Patient case: 58-year-old female with endometrial cancer; genetic feature: PIK3R1

Clinical trial: A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

Summary: This is a Phase II, multicenter, open-label, single arm, 2-stage study of tazemetostat 800 mg BID administered orally in continuous 28 day cycles. Screening of subjects to determine eligibility for the study will be performed within 21 days of the first planned dose of tazemetostat. Eligible subjects will be enrolled into one of fivecohorts based on tumor type:
  -  Cohort 1 (Closed for enrollment): MRT, RTK, ATRT, or 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 INI1 negative tumors or any solid tumor with an 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 (Opened for enrollment): Poorly differentiated chordoma (or other chordoma with Sponsor approval)
  Treatment with tazemetostat will continue until disease progression, unacceptable toxicity or withdrawal of consent, or termination of the study. Response assessment will be evaluated after 8 weeks of treatment and then every 8 weeks thereafter while on study.


Eligibility: 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 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 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 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, 5 and 7 (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 epithelioid sarcoma undergoing mandatory tumor biopsy):
  -  Morphology and immunophenotypic panel consistent with epithelioid sarcoma (e.g., CD34, EMA, Keratin, and INI1)
  -  Tumor that is accessible for mandatory biopsy
  -  Note: Subjects who are unable to undergo pre-dose (screening biopsy) will not be eligible
  -  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 4.0.3 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 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
  15. Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function as defined by criteria below:
  -  Hematologic (BM Function):
  -  Hemoglobin ≥9 mg/dL
  -  Platelets ≥100,000/mm^3 (≥100x10^9/L)
  -  ANC ≥1,000/mm^3 (≥1.0x10^9/L)
  -  Hematologic (Coagulation Factors):
  -  INR/PT₫ <1.5 ULN
  -  PTT>1.5 ULN
  -  Renal Function:
  - Serum creatinine ≤1.5 x ULN
  -  Hepatic Function:
  -  Total bilirubin <1.5 x ULN(Eligibility can be determined by conjugated or total bilirubin)
  -  AST and ALT <3 x ULN NOTE: Laboratory results obtained during screening should be used to determine eligibility criteria. In situations where laboratory results are outside the permitted range, the Investigator may retest the subject and the subsequent within range screening result may be used to determine the subject's eligibility.
  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 NOTE: Subjects may receive glucocorticoids (at stable or tapering dose) to control CNS symptoms prior to enrollment; however, subjects should receive a stable or tapering dose for at least 7 days prior to 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 (urine or serum test is acceptable however, positive urine tests must be confirmed with serum testing), and
  -  Agree to use effective contraception, from start of screening until 30 days following the last dose of tazemetostat and have a male partner who uses a condom, or
  -  Practice true abstinence (when this is in line with the preferred and usual lifestyle of the subject,), 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 8.5.13.4.2, from first dose of tazemetostat until 30 days 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 - NOTE: 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 7 days prior to first dose of study drug.
  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 re-vision) is permitted 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 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
  -  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 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 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 30 days after last dose of tazemetostat.

Relevance to patient case: not relevant