Neoadjuvant Finotonlimab Plus TP Regimen in Locally Advanced INI-1-Deficient Sinonasal Carcinoma (SDSC-IO-TP)
Neoadjuvant Finotonlimab Plus TP Regimen in Locally Advanced INI-1 (SMARCB1)-Deficient Sinonasal Carcinoma: A Prospective, Multicenter, Single-Arm Phase II Clinical Study
This is a prospective, multicenter, single-arm phase 2 study in adults with locally advanced (T3/T4) INI-1 (SMARCB1)-deficient sinonasal carcinoma, a very rare and aggressive cancer of the nasal cavity and sinuses. This cancer often invades the skull base, eyes, nerves, and surrounding critical structures, making surgery difficult and potentially disabling. Current standard treatment is usually surgery followed by radiotherapy, but complete removal is often difficult and recurrence is common. Standard chemotherapy before surgery has shown limited tumor shrinkage, so better pre-surgical treatment is urgently needed.
The purpose of this study is to find out whether giving an immunotherapy drug, finotonlimab, together with standard chemotherapy (paclitaxel plus cisplatin, the "TP" regimen) before surgery can shrink the tumor and improve treatment results. Finotonlimab is a PD-1 inhibitor that may help the immune system attack the cancer, and it is being given together with chemotherapy because the two treatments may work better in combination. All participants will receive 2 cycles of this combined treatment (each cycle is 21 days), followed by imaging tests to measure tumor response. If the tumor is considered removable, participants will then undergo surgery and, after recovery, standard postoperative radiotherapy.
The main question this study is trying to answer is: how many participants experience significant tumor shrinkage (objective response, defined as complete or partial response) after 2 cycles of neoadjuvant finotonlimab plus TP chemotherapy, as assessed by blinded independent imaging review using RECIST v1.1. The study will also look at safety, the rate of complete surgical removal (R0 resection), pathological response, disease-free and overall survival, quality of life, and whether important organs such as the eye can be preserved. About 20 participants will be enrolled across multiple centers. This study is expected to provide the first prospective evidence for this combination in this rare cancer and may help establish a new treatment option before surgery.
Visão geral do estudo
Status
Condições
Intervenção / Tratamento
Descrição detalhada
This phase 2 study is designed to evaluate the efficacy and safety of neoadjuvant finotonlimab combined with TP chemotherapy in patients with locally advanced INI-1 (SMARCB1)-deficient sinonasal carcinoma. INI-1 deficiency defines a rare, aggressive subtype of sinonasal carcinoma with a high propensity for skull base invasion and limited response to conventional induction chemotherapy. The study hypothesis is that adding PD-1 blockade to standard TP chemotherapy will increase the preoperative objective response rate, facilitate tumor downstaging, improve R0 resection, and potentially reduce surgical morbidity while preserving organ function.
Approximately 20 eligible participants will be enrolled across multiple centers. All participants will receive 2 cycles of neoadjuvant therapy every 21 days: finotonlimab 200 mg intravenously on day 1, followed by paclitaxel 135-175 mg/m² on day 1 and cisplatin 70-75 mg/m² on days 1-3, with standard premedication, hydration, and antiemetic support. After 2 cycles, tumor response will be assessed by contrast-enhanced MRI of the skull base and chest CT, with independent blinded central review using RECIST v1.1. Participants with complete response, partial response, or stable disease will proceed to definitive surgery aiming for R0 resection, followed by postoperative intensity-modulated radiotherapy (60-66 Gy in 30-33 fractions) after adequate wound healing. Participants with progressive disease will discontinue the study regimen and receive salvage therapy as determined by the multidisciplinary team.
The primary endpoint is objective response rate after 2 cycles of neoadjuvant therapy, assessed by blinded independent central review. Secondary assessments include disease control rate, R0 resection rate, major pathological response, pathological complete response, disease-free survival, overall survival, safety and tolerability according to CTCAE v5.0, surgery- and radiotherapy-related complications, quality of life using EORTC QLQ-C30 and QLQ-H&N35, and organ preservation rate. Exploratory analyses will evaluate the association of PD-L1 CPS, Ki-67, TP53 mutation status, and serial circulating tumor DNA dynamics with treatment response and recurrence risk, and will explore baseline clinical features such as T stage and cranial nerve involvement as potential predictors of benefit.
