En to-arm (fase 2) utforskende studie av Nivolumab monoterapi eller i kombinasjon med Nab-paclitaxel og Carboplatin i tidlig stadium NSCLC i Kina
Nivolumab (BMS-936558) er en fullstendig human, IgG4 (kappa) isotype mAb som binder PD-1 på aktiverte immunceller og forstyrrer engasjementet av reseptoren med dens ligander PD-L1 (B7 H1/CD274) og PD-L2 (B7) -DC/CD273), og opphever dermed hemmende signaler og øker vertens antitumorrespons. I tidlige kliniske studier har nivolumab vist aktivitet i flere tumortyper, inkludert melanom, nyrecellekarsinom (RCC) og ikke-småcellet lungekreft (NSCLC).
Nivolumab er i klinisk utvikling for behandling av pasienter med NSCLC, RCC, melanom, plateepitelkarsinom i hode og nakke (SCCHN) og andre svulster (f.eks. glioblastoma multiforme, mesothelioma, småcellet lungekreft, gastrisk).
Nivolumab er godkjent i USA (USA), EU og andre land for behandling av pasienter med inoperabelt eller metastatisk melanom, avansert NSCLC med progresjon på eller etter platinabasert kjemoterapi, avansert RCC hvis sykdom progredierte etter en antiangiogen terapi, klassisk Hodgkin-lymfom som har residivert eller progrediert etter autolog hematopoetisk stamcelletransplantasjon og post-transplantasjonsbehandling med brentuximab vedotin, og tilbakevendende eller metastatisk plateepitelkarsinom i hode og hals med sykdomsprogresjon på eller etter platinabasert behandling.
Den foreslåtte studien vil evaluere effektiviteten og sikkerheten ved preoperativ administrasjon av Nivolumab eller Nivolumab kombinert med nab-paklitaksel og karboplatin i neoadjuvant setting og administrasjon av Nivolumab i adjuvant setting hos pasienter med høyrisiko resektabel NSCLC, og vil lette en omfattende eksplorativ karakterisering av tumorimmune mikromiljøet og sirkulerende immunceller hos disse pasientene. Data innhentet i denne studien vil gi verdifull informasjon for planlegging av ytterligere prospektive kliniske studier av anti-PD-1 og andre immunterapier ved NSCLC, både i perioperative og avanserte sykdommer. Til syvende og sist er det svært ønskelig å oppdage potensielle biomarkører for respons og toksisitet for å tillate pasienter med NSCLC som mest sannsynlig vil ha fordel å motta anti-PD-1-behandling, og omvendt for å minimere risikoen for toksisitet og ineffektiv behandling for pasienter som er neppe til nytte.
Studieoversikt
Status
Forhold
Studietype
Registrering (Antatt)
Fase
- Fase 2
Kontakter og plasseringer
Studiesteder
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Guangdong
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Guangzhou, Guangdong, Kina, 510080
- Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences
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Deltakelseskriterier
Kvalifikasjonskriterier
Alder som er kvalifisert for studier
Tar imot friske frivillige
Beskrivelse
Inklusjonskriterier:
- Tidlig stadium IB-IIIA, operabel ikke-småcellet lungekreft, bekreftet i vev
- Lungefunksjonskapasitet som er i stand til å tolerere den foreslåtte lungeoperasjonen
- Eastern Cooperative Oncology Group (ECOG) ytelsesstatus på 0-1
- Tilgjengelig vev av primær lungetumor
Ekskluderingskriterier:
- Tilstedeværelse av lokalt avansert, inoperabel eller metastatisk sykdom
- Deltakere med aktiv, kjent eller mistenkt autoimmun sykdom
- Tidligere behandling med et hvilket som helst medikament som retter seg mot T-celle-co-stimuleringsveier (som sjekkpunkthemmere)
Andre protokolldefinerte inklusjons-/eksklusjonskriterier kan gjelde
Studieplan
Hvordan er studiet utformet?
Designdetaljer
- Primært formål: Behandling
- Tildeling: Ikke-randomisert
- Intervensjonsmodell: Enkeltgruppeoppdrag
- Masking: Ingen (Open Label)
Våpen og intervensjoner
Deltakergruppe / Arm |
Intervensjon / Behandling |
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Eksperimentell: 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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Eksperimentell: 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 hver tredje uke
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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Eksperimentell: 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 hver tredje uke
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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Eksperimentell: 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 hver tredje uke
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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Hva måler studien?
Primære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
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MPR (Major Pathological Response) rate
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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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Sekundære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
|---|---|---|
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MPR (Major Pathological response) rate in 2 subgroups patients (PD-L1 <1%, and 1-49%) in Arm B
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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%)
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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)
Tidsramme: 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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Andre resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
|---|---|---|
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pCR rate
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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
Tidsramme: 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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Samarbeidspartnere og etterforskere
Samarbeidspartnere
Publikasjoner og nyttige lenker
Studierekorddatoer
Studer hoveddatoer
Studiestart (Faktiske)
Primær fullføring (Antatt)
Studiet fullført (Antatt)
Datoer for studieregistrering
Først innsendt
Først innsendt som oppfylte QC-kriteriene
Først lagt ut (Faktiske)
Oppdateringer av studieposter
Sist oppdatering lagt ut (Faktiske)
Siste oppdatering sendt inn som oppfylte QC-kriteriene
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Mer informasjon
Begreper knyttet til denne studien
Ytterligere relevante MeSH-vilkår
- Neoplasmer etter nettsted
- Neoplasmer
- Sykdommer i luftveiene
- Lungesykdommer
- Neoplasmer i luftveiene
- Thoracale neoplasmer
- Lungeneoplasmer
- Karsinom, bronkogent
- Bronkiale neoplasmer
- Karsinom, ikke-småcellet lunge
- Aminosyrer, peptider og proteiner
- Proteiner
- Organiske kjemikalier
- Terapeutikk
- Antistoffer, monoklonalt, humanisert
- Antistoffer, monoklonalt
- Antistoffer
- Immunoglobuliner
- Immunoproteiner
- Blodproteiner
- Serumglobuliner
- Globuliner
- Uorganiske kjemikalier
- Klorforbindelser
- Nitrogenforbindelser
- Koordinasjonskomplekser
- Platinumforbindelser
- Nivolumab
- Karboplatin
- Cisplatin
- Medikamentell terapi
- 130-nm albuminbundet paclitaxel
Andre studie-ID-numre
- CTONG 1804
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