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

NCT05151588 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: SMART-PNS
• Study Type: interventional
• Target: 30
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Sinonasal Carcinoma

Keywords

Induction therapy; Chemotherapy; Surgery

Outcome Measures

Primary Outcomes (2)

• Best objective response

  Best objective response

  48 months

• R0 resection rate

  R0 resection rate

  48 months

Secondary Outcomes (6)

• R1 resection rate

  48 months

• Complete pathological response rate

  48 months

• Orbit preservation rate

  48 months

• Progression-free survival

  48 months

• Overall survival

  48 months

Study Arms (1)

Induction therapy followed by surgery and postoperative therapy

EXPERIMENTAL

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; Drug: Cis Platinum; Drug: 5-FU; Drug: Tazemetostat; Procedure: Surgery; Other: Chemoradiation

Interventions

Docetaxel DRUG

Docetaxel 75mg/m2 intravenous infusion on day 1 every 3 weeks for 3 cycles as induction therapy

Also known as: Taxotere

Induction therapy followed by surgery and postoperative therapy

Cis Platinum DRUG

Cisplatin 75mg/m2 intravenous infusion on day 1 every 3 weeks for 3 cycles as induction therapy

Also known as: CDDP

Induction therapy followed by surgery and postoperative therapy

5-FU DRUG

5-FU 750mg/m2 intravenous infusion from day 1 to day 5 every 3 weeks for 3 cycles as induction therapy

Also known as: 5-fluorouracil

Induction therapy followed by surgery and postoperative therapy

Tazemetostat DRUG

Tazemetostat 800mg twice per day orally in continuously for 3 cycles as induction therapy and maintenance therapy

Also known as: TAZVERIK

Induction therapy followed by surgery and postoperative therapy

Surgery PROCEDURE

Radical surgery

Also known as: Resection

Induction therapy followed by surgery and postoperative therapy

Chemoradiation OTHER

Chemoradiation as either radical treatment or post-operative treatment after surgery

Also known as: Chemoradiotherapy

Induction therapy followed by surgery and postoperative therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males or females are \>18 years of age with body weight ≥40kg at the time of providing voluntary written informed consent.
• 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,
• Histologically and/or cytologically confirmed locally advanced (T3-T4bN0-N3M0) non-metastatic SMARCB1 (INI-1)-deficient sinonasal carcinoma
• 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.
• Have measurable disease as defined by RECIST 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
• Must have a life expectancy of at least 12 weeks 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.
• 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
• 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.
• Adequate renal function as defined below:
• Creatinine \< 2.0 or calculated creatinine clearance ≥ 35 mL/minute per the Cockcroft and Gault formula

You may not qualify if:

• Pre-existing or co-existing epithelioid sarcoma.
• Has a prior history of T-Cell lymphoblastic lymphoma, T-cell acute lymphoblastic leukemia, myelodysplastic syndrome, acute myeloid leukemia, or myeloproliferative neoplasm.
• Have undergone a solid organ transplant.
• Prior malignancy in the past 5 years.
• Confirm pregnant or breastfeeding.
• Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
• On investigational therapy within 21 days at time of recruitment.
• Uncontrolled central nervous system (CNS) metastases requiring steroids.
• On medications that are known potent CYP3A4 inducers/inhibitors (including St. John's wort)
• Unwilling to exclude Seville oranges, grapefruit juice, and grapefruit from their diet.
• 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.
• 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.

Sponsors & Collaborators

• Dr. Victor H.F. Lee: lead

MeSH Terms

Interventions

Docetaxel; Cisplatin; Fluorouracil; tazemetostat; Surgical Procedures, Operative; Chemoradiotherapy

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Combined Modality Therapy; Therapeutics; Drug Therapy; Radiotherapy

Study Officials

• Victor Ho Fun Lee, MD

  Department of Clinical Oncology, The University of Hong Kong

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Victor Ho Fun Lee, MD

CONTACT

852-2255-4352; vhflee@hku.hk

Mike Law, BSc

CONTACT

852-2255-5034; lawhc703@hku.hk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Masking Details: No masking
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Clinical Associate Professor

Model Details: Induction treatment with docetaxel, cisplatin, 5-FU and tazemetostat followed by surgery or radical chemoradiation and maintenance tazemetostat

Study Record Dates

• First Submitted: November 27, 2021
• First Posted: December 9, 2021
• Study Start: September 1, 2023
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): August 31, 2027
• Last Updated: February 28, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share