This study is expected to provide the first prospective multicenter evidence for neoadjuvant PD-1 blockade combined with TP chemotherapy in this ultra-rare sinonasal malignancy. If positive, the results may support a new preoperative treatment paradigm aimed at improving resectability and functional outcomes, and will inform future larger studies.
Tipo de estudo
Inscrição (Estimado)
Estágio
- Fase 2
Contactos e Locais
Contato de estudo
- Nome: Quan Liu, MD
- Número de telefone: 15001959681
- E-mail: liuqent@163.com
Estude backup de contato
- Nome: Wanpeng Li, MD
- E-mail: 18879117831@163.com
Locais de estudo
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Shanghai Municipality
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Shanghai, Shanghai Municipality, China, 200031
- Recrutamento
- Eye & ENT Hospital of Fudan University
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Contato:
- Qaun Liu, MD
- Número de telefone: 15001959681
- E-mail: Liuqent@163.com
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Descrição
Inclusion Criteria:
- Age 18-75 years, male or female.
- Complete loss of nuclear INI-1 (SMARCB1) expression in tumor cells confirmed by central pathology immunohistochemistry, with a pathological diagnosis of primary malignant tumor of the sinonasal cavity and skull base.
- No prior radiotherapy of any type, including proton/heavy-ion radiotherapy or intensity-modulated radiotherapy.
- AJCC 8th edition stage T3, T4a, or T4b; N0-N2 lymph node metastasis is allowed; isolated distant metastases assessed by MDT as stable and amenable to concurrent local treatment are allowed; extensive multiple distant metastases are excluded.
- MDT assessment indicates extensive local invasion of the skull base and/or orbit, high difficulty for direct surgery, high risk of residual disease, and suitability for neoadjuvant downstaging.
- ECOG performance status 0-1 and expected survival ≥6 months.
- Baseline laboratory values meet treatment safety standards: absolute neutrophil count ≥1.5 × 10⁹/L; platelet count ≥100 × 10⁹/L; hemoglobin ≥90 g/L; ALT/AST ≤2.5 × ULN; total bilirubin ≤1.5 × ULN; serum creatinine ≤1.5 × ULN; creatinine clearance ≥60 mL/min; LVEF ≥50%; and no significant thyroid dysfunction.
- Voluntary participation with full understanding of benefits and risks, and signing of two copies of the informed consent form.
Exclusion Criteria:
- Prior use of PD-1/PD-L1 inhibitors, taxane chemotherapy, or platinum-based chemotherapy.
- History of severe allergy to finotonlimab, paclitaxel, cisplatin, or any of their excipients.
- Active autoimmune disease, interstitial lung disease, active tuberculosis, or uncontrolled severe infection.
- Severe cardiovascular or cerebrovascular disease, uncontrolled hypertension, or severe hepatic or renal failure.
- History of another malignancy within 5 years, except adequately treated basal cell skin cancer or carcinoma in situ.
- Pregnant or breastfeeding women.
- Men or women of childbearing potential who are unwilling to use adequate contraception during treatment and for 6 months after the end of treatment.
- Participation in another anticancer clinical trial within 30 days before enrollment.
- Psychiatric disorders, poor compliance, or inability to complete follow-up.
- Extensive multiple intracranial metastases or inability to tolerate systemic treatment.
