Um estudo exploratório de dois braços (fase 2) da monoterapia com nivolumabe ou em combinação com nab-paclitaxel e carboplatina em estágio inicial de NSCLC na China
Nivolumab (BMS-936558) é um mAb de isotipo IgG4 (kappa) totalmente humano que se liga a PD-1 em células imunológicas ativadas e interrompe o envolvimento do receptor com seus ligantes PD-L1 (B7 H1/CD274) e PD-L2 (B7 -DC/CD273), anulando assim os sinais inibitórios e aumentando a resposta antitumoral do hospedeiro. Em ensaios clínicos iniciais, nivolumab demonstrou atividade em vários tipos de tumor, incluindo melanoma, carcinoma de células renais (RCC) e câncer de pulmão de células não pequenas (NSCLC).
Nivolumab está em desenvolvimento clínico para o tratamento de pacientes com NSCLC, RCC, melanoma, carcinoma de células escamosas da cabeça e pescoço (SCCHN) e outros tumores (por exemplo, glioblastoma multiforme, mesotelioma, câncer de pulmão de pequenas células, gástrico).
Nivolumab é aprovado nos Estados Unidos (EUA), União Europeia e outros países para o tratamento de pacientes com melanoma irressecável ou metastático, NSCLC avançado com progressão durante ou após quimioterapia à base de platina, RCC avançado cuja doença progrediu com terapia antiangiogênica, linfoma de Hodgkin clássico que recidivou ou progrediu após transplante autólogo de células-tronco hematopoiéticas e tratamento pós-transplante com brentuximabe vedotina e carcinoma de células escamosas recorrente ou metastático da cabeça e pescoço com progressão da doença durante ou após uma terapia à base de platina.
O estudo proposto avaliará a eficácia e segurança da administração pré-operatória de Nivolumab ou Nivolumab combinado com nab-paclitaxel e carboplatina em ambiente neoadjuvante e administração de Nivolumab em ambiente adjuvante em pacientes com NSCLC ressecável de alto risco e facilitará uma caracterização exploratória abrangente de o microambiente imune do tumor e as células imunes circulantes nesses pacientes. Os dados obtidos neste estudo fornecerão informações valiosas para o planejamento de novos ensaios clínicos prospectivos de anti-PD-1 e outras imunoterapias em NSCLC, tanto no cenário de doença perioperatória quanto avançada. Em última análise, é altamente desejável descobrir biomarcadores prospectivos de resposta e toxicidade para permitir que pacientes com NSCLC com maior probabilidade de obter benefícios recebam tratamento anti-PD-1 e, inversamente, minimizar o risco de toxicidade e tratamento ineficaz para pacientes que são improvável de se beneficiar.
Visão geral do estudo
Status
Condições
Tipo de estudo
Inscrição (Estimado)
Estágio
- Fase 2
Contactos e Locais
Locais de estudo
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Guangdong
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Guangzhou, Guangdong, China, 510080
- Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Descrição
Critério de inclusão:
- Estágio inicial IB-IIIA, câncer de pulmão de células não pequenas operável, confirmado em tecido
- Capacidade de função pulmonar capaz de tolerar a cirurgia pulmonar proposta
- Status de Desempenho do Eastern Cooperative Oncology Group (ECOG) de 0-1
- Tecido disponível de tumor pulmonar primário
Critério de exclusão:
- Presença de doença localmente avançada, inoperável ou metastática
- Participantes com doença autoimune ativa, conhecida ou suspeita
- Tratamento prévio com qualquer medicamento que tenha como alvo as vias de coestimulação de células T (como inibidores de checkpoint)
Outros critérios de inclusão/exclusão definidos pelo protocolo podem ser aplicados
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: Não randomizado
- Modelo Intervencional: Atribuição de grupo único
- Mascaramento: Nenhum (rótulo aberto)
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
|---|---|
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Experimental: Part 1: Nivolumab Mono
In arm A, 24 participants will be enrolled into this arm according to PD-L1 expressing level (≥50%).Arm A consists of 3 cycles of neoadjuvant nivolumab (360mg every 3 weeks), and adjuvant nivolumab (360mg IV, every 3 weeks) up to 12 months
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Nivolumab 360 mg IV (administered intravenously for more than 30 minutes) every 3 weeks
Including lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy.
Segmentectomy and wedge resection are not permitted.
Within 6 weeks after definitive surgery, subjects in each cohort who are assessed to have benefited from neoadjuvant therapy (CR, PR, or SD) and have adequately recovered from surgery may receive adjuvant nivolumab (360 mg via IV infusion over at least 30 minutes, every 3 weeks) for up to 12 months, or until disease recurrence or unacceptable toxicity.
