Clinical trial NCT02601950: A Study of Tazemetostat in Adult Participants With Soft Tissue Sarcoma
Official title: A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Malignant Rhabdoid Tumors (MRT)
Rhabdoid Tumors of the Kidney (RTK)
Atypical Teratoid Rhabdoid Tumors (ATRT)
Selected Tumors With Rhabdoid Features
Synovial Sarcoma
INI1-negative Tumors
Malignant Rhabdoid Tumor of Ovary
Renal Medullary Carcinoma
Epithelioid Sarcoma
Poorly Differentiated Chordoma (or Other Chordoma With Sponsor Approval)
Any Solid Tumor With an EZH2 GOF Mutation
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
First posted: 2015-11-11
Enrollment: 267
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study will include participants with various types of cancer known as soft-tissue sarcomas.

Tissues that can be affected by soft tissue sarcomas include fat, muscle, blood vessels, deep skin tissues, tendons and ligaments.

Soft tissue cancers are rare and can occur almost anywhere in the body.

Part 1 of this trial will study the safety and the level that adverse effects of the study drug tazemetostat in combination with doxorubicin (current front line treatment) can be tolerated (known as tolerability).

It is also designed to establish a recommended study drug dosage for the next part of the study.

Part 2 will evaluate and compare how long participants live without their disease getting worse when receiving the study drug plus doxorubicin versus doxorubicin plus placebo (dummy treatment).

Detailed description: This is a Phase II, multicenter, open-label, single arm, 2-stage study of tazemetostat 800 mg BID (twice daily) and 1600 mg QD (once daily). Subjects will be screened for eligibility within 21 days of the planned date of the first dose of tazemetostat and enrolled into one of 8 cohorts:

Cohort using tazemetostat 800 mg BID

* Cohort 1 (Closed for enrollment): malignant rhabdoid tumor (MRT), rhabdoid tumor of the kidney (RTK), atypical teratoid rhabdoid tumor (ATRT), and selected tumors with rhabdoid features, including small cell carcinoma of the ovary hypercalcemic type (SCCOHT), also known as malignant rhaboid tumor of the ovary (MRTO)
* Cohort 2 (Closed for enrollment): Relapsed or refractory synovial sarcoma with SS18-SSX rearrangement
* Cohort 3 (Closed for enrollment): Other integrase interactor 1 (INI1) negative tumors or any solid tumor with an enhancer of zeste homologue-2 (EZH2) gain of function (GOF) mutation, including: epithelioid malignant peripheral nerve sheath tumor (EMPNST), extraskeletal myxoid chondrosarcoma (EMC), myoepithelial carcinoma, other INI1-negative malignant tumors with Sponsor approval (e.g., dedifferentiated chordoma) any solid tumor with an EZH2 GOF mutation including but not limited to Ewing's sarcoma and melanoma
* Cohort 4 (Closed for enrollment): Renal medullary carcinoma (RMC)
* Cohort 5 (Closed for enrollment): Epithelioid sarcoma (ES)
* Cohort 6 (Closed for enrollment): Epithelioid sarcoma (ES) undergoing mandatory tumor biopsy
* Cohort 7 (Closed for enrollment): Poorly differentiated chordoma (or other chordoma with Sponsor approval)

Cohort using tazemetostat 1600 mg QD

• Cohort 8 (Closed for enrollment): Epitheliod sarcoma

Participants will be dosed in continuous 28-day cycles. (Note: if treatment with study drug is discontinued prior to completing 2 years, subjects will be followed for a maximum duration of 2 years from start of study drug dosing.) Response assessment will be performed every 8 weeks while on study.

Treatment with tazemetostat will continue until disease progression, unacceptable toxicity or withdrawal of consent, or termination of the study.

