SMARCB1-deficient sinonasal carcinoma is very locally advanced malignancy at diagnosis which often precluded upfront radical resection. The investigators are now proposing a phase II single-arm study on tazemetostat in combination with docetaxel, cisplatin and 5-FU (known as TPF regimen) as preoperative therapy for locally advanced non-metastatic SMARCB1 (INI-1)-deficient sinonasal carcinoma, followed by radical resection and/or post-operative radiation therapy (with or without concurrent chemotherapy), and tazemetostat for another 6 months. It is hypothesized that addition of tazemetostat will improve objective response rate, resectability rate, orbit preservation rate after surgery, and hopefully survival outcomes with manageable safety profiles.

SMARCB1 (INI-1)-deficient sinonasal carcinoma is a rare but locally aggressive malignancy of the nasal cavity and paranasal sinuses, representing about only 1 % of all head and neck malignancies. It is characterized by loss of INI-1 in the tumour cells under immunohistochemical staining. The overwhelming majority of INI-1 deficient sinonasal carcinoma presents very late at diagnosis, owing to its very similar clinical presentation to other benign conditions like allergic rhinitis, nasal polyps, chronic sinusitis, and some more common malignancies like human papilloma virus-associated squamous cell carcinoma, extranodal NK/T cells lymphoma, mucosal melanoma. Therefore, complete surgical removal remains very challenging and most of the time impossible.

Currently, aggressive multimodality treatment of INI-1-deficient sinonasal carcinomas is based on experience with other sinonasal malignancies including case series of sinonasal undifferentiated carcinoma. Upfront surgical resection for potentially resectable cases, followed by adjuvant radiation therapy or adjuvant chemoradiation. Also under investigation is the use of induction chemotherapy followed by surgery and adjuvant radiation in the treatment of sinonasal malignancy.

In view of the above, the investigators are now proposing a phase II single-arm study on tazemetostat in combination with TPF as preoperative therapy for locally advanced non-metastatic SMARCB1 (INI-1)-deficient sinonasal carcinoma, followed by radical resection and/or post-operative radiation therapy (with or without concurrent chemotherapy), and tazemetostat for another 6 months. It is hypothesized that addition of tazemetostat will improve objective response rate, resectability rate, orbit preservation rate, and hopefully survival outcomes with manageable safety profiles.

Inclusion Criteria:

1. Males or females are >18 years of age with body weight ≥40kg at the time of providing voluntary written informed consent.

2. Voluntarily sign the written informed consent and demonstrated willingness and ability to comply with all aspects of the protocol which includes compliance with the requirements and restrictions listed in the informed consent form (ICF), and undergoing treatment and scheduled visits and examinations including follow up during the study period,

3. Histologically and/or cytologically confirmed locally advanced (T3-T4bN0-N3M0) non-metastatic SMARCB1 (INI-1)-deficient sinonasal carcinoma

4. 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 OR are clinically stable and no longer clinically significant.

5. Have measurable disease as defined by RECIST 1.1.

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

7. Must have a life expectancy of at least 12 weeks before enrollment.

8. 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.

9. Adequate haematological functions at baseline before commencement of study medication as defined below:

   i. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/liter without growth factor support (filgrastim or pegfilgrastim) for at least 14 days; and ii. Platelets ≥ 100 × 10^9/liter evaluated at least 7 days after platelet transfusion; and iii. Hemoglobin ≥ 9.0 x 10 /litre with blood transfusion allowed before study entry; and after treatment commencement

10. Adequate liver function as defined at baseline before commencement of study medication below:

    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), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN.

11. Adequate renal function as defined below:

    Creatinine < 2.0 or calculated creatinine clearance ≥ 35 mL/minute per the Cockcroft and Gault formula

12. For women of childbearing potential, a negative serum or urine pregnancy test within 14 days prior to the start of treatment. Women will be considered postmenopausal if they are amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

    i.) Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). ii.) Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

13. For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and partner) to use a highly effective form(s) of contraception that results in a low failure rate (<1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire program period, and six months for female and at least three months for male patients after taking the last dose of tazemetostat.

Exclusion Criteria:

1. Pre-existing or co-existing epithelioid sarcoma.
2. Has a prior history of T-Cell lymphoblastic lymphoma, T-cell acute lymphoblastic leukemia, myelodysplastic syndrome, acute myeloid leukemia, or myeloproliferative neoplasm.
3. Have undergone a solid organ transplant.
4. Prior malignancy in the past 5 years.
5. Confirm pregnant or breastfeeding.
6. Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
7. On investigational therapy within 21 days at time of recruitment.
8. Uncontrolled central nervous system (CNS) metastases requiring steroids.
9. On medications that are known potent CYP3A4 inducers/inhibitors (including St. John's wort)
10. Unwilling to exclude Seville oranges, grapefruit juice, and grapefruit from their diet.
11. Had 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.
12. 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.
13. 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.
14. Have an active infection requiring systemic therapy.
15. Known hypersensitivity to any component of tazemetostat.
16. 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.

There is no plan to make individual participant data (IPD) available to other researchers.

No masking