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: N / D
- Modelo Intervencional: Atribuição de grupo único
- Mascaramento: Nenhum (rótulo aberto)
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
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Experimental: Neoadjuvant Finotonlimab Plus TP Chemotherapy
All participants are enrolled in this single experimental arm and receive the same study-specified treatment sequence. Participants first receive 2 cycles of neoadjuvant therapy, with each cycle lasting 21 days: finotonlimab 200 mg by intravenous infusion on day 1; paclitaxel 135-175 mg/m² by intravenous infusion on day 1; and cisplatin 70-75 mg/m² by intravenous infusion on days 1-3. Standard premedication, hydration, antiemetic prophylaxis, and supportive care are given according to institutional practice. After 2 cycles, tumor response is assessed by contrast-enhanced MRI of the skull base and chest CT with blinded independent central review using RECIST v1.1. Participants with complete response, partial response, or stable disease then undergo definitive surgery aiming for R0 resection. Postoperative intensity-modulated radiotherapy (IMRT) of 60-66 Gy in 30-33 fractions is planned to start 4-6 weeks after surgery, once wound healing and general condition permit. Participants with |
Finotonlimab is an anti-PD-1 monoclonal antibody administered as part of neoadjuvant therapy. It is given intravenously at a fixed dose of 200 mg on day 1 of each 21-day cycle, for a total of 2 cycles. It is infused before paclitaxel and cisplatin on the same day. This is the experimental immunotherapy component of the study regimen. Paclitaxel is a standard cytotoxic chemotherapy agent administered as part of the neoadjuvant TP regimen. It is given by intravenous infusion over 3 hours on day 1 of each 21-day cycle, at a dose of 135-175 mg/m², for a total of 2 cycles. Standard premedication (dexamethasone, diphenhydramine, and cimetidine or an equivalent H2 blocker) is given before infusion to prevent hypersensitivity reactions. Paclitaxel is administered after finotonlimab and before cisplatin. Cisplatin is a standard platinum-based chemotherapy agent administered as part of the neoadjuvant TP regimen. It is given by intravenous infusion at a dose of 70-75 mg/m² on days 1-3 of each 21-day cycle, with the total dose for the cycle divided across the three days, for a total of 2 cycles. It is administered after paclitaxel on day 1. Standard hydration, diuresis, and electrolyte supplementation (potassium and magnesium) are provided. This divided-day schedule is used to reduce acute nephrotoxicity and severe emesis associated with single high-dose cisplatin. |
O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
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Objective Response Rate
Prazo: After completion of 2 cycles of neoadjuvant therapy (each cycle is 21 days; response assessment performed approximately 3 weeks after the last dose of cycle 2)
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Objective response rate (ORR) is defined as the proportion of participants who achieve a complete response (CR) or partial response (PR) after 2 cycles of neoadjuvant finotonlimab plus TP chemotherapy. Tumor response is assessed by contrast-enhanced MRI of the skull base and chest CT, and evaluated by a blinded independent central review (BICR) according to RECIST v1.1. ORR is calculated as (CR + PR) divided by the number of participants in the full analysis set (all enrolled participants who signed informed consent and received at least 1 dose of study treatment). The 95% confidence interval will be estimated using the Clopper-Pearson exact method. |
After completion of 2 cycles of neoadjuvant therapy (each cycle is 21 days; response assessment performed approximately 3 weeks after the last dose of cycle 2)
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Medidas de resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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Disease Control Rate (DCR)
Prazo: Approximately 9 weeks after the first dose of neoadjuvant therapy (after 2 cycles of 21 days each), consistent with the primary ORR assessment time point.
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DCR is defined as the proportion of participants who achieve complete response (CR), partial response (PR), or stable disease (SD) after 2 cycles of neoadjuvant finotonlimab plus TP chemotherapy, assessed by blinded independent central review (BICR) using RECIST v1.1. DCR is calculated as (CR + PR + SD) divided by the number of evaluable participants. |
Approximately 9 weeks after the first dose of neoadjuvant therapy (after 2 cycles of 21 days each), consistent with the primary ORR assessment time point.