Eligibility criteria: 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
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 and 5)
   * That is relapsed or refractory after treatment with an approved therapy(ies), defined as metastatic or non-resectable, locally advanced disease that has previously been treated with and progressed following approved therapy(ies) (Cohort 2)

     * That has progressed within 6 months prior to study enrollment (Cohort 5 Expansion, Cohort 6 and Cohort 8 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 equivalent laboratory certification
7. For Cohort 1 (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 tests must be available by local laboratory: Morphology consistent with synovial sarcomas, 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, 7 and 8 (subjects with INI1-negative/aberrant tumors 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 ES undergoing optional tumor biopsy) only:

    * Morphology and immunophenotypic panel consistent with ES (e.g., CD34, EMA, Keratin, and INI1)
11. Has all prior treatment (i.e. chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤Grade 1 per CTCAE version 4.0.3 or are clinically stable and not clinically significant, at time of enrollment.
12. Prior anti-cancer therapy(ies), if applicable, must be completed according to the criteria below:

    * Chemotherapy: cytotoxic (At least 14 days since last dose of chemotherapy prior to first dose of tazemetostat)
    * Chemotherapy: nitrosoureas (At least 6 weeks since last dose of nitrosoureas prior to first dose of tazemetostat)
    * Chemotherapy: non-cytotoxic (e.g., small molecule inhibitor) (At least 14 days since last dose of non-cytotoxic chemotherapy prior to first dose of tazemetostat)
    * Monoclonal antibody(ies) (At least 28 days since the last dose of any monoclonal antibody prior to first dose of tazemetostat)
    * Immunotherapy (e.g. tumor vaccine) (At least 42 days since last dose of immunotherapy agent(s) prior to first dose of tazemetostat)
    * Radiotherapy (RT) (At least 14 days from last local site RT prior to first dose of tazemetostat/At least 21 days from stereostatic radiosurgery prior to first dose of tazemetostat/At least 12 weeks from craniospinal, ≥50% radiation of pelvis, or total body irradiation prior to first dose of tazemetostat)
    * High dose therapy with autologous hematopoietic cell infusion (At least 60 days from last infusion prior to first dose of tazemetostat)
    * Hematopoietic growth factor (At least 14 days from last dose of hematopoietic growth factor prior to first dose of tazemetostat)
13. Has sufficient tumor tissue (slides or blocks) available for central confirmatory testing
14. Has measurable disease based on either RECIST 1.1 for solid tumors or RANO for CNS tumors
15. Has adequate hematologic (bone marrow \[BM\] and coagulation factors), renal and hepatic function.
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 ≤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 and
    * Agree to use effective contraception from a minimum of 7 days prior to first dose 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 as defined in Section 8.6.2, 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

Exclusion Criteria:

1. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (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.
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
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.
7. Has a prior history of T-LBL /T-ALL
8. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet
9. Has cardiovascular impairment, history of congestive heart failure greater than NYHA Class II, 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)
11. Has an active infection requiring systemic treatment
12. Is immunocompromised (i.e. has congenital immunodeficiency), including subjects known history of infection with human immunodeficiency virus (HIV)
13. Has known active infection with hepatitis B virus or hepatitis C virus
14. Has had a symptomatic venous thrombosis within 2 weeks prior to study enrollment -
15. For subjects with CNS involvement (primary tumor or metastatic disease), have any active bleeding or new intratumoral hemorrhage of more than punctuate size of 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 component of tazemetostat or other inhibitor(s)of EZH2
17. Is unable to take oral medications, or has a malabsorption syndrome or any uncontrolled gastrointestinal condition (e.g., nausea, diarrhea or vomiting) that would limit compliance with study requirements.
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 the study to at least 3 months after last dose of tazemetostat.

