A Phase II Study of Tazemetostat in Solid Tumors Harboring an ARID1A Mutation
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.
• 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).