Induction Chemotherapy and Tazemetostat for Locally Advanced SMARCB1-deficient Sinonasal Carcinoma

A Phase II Single-arm Study of Tazemetostat With Docetaxel, Cisplatin, and 5-fluorouracil as Preoperative Treatment for Locally Advanced Potentially Resectable SMARCB1 (INI-1)- Deficient Sinonasal Carcinoma

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Sinonasal Carcinoma
• Intervention / Treatment: Drug: Docetaxel; Drug: Cis Platinum; Drug: 5-FU; Drug: Tazemetostat; Procedure: Surgery; Other: Chemoradiation

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Victor Ho Fun Lee, MD; Phone Number: 852-2255-4352; Email: vhflee@hku.hk
• Study Contact Backup: Name: Mike Law, BSc; Phone Number: 852-2255-5034; Email: lawhc703@hku.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Induction therapy followed by surgery and postoperative therapy; Induction chemotherapy with docetaxel 75mg/m2 on day 1, cisplatin 75mg/m2 on day 1, 5-FU 750mg from day 1 to day 5, given every 3 weeks for 3 cycles and tazemetostat 800mg twice daily orally for 3 cycles, followed by radical surgery or radical chemoradiation, and maintenance tazemetostat 800mg twice daily orally for 6 months

Drug: Docetaxel; Docetaxel 75mg/m2 intravenous infusion on day 1 every 3 weeks for 3 cycles as induction therapy; Other Names: Taxotere; Drug: Cis Platinum; Cisplatin 75mg/m2 intravenous infusion on day 1 every 3 weeks for 3 cycles as induction therapy; Other Names: CDDP; Drug: 5-FU; 5-FU 750mg/m2 intravenous infusion from day 1 to day 5 every 3 weeks for 3 cycles as induction therapy; Other Names: 5-fluorouracil; Drug: Tazemetostat; Tazemetostat 800mg twice per day orally in continuously for 3 cycles as induction therapy and maintenance therapy; Other Names: TAZVERIK; Procedure: Surgery; Radical surgery; Other Names: Resection; Other: Chemoradiation; Chemoradiation as either radical treatment or post-operative treatment after surgery; Other Names: Chemoradiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best objective response	Best objective response	48 months
R0 resection rate	R0 resection rate	48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
R1 resection rate	R1 resection rate	48 months
Complete pathological response rate	Complete pathological response rate	48 months
Orbit preservation rate	Orbit preservation rate defined as the rate that sums up that of orbit preservation surgery with a clear resection and that of radical chemoradiation after induction TPF and tazemetostat	48 months
Progression-free survival	Progression-free survival	48 months
Overall survival	Overall survival	48 months
Incidence of treatment-related side effects	Incidence of treatment-related side effects as determined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0	48 months

Collaborators and Investigators

• Sponsor: Dr. Victor H.F. Lee
• Investigators: Principal Investigator: Victor Ho Fun Lee, MD, Department of Clinical Oncology, The University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Anticipated): September 1, 2023
• Primary Completion (Anticipated): August 31, 2026
• Study Completion (Anticipated): August 31, 2027

Study Registration Dates

• First Submitted: November 27, 2021
• First Submitted That Met QC Criteria: November 27, 2021
• First Posted (Actual): December 9, 2021

Study Record Updates

• Last Update Posted (Estimate): February 28, 2023
• Last Update Submitted That Met QC Criteria: February 26, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Surgery; Chemotherapy; Induction therapy
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Docetaxel; Cisplatin; Fluorouracil
• Other Study ID Numbers: SMART-PNS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is no plan to make individual participant data (IPD) available to other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No