Primary outcomes:
measure: Cohorts 1, 3, 4, 5, 6 and 7: Objective Response Rate (ORR)
timeFrame: Tumor assessment performed at screening and every 8 weeks beginning at Cycle 3 Day 1, until disease progression or the start of subsequent anti-cancer therapy, whichever occurred first, up to 5.75 years (cycle duration: 28 days)
measure: Cohort 2: Progression-Free Survival (PFS) Rate at 16 Weeks of Treatment With Tazemetostat
timeFrame: At 16 Weeks
measure: Cohort 8: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment, approximately 148 weeks
Secondary outcomes:
measure: All Cohorts: Duration of Response (DOR)
timeFrame: Tumor assessment performed at screening and every 8 weeks beginning at Cycle 3 Day 1, until disease progression or the start of subsequent anti-cancer therapy, whichever occurred first, up to 5.75 years (cycle duration 28 days)
measure: All Cohorts: Progression-Free Survival (PFS)
timeFrame: Tumor assessment performed at screening and every 8 weeks beginning at Cycle 3 Day 1, until disease progression or the start of subsequent anti-cancer therapy, whichever occurred first, up to 5.75 years (cycle duration 28 days)
measure: All Cohorts: Progression-Free Survival (PFS) Rate at Weeks 24, 32 and 56
timeFrame: At Weeks 24, 32 and 56
measure: All Cohorts: Overall Survival (OS)
timeFrame: Tumor assessment performed at screening and every 8 weeks beginning at Cycle 3 Day 1, until disease progression or the start of subsequent anti-cancer therapy, whichever occurred first, up to 5.75 years (cycle duration: 28 days)
measure: All Cohorts: Overall Survival (OS) Rate at Weeks 24, 32 and 56
timeFrame: At Weeks 24, 32 and 56
measure: All Cohorts: Disease Control Rate (DCR) at Weeks 12, 24, 32 and 48
timeFrame: At Weeks 12, 24, 32 and 48
measure: Cohorts 2 and 8: Objective Response Rate (ORR)
timeFrame: Tumor assessment performed at screening and every 8 weeks beginning at Cycle 3 Day 1, until disease progression or the start of subsequent anti-cancer therapy, whichever occurred first, up to 5.75 years (cycle duration: 28 days)
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital - Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Woolloongabba
country: Australia
facility: Metro South Hospital and Health Service via Princess Alexandra Hospital
city: Brussels
country: Belgium
facility: Institut Jules Bordet Medical Oncology Clinic
city: Leuven
country: Belgium
facility: University Hospital Leuven
city: Edmonton
country: Canada
facility: Alberta Health Services
state: Alberta
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre - Royal Victoria Hospital
state: Quebec
city: Bordeaux
country: France
facility: Institut Bergonie
city: Lyon
country: France
facility: Centre Leon Berard
city: Paris Cedex 13
country: France
facility: Hospital Pitie Salpetriere
city: Paris
country: France
facility: Institut Curie
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Augsburg
country: Germany
facility: Children's Hospital Augsburg Klinikum
city: Berlin
country: Germany
facility: Sarcoma Center HELIOS Klinikum Berlin
city: Milano
country: Italy
facility: Instituto Nazionale Tumori - National Cancer Institute Via Giacomo Venezian
city: Taipei City
country: Taiwan
facility: National Taiwan University Hospital
city: London
country: United Kingdom
facility: University College London Hospital
city: London
country: United Kingdom
facility: Royal Marsden Foundation Trust
Study officials:
affiliation: Ipsen
name: Ipsen Medical Director
role: STUDY_DIRECTOR
References:
citation: Gounder M, Schoffski P, Jones RL, Agulnik M, Cote GM, Villalobos VM, Attia S, Chugh R, Chen TW, Jahan T, Loggers ET, Gupta A, Italiano A, Demetri GD, Ratan R, Davis LE, Mir O, Dileo P, Van Tine BA, Pressey JG, Lingaraj T, Rajarethinam A, Sierra L, Agarwal S, Stacchiotti S. Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol. 2020 Nov;21(11):1423-1432. doi: 10.1016/S1470-2045(20)30451-4. Epub 2020 Oct 6.