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R0 Resection Rate
Prazo: At the time of definitive surgery (after completion of 2 cycles of neoadjuvant therapy)
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R0 resection rate is defined as the proportion of participants who undergo surgery and achieve microscopically negative surgical margins (R0), as confirmed by central pathology review. The denominator is all participants who undergo definitive surgery. |
At the time of definitive surgery (after completion of 2 cycles of neoadjuvant therapy)
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Disease-Free Survival (DFS)
Prazo: From the date of surgery until the date of first documented recurrence, metastasis, or death from any cause, assessed up to 3 years after surgery.
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DFS is defined as the time from the date of surgery to the date of local recurrence, distant metastasis, or death from any cause, whichever occurs first. DFS will be estimated using the Kaplan-Meier method. |
From the date of surgery until the date of first documented recurrence, metastasis, or death from any cause, assessed up to 3 years after surgery.
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Overall Survival (OS)
Prazo: From the date of enrollment until the date of death from any cause, assessed up to 3 years after enrollment.
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OS is defined as the time from enrollment (or randomization, if applicable) to the date of death from any cause. Participants alive at the last follow-up will be censored at that date. OS will be estimated using the Kaplan-Meier method. |
From the date of enrollment until the date of death from any cause, assessed up to 3 years after enrollment.
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Major Pathological Response (MPR) Rate
Prazo: At the time of definitive surgery (after completion of 2 cycles of neoadjuvant therapy).
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MPR is defined as the proportion of participants whose surgically resected specimens contain ≤10% viable tumor cells, as assessed by central pathology review. The denominator is all participants who undergo definitive surgery and have evaluable pathological specimens. |
At the time of definitive surgery (after completion of 2 cycles of neoadjuvant therapy).
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Pathological Complete Response (pCR) Rate
Prazo: At the time of definitive surgery (after completion of 2 cycles of neoadjuvant therapy).
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pCR is defined as the proportion of participants whose surgically resected specimens contain no viable tumor cells, as assessed by central pathology review. The denominator is all participants who undergo definitive surgery and have evaluable pathological specimens. |
At the time of definitive surgery (after completion of 2 cycles of neoadjuvant therapy).
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Incidence and Severity of Adverse Events During Neoadjuvant Therapy
Prazo: From the first dose of neoadjuvant therapy until 30 days after the last dose of neoadjuvant therapy (approximately 3 months).
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All adverse events (AEs), Grade ≥3 AEs, and serious adverse events (SAEs) occurring during neoadjuvant therapy will be recorded and graded according to CTCAE v5.0. The type, incidence, and outcome of each event will be summarized descriptively. |
From the first dose of neoadjuvant therapy until 30 days after the last dose of neoadjuvant therapy (approximately 3 months).
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Incidence of Surgery- and Radiotherapy-Related Complications
Prazo: From the date of surgery until 12 months after completion of postoperative radiotherapy.
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The incidence of prespecified complications will be recorded, including cerebrospinal fluid leak, intracranial infection, cranial nerve injury, major hemorrhage, trismus, and radiation-induced brain injury. Complications will be documented from the surgical record and during the postoperative radiotherapy and follow-up periods |
From the date of surgery until 12 months after completion of postoperative radiotherapy.
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Change in Quality of Life Scores Assessed by EORTC QLQ-C30 and QLQ-H&N35
Prazo: Baseline, before surgery (after neoadjuvant therapy), after surgery, and every 6 months during follow-up, assessed up to 3 years after enrollment.
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Quality of life will be assessed using the EORTC QLQ-C30 (Version 3.0) and the head and neck module QLQ-H&N35. Scores for functional scales, symptom scales, and the global health status/QoL scale will be collected and the change from baseline will be summarized at each prespecified time point. |
Baseline, before surgery (after neoadjuvant therapy), after surgery, and every 6 months during follow-up, assessed up to 3 years after enrollment.
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Organ Preservation Rate
Prazo: At the time of definitive surgery (after completion of 2 cycles of neoadjuvant therapy).
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Organ preservation rate is defined as the proportion of participants who undergo definitive surgery without orbital exenteration or extensive craniofacial/maxillary resection. Organ preservation status will be determined from the surgical record and multidisciplinary team assessment. |
At the time of definitive surgery (after completion of 2 cycles of neoadjuvant therapy).
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Colaboradores e Investigadores
Patrocinador
Publicações e links úteis
Publicações Gerais
- Gounder M, Schoffski P, Jones RL, Agulnik M, Cote GM, Villalobos VM, Attia S, Chugh R, Chen TW, Jahan T, Loggers ET, Gupta A, Italiano A, Demetri GD, Ratan R, Davis LE, Mir O, Dileo P, Van Tine BA, Pressey JG, Lingaraj T, Rajarethinam A, Sierra L, Agarwal S, Stacchiotti S. Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol. 2020 Nov;21(11):1423-1432. doi: 10.1016/S1470-2045(20)30451-4. Epub 2020 Oct 6.
- Tang S, Lin G, Wu X, Chen Z. Efficacy of neoadjuvant pembrolizumab combined with paclitaxel and cisplatin in locally advanced oropharyngeal and hypopharyngeal squamous cell carcinoma: a retrospective study. Front Immunol. 2025 Nov 21;16:1690935. doi: 10.3389/fimmu.2025.1690935. eCollection 2025.
- Amit M, Abdelmeguid AS, Watcherporn T, Takahashi H, Tam S, Bell D, Ferrarotto R, Glisson B, Kupferman ME, Roberts DB, Su SY, Raza SM, DeMonte F, Hanna EY. Induction Chemotherapy Response as a Guide for Treatment Optimization in Sinonasal Undifferentiated Carcinoma. J Clin Oncol. 2019 Feb 20;37(6):504-512. doi: 10.1200/JCO.18.00353. Epub 2019 Jan 7.
- Zhao S, Du H, Zhang Z, Yang J, Zhou Y, Xiao G, Ma H, Lan C, Liang J, Yang K, Wen L. SMARCB1/INI-1-Deficient sinonasal carcinoma demonstrates a poor prognosis but favorable clinical outcomes after PD-1/PD-L1 inhibitor therapy: A case series. Sci Prog. 2025 Jan-Mar;108(1):368504251315075. doi: 10.1177/00368504251315075.
- Lee VH, Tsang RK, Lo AWI, Chan SY, Chung JC, Tong CC, Leung TW, Kwong DL. SMARCB1 (INI-1)-Deficient Sinonasal Carcinoma: A Systematic Review and Pooled Analysis of Treatment Outcomes. Cancers (Basel). 2022 Jul 5;14(13):3285. doi: 10.3390/cancers14133285.
- Contrera KJ, Shakibai N, Su SY, Gule-Monroe MK, Roberts D, Brahimaj B, Williams MD, Ferrarotto R, Phan J, Gunn B, Raza S, DeMonte F, Hanna EY. Impact of Clinical Factors and Treatments on SMARCB1 (INI-1)-Deficient Sinonasal Carcinoma. Otolaryngol Head Neck Surg. 2023 Aug;169(2):435-440. doi: 10.1002/ohn.310. Epub 2023 Mar 1.
- Woods R, Scholfield D, Axiotakis L, Fitzgerald C, Adilbay D, Cracchiolo J, Patel S, Shah J, Dunn L, Pfister D, Lee N, Dogan S, Ganly I, Cohen M. Outcomes of SMARCB1-deficient sinonasal carcinoma: Largest single-center cross-sectional study. Head Neck. 2024 Dec;46(12):3076-3084. doi: 10.1002/hed.27859. Epub 2024 Jul 23.
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- 2026211-1
Plano para dados de participantes individuais (IPD)
Planeja compartilhar dados de participantes individuais (IPD)?
Descrição do plano IPD
Individual participant data will not be shared. This is an investigator-initiated study in an ultra-rare cancer, where even limited demographic and clinical data could risk re-identification. The informed consent and ethics approval restrict use of biological samples and data to this specific research; samples will not be transferred to third parties and will be destroyed after 5 years. The study does not have infrastructure for external data access. If the sharing plan changes, this record will be updated accordingly.
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