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Experimental: Part 1: Nivolumab Plus Chemo
In arm B, up to 12 participants will be enrolled into each subgroup according to PD-L1 expressing level (<1% and 1%-49%).arm
B consists of 3 cycles of neoadjuvant nivolumab (360mg every 3 weeks) with nab-paclitaxel and carboplatin(nab-paclitaxel 135 mg/m2, d1, 8 and carboplatin AUC 5, d1 every three weeks ), and adjuvant nivolumab (360mg IV, every 3 weeks) up to 12 months
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AUC 5, d1 a cada três semanas
135 mg/m2, d1, 8
Nivolumab 360 mg IV (administered intravenously for more than 30 minutes) every 3 weeks
Including lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy.
Segmentectomy and wedge resection are not permitted.
Within 6 weeks after definitive surgery, subjects in each cohort who are assessed to have benefited from neoadjuvant therapy (CR, PR, or SD) and have adequately recovered from surgery may receive adjuvant nivolumab (360 mg via IV infusion over at least 30 minutes, every 3 weeks) for up to 12 months, or until disease recurrence or unacceptable toxicity.
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Experimental: Part:2: Exploratory cohort
In part 2，the treatment regimen consists of three cycles of neoadjuvant nivolumab (360 mg every 3 weeks) in combination with nab-paclitaxel and carboplatin (nab-paclitaxel 135 mg/m² on days 1 and 8, and carboplatin AUC 5 on day 1, every 3 weeks), followed by adjuvant nivolumab (360 mg every 3 weeks, administered via IV infusion over at least 30 minutes) for up to 12 months.
A total of 53 subjects will be enrolled in this study, regardless of PD-L1 expression.
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AUC 5, d1 a cada três semanas
135 mg/m2, d1, 8
Nivolumab 360 mg IV (administered intravenously for more than 30 minutes) every 3 weeks
Including lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy.
Segmentectomy and wedge resection are not permitted.
Within 6 weeks after definitive surgery, subjects in each cohort who are assessed to have benefited from neoadjuvant therapy (CR, PR, or SD) and have adequately recovered from surgery may receive adjuvant nivolumab (360 mg via IV infusion over at least 30 minutes, every 3 weeks) for up to 12 months, or until disease recurrence or unacceptable toxicity.
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Experimental: Part 3: Real-world cohort
Part 3 aims to evaluate the real-world effectiveness of neoadjuvant chemoimmunotherapy in patients with EGFR/ALK wild-type, potentially resectable or unresectable Stage III NSCLC. Treatment Paradigm: Eligible subjects will receive 3 cycles of neoadjuvant chemoimmunotherapy. Subsequently, a Multidisciplinary Team (MDT) will evaluate and determine the optimal definitive local therapy, triage patients to either radical resection or concurrent chemoradiotherapy (CCRT). Following the completion of local therapy, patients will receive adjuvant or consolidation immunotherapy for a duration of 1 year, administered every 3 weeks (Q3W). Sample Size: The planned enrollment for Part 3 is 215 patients. |
AUC 5, d1 a cada três semanas
135 mg/m2, d1, 8
Nivolumab 360 mg IV (administered intravenously for more than 30 minutes) every 3 weeks
Including lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy.
Segmentectomy and wedge resection are not permitted.
Within 6 weeks after definitive surgery, subjects in each cohort who are assessed to have benefited from neoadjuvant therapy (CR, PR, or SD) and have adequately recovered from surgery may receive adjuvant nivolumab (360 mg via IV infusion over at least 30 minutes, every 3 weeks) for up to 12 months, or until disease recurrence or unacceptable toxicity.
In Part 3, for patients who are assessed by a Multidisciplinary Team (MDT) as unable to achieve R0 resection following neoadjuvant chemo-immunotherapy induction, the recommended radiotherapy regimen is: 60 Gy in 30 fractions (5 fractions per week) to 95% of the planning target volume (PTV).
Part 3: For patients who are determined by a Multidisciplinary Team (MDT) to be ineligible for R0 resection following neoadjuvant chemo-immunotherapy induction and require definitive radiotherapy, concurrent chemotherapy will be administered.
The regimen consists of cisplatin 30 mg/m² administered once weekly
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O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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MPR (Major Pathological Response) rate
Prazo: The patients considered to be technically resectable will undergo resection，an expected average of 13 weeks
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As the primary outcome in part 1. MPR rate, defined as the number of participants with <10% residual tumor in lung and lymph nodes, divided by the number of treated participants for each arm.
Viable tumors in situ carcinoma should not be included in the MPR calculation.
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The patients considered to be technically resectable will undergo resection，an expected average of 13 weeks
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EFS
Prazo: Since the last patient was enrolled for follow-up for 36 months
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Primary Outcome for Part 2. Outcome Measure Definition: Event-Free Survival (EFS) is defined as the time from randomization to the first occurrence of any of the following events: Disease progression that precludes surgical treatment; Local or distant recurrence; Death from any cause. Progression and recurrence will be assessed by the investigator according to RECIST 1.1. Subjects who die without documented disease progression or recurrence will be considered to have experienced an EFS event on the date of death. |
Since the last patient was enrolled for follow-up for 36 months
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18 months EFS rate
Prazo: The patient was followed up for 18 months after frist cycle neoajuvant treatment.
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Primary Outcome for Part 3. Outcome Measure Definition: 18months Event-Free Survival (EFS) is defined as the time from randomization to the first occurrence of any of the following events: Disease progression that precludes surgical treatment; Local or distant recurrence; Death from any cause. Progression and recurrence will be assessed by the investigator according to RECIST 1.1. Subjects who die without documented disease progression or recurrence will be considered to have experienced an EFS event on the date of death. |
The patient was followed up for 18 months after frist cycle neoajuvant treatment.
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Surgical Conversion Rate
Prazo: Perioperative/Periprocedural
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The primary endpoint of Part 3 is the surgical conversion rate, defined as the proportion of patients who successfully undergo definitive surgery following neoadjuvant chemoimmunotherapy, relative to the total enrolled population (Intent-to-Treat [ITT] analysis set). Statistical Analysis: The surgical conversion rate will be summarized descriptively using frequencies and percentages. The two-sided 95% exact confidence interval (CI) for the proportion will be calculated using the Clopper-Pearson method. |
Perioperative/Periprocedural
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Medidas de resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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MPR (Major Pathological response) rate in 2 subgroups patients (PD-L1 <1%, and 1-49%) in Arm B
Prazo: The patients considered to be technically resectable will undergo resection，an expected average of 13 weeks
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In part 1
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The patients considered to be technically resectable will undergo resection，an expected average of 13 weeks
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Proportion of resection without delay
Prazo: The patients considered to be technically resectable will undergo resection，an expected average of 13 weeks
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In part 1and 2
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The patients considered to be technically resectable will undergo resection，an expected average of 13 weeks
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Number of Participants with Adverse Events
Prazo: During the treatment period, within at least 100 days after the cessation of neoadjuvant therapy, within 90 days after surgery, and within 30 days after adjuvant therapy.
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In parts 1 and 2 Safety and tolerability will be measured by incidence of AE, SAE, immune related AEs, deaths, and laboratory abnormalities
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During the treatment period, within at least 100 days after the cessation of neoadjuvant therapy, within 90 days after surgery, and within 30 days after adjuvant therapy.
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MRP rate
Prazo: The patients considered to be technically resectable will undergo resection，an expected average of 13 weeks
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Also, as the primary outcome in part 1. MPR rate, defined as number participants with <10% residual tumor in lung and lymph nodes, divided by the number of treated participants for each arm Viable tumors in situ carcinoma should not be included in MPR calculation.
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The patients considered to be technically resectable will undergo resection，an expected average of 13 weeks
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The EFS rates of all subjects with different PD-L1 expression statuses (PD-L1 < 1%, 1-49% and ≥ 50%)
Prazo: From date of enrollment up to the end of study, 5 years.
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In parts 1 and 2. Outcome Measure Definition: Event-Free Survival (EFS) is defined as the time from randomization to the first occurrence of any of the following events: Disease progression that precludes surgical treatment; Local or distant recurrence; Death from any cause. Progression and recurrence will be assessed by the investigator according to RECIST 1.1. Subjects who die without documented disease progression or recurrence will be considered to have experienced an EFS event on the date of death. |
From date of enrollment up to the end of study, 5 years.
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12 months EFS rate
Prazo: After 12 months of enrollment for all patientsAfter 12 months of enrollment for all patients
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In part 3, the 12-month EFS rate is the proportion of subjects who are alive and event-free at 12 months after the start of treatment.
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After 12 months of enrollment for all patientsAfter 12 months of enrollment for all patients
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OS
Prazo: From the date of enrollment until the date of death, assessed up to 100 months
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In part 3, OS is defined as the time from the start of treatment to death for any reason
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From the date of enrollment until the date of death, assessed up to 100 months
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TDDM (Time to Death or Distant Metastasis)
Prazo: From the date of the first dose of study treatment until the date of first documented distant metastasis or death from any cause, whichever occurs first, assessed up to approximately 60 months.
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In part 3, TDDM is defined as the start of the first treatment to distant metastasis, or death from any cause, whichever occurs first
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From the date of the first dose of study treatment until the date of first documented distant metastasis or death from any cause, whichever occurs first, assessed up to approximately 60 months.
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Outras medidas de resultado
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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pCR rate
Prazo: The patients considered to be technically resectable will undergo resection，an expected average of 13 weeks
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The pCR (complete pathological response) rate is defined as the number of subjects with no residual tumor cells in the lungs and lymph nodes divided by the number of subjects receiving treatment.
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The patients considered to be technically resectable will undergo resection，an expected average of 13 weeks
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OS rate
Prazo: From date of enrollment up to the end of study, 5 years.
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OS is defined as the time since the treatment date and the death date, with the deletion date being the last known date when the subject was still alive
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From date of enrollment up to the end of study, 5 years.
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ORR
Prazo: Within 4 to 6 weeks after the patient completes the neoadjuvant treatment
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ORR is defined as the optimal objective tumor response rate between neoadjuvant therapy and surgery (according to RECIST 1.1 criteria).
All subjects will have their ORR calculated.
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Within 4 to 6 weeks after the patient completes the neoadjuvant treatment
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Safty
Prazo: From the time of enrollment until the completion of adjuvant therapy, which lasted for 13 weeks
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Descriptive statistical analysis of safety data was conducted based on the 4th edition of NCI CTCAE.
According to the most severe level determined by NCI CTCAE V4, all AE/ SAEs that occur after treatment and treatment-related AE/ SAEs will be summarized by systemic organ classification and standard terms.
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From the time of enrollment until the completion of adjuvant therapy, which lasted for 13 weeks
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18m-DFS rate
Prazo: The 18-month DFS rate refers to the probability of being event-free at 18 months calculated from the date of surgery.
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Disease-Free Survival (DFS) is defined as the time from the date of surgery to any of the following events: disease progression, recurrence, or death from any cause.
Disease progression and recurrence will be assessed according to RECIST 1.1 criteria.
For subjects who do not experience a DFS event, the date of censoring will be the date of the last evaluable tumor assessment after surgery.
For subjects who do not experience a DFS event but start subsequent anti-cancer therapy, the date of censoring will be the date of the last evaluable tumor assessment prior to receiving the subsequent anti-cancer therapy.
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The 18-month DFS rate refers to the probability of being event-free at 18 months calculated from the date of surgery.
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Landmark MRD positive rate
Prazo: One month after local therapy
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In part 3, the Landmark MRD positive rate is defined as the proportion of patients who were MRD positive at the Landmark time point among the total study population.
Furthermore, the comparison is made between the proportion of patients with MRD positivity among those who underwent surgery and the proportion of patients with MRD positivity among those who received radiotherapy.
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One month after local therapy
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Colaboradores e Investigadores
Patrocinador
Colaboradores
Publicações e links úteis
Datas de registro do estudo
Datas Principais do Estudo
Início do estudo (Real)
Conclusão Primária (Estimado)
Conclusão do estudo (Estimado)
Datas de inscrição no estudo
Enviado pela primeira vez
Enviado pela primeira vez que atendeu aos critérios de CQ
Primeira postagem (Real)
Atualizações de registro de estudo
Última Atualização Postada (Real)
Última atualização enviada que atendeu aos critérios de controle de qualidade
Última verificação
Mais Informações
Termos relacionados a este estudo
Termos MeSH relevantes adicionais
- Neoplasias por local
- Neoplasias
- Doenças Respiratórias
- Doenças pulmonares
- Neoplasias do Trato Respiratório
- Neoplasias Torácicas
- Neoplasias Pulmonares
- Carcinoma Broncogênico
- Neoplasias Brônquicas
- Carcinoma pulmonar de células não pequenas
- Aminoácidos, peptídeos e proteínas
- Proteínas
- Produtos químicos orgânicos
- Terapêutica
- Anticorpos, monoclonais, humanizados
- Anticorpos, monoclonais
- Anticorpos
- Imunoglobulinas
- Imunoproteínas
- Proteínas sanguíneas
- Globulinas de soro
- Globulins
- Produtos químicos inorgânicos
- Compostos de cloro
- Compostos de nitrogênio
- Complexos de coordenação
- Compostos de platina
- Nivolumabe
- Carboplatina
- Cisplatina
- Terapia medicamentosa
- Paclitaxel com 130 nm de albumina
Outros números de identificação do estudo
- CTONG 1804
Plano para dados de participantes individuais (IPD)
Planeja compartilhar dados de participantes individuais (IPD)?
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