Phase II Study of Tazemetostat in Solid Tumors Harboring an ARID1A Mutation

• Status: Not yet recruiting
• Trial end date: 2024-11-01
• Target enrollment: 0
• Participant gender: All

Summary

The FDA approved targeted agent tazemetostat inhibits EZH2 and induces durable tumor responses in patients with B-cell non-Hodgkin's lymphoma and epithelioid sarcomas. Responses have also been demonstrated in INI1 and SMARCA4 negative solid tumors patients. Since EZH2 plays a critical role in driving the biology of ARID1A mutated malignancies, we hypothesize that inhibition of EZH2 with tazemetostat will lead to significant clinical benefit in ARID1A mutated malignancies.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Prisma Health-Upstate
• Collaborator: Epizyme, Inc.

Criteria

Inclusion Criteria:

• Have voluntarily agreed to provide written informed consent and demonstrated willingness and ability to comply with all aspects of the protocol.

• Histologically and/or cytologically confirmed advanced or metastatic solid tumor harboring ARID1A mutation (except epithelioid sarcoma)

• Progression of disease following approved therapies or for which no standard therapy exists

• For subjects who have experienced any clinically significant toxicity related to a prior anticancer treatment (i.e., chemotherapy, immunotherapy, and/or radiotherapy): at the time the subject provides voluntary written informed consent, all toxicities have either resolved to grade 1 per NCI CTCAE Version 5.0 [11] OR are clinically stable and no longer clinically significant.

• Have measurable disease as defined by RECIST 1.1.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

• Males or females are >18 years of age at the time of providing voluntary written informed consent.

• Life expectancy >3 months before enrollment.

• Time between prior anticancer therapy and first dose of tazemetostat as follows:

Cytotoxic chemotherapy - At least 21 days Noncytotoxic chemotherapy (e.g., small molecule inhibitor) - At least 14 days. Nitrosoureas - At least 6 weeks. Monoclonal antibody - At least 28 days. Radiotherapy - At least 14 days. In addition, at least 6 weeks from prior radioisotope therapy; and at least 12 weeks from 50% pelvic or total body irradiation.

• Adequate renal function: Creatinine < 2.0 or calculated creatinine clearance ≥ 35 mL/minute per the Cockcroft and Gault formula

• Adequate bone marrow function:

ANC ≥ 750mm3 without growth factor support (filgrastim or pegfilgrastim) for at least 14 days.

Platelets ≥ 75,000mm3 (≥75 × 109/L) evaluated at least 7 days after platelet transfusion.

Hemoglobin ≥9.0 g/dL and may receive transfusion Adequate liver function: Total bilirubin <1.5 × the upper limit of normal (ULN) (except for unconjugated hyperbilirubinemia of Gilbert's syndrome); Alkaline phosphatase (ALP) (in the absence of bone disease), ALT, and AST <3 × ULN (or <5 × ULN if subject has liver metastases).

Exclusion Criteria:

• Subjects with epithelioid sarcoma are excluded.

• Has a prior history of T-Cell Lymphoblastic Lymphoma, T-Cell Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome, Acute Myeloid Leukemia, or Myeloproliferative Neoplasm.

• Female subjects who are pregnant or breastfeeding.

• Prior exposure to tazemetostat or other inhibitor(s) of EZH2.

• Subjects with uncontrolled CNS metastases requiring steroids.

• Subjects taking medications that are known potent CYP3A4 inducers/inhibitors (including St. John's wort)

• Are unwilling to exclude Seville oranges, grapefruit juice, AND grapefruit from their diet.

• Major surgery within 4 weeks before the first dose of study drug. NOTE: Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 1 week prior to enrollment.

• Are unable to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, vomiting) that might impair the bioavailability of tazemetostat.

• Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II (Appendix 3), uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug; or cardiac ventricular arrhythmia.

• Have an active infection requiring systemic therapy.

• Known hypersensitivity to any component of tazemetostat.

• 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.

• Subjects who have undergone a solid organ transplant.

• Prior malignancy in the past 5 years.