunocompromised (ie congenital immunodeficiency), including subjects with a known history of infection with human immunodeficiency virus (HIV)
12.Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable HCV RNA)
13.Has had a symptomatic venous thrombosis within 14 days prior to study enrollment
14.For subjects with CNS involvement (primary tumor or metastatic disease): Have any active bleeding, or new intratumoral 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
15.Has known hypersensitivity to any of the components of tazemetostat or other inhibitor(s) of EZH2, or hypersensitivity to Ora-sweet or methylparaben
16.Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements
17.For female subjects of childbearing potential: Is pregnant or nursing
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.
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E.5 End points |
E.5.1 | Primary end point(s) |
Dose Escalation:
•Incidence and severity of treatment -emergent AEs (TEAEs) qualifying as protocol-defined dose-limiting toxicities (DLTs), and establishment of the protocol-defined RP2D and/or MTD.
Dose Expansion:
•Overall response rate CR + PR to tazemetostat in pediatric subjects with relapsed or refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1), non-ATRT rhabdoid tumors (Cohort 2), (outside of Germany) INI1-negative tumors (Cohort 3), and tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Cohort 4 [outside Germany only]) using disease- appropriate standardized response criteria . |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Dose Escalation: All DLTs occurring during the first 28 days of exposure summarized.
Dose Expansion: Data sets for each cohort will be reviewed as completed.
timepoint for every 8 weeks until documented disease progression or new anti-cancer therapy started. |
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E.5.2 | Secondary end point(s) |
Dose Escalation:
•Overall response rate (CR+PR) to tazemetostat in pediatric subjects with relapsed or refractory CNS and solid tumors, using disease-appropriate standardized response criteria;
Dose Expansion:
•Progression-free survival (PFS) and overall survival (OS) at 24 and 56 weeks and overall following receipt of tazemetostat for subjects with relapsed/refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1), non-ATRT rhabdoid tumors (Cohort 2), (outside of Germany) INI1-negative tumors (Cohort 3), and tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Cohort 4 [outside of Germany]) using disease-appropriate standardized response;
All Parts and Cohorts:
•Safety and tolerability parameters including treatment-emergent adverse events (TEAEs), clinical laboratory evaluations, and other safety measures
•PK parameters including Cmax, Tmax, t1/2, AUC(0-t), AUC(0-12hr), CL/F, Vd/F, Ka (if data permit)
•Response duration, for the subset of subjects with a confirmed CR or PR, defined as the time from the first documented evidence of CR or PR to time of first documented disease progression or death due to any cause, using disease appropriate standardized response criteria.
Exploratory Endpoints:
•To assess the PK and pharmacodynamic (PD) relationship for tazemetostat in pediatric subjects
•Tumor target gene expression and phenotypic markers including those for differentiation, apoptosis, inflammation, and cell proliferation and
their correlation with activity
•H3K27 methylation in PBMC population
•Somatic mutation analysis of tumor tissue and blood derived circulating DNA |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Dose Escalation
ORR: every 8 weeks for tumor response until disease progression
2.Dose Expansion
PFS: every 8 weeks until disease progression or death
OS: throughout the treatment period and then every 16 weeks until death, withdrawal of consent or they are lost to follow up
3.All Groups
•Safety: At each visit or required timepoint during treatment and until for 30 days after last dose of tazemetostat or until new anti-cancer therapy
•PK parameters: Cycle 1 (Days 1 and 15) and Cycles 2, 3 and 4 (Day 1).
•Response duration: every 8 weeks from the time of confirmed response (CR or PR) until disease progression or death. |
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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 | Yes |
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) | 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 |
Dose Escalation and Dose Expansion |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
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 | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 |
Canada |
Denmark |
France |
Germany |
Italy |
Netherlands |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 8 |
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 | 8 |