Een verkennend onderzoek met twee armen (fase 2) van nivolumab als monotherapie of in combinatie met Nab-paclitaxel en carboplatine bij NSCLC in een vroeg stadium in China
Nivolumab (BMS-936558) is een volledig humaan, IgG4 (kappa) isotype mAb dat PD-1 bindt aan geactiveerde immuuncellen en de binding van de receptor met zijn liganden PD-L1 (B7 H1/CD274) en PD-L2 (B7 -DC/CD273), waardoor remmende signalen worden opgeheven en de antitumorrespons van de gastheer wordt versterkt. In vroege klinische onderzoeken heeft nivolumab activiteit aangetoond bij verschillende tumortypen, waaronder melanoom, niercelcarcinoom (RCC) en niet-kleincellige longkanker (NSCLC).
Nivolumab is in klinische ontwikkeling voor de behandeling van patiënten met NSCLC, RCC, melanoom, plaveiselcelcarcinoom van het hoofd en de nek (SCCHN) en andere tumoren (bijv. Multiform glioblastoom, mesothelioom, kleincellige longkanker, maag).
Nivolumab is goedgekeurd in de Verenigde Staten (VS), de Europese Unie en andere landen voor de behandeling van patiënten met inoperabel of gemetastaseerd melanoom, gevorderd NSCLC met progressie op of na op platina gebaseerde chemotherapie, gevorderd RCC bij wie de ziekte voortschreed op een antiangiogene therapie, klassiek Hodgkin-lymfoom dat is teruggevallen of gevorderd na autologe hematopoëtische stamceltransplantatie en behandeling met brentuximab vedotin na transplantatie, en recidiverend of gemetastaseerd plaveiselcelcarcinoom van het hoofd-halsgebied met ziekteprogressie tijdens of na een op platina gebaseerde therapie.
De voorgestelde studie zal de werkzaamheid en veiligheid evalueren van preoperatieve toediening van nivolumab of nivolumab gecombineerd met nab-paclitaxel en carboplatine in neoadjuvante setting en toediening van nivolumab in adjuvante setting bij patiënten met resectabele NSCLC met een hoog risico, en zal een uitgebreide verkennende karakterisering van de tumor-immuun micro-omgeving en circulerende immuuncellen bij deze patiënten. De gegevens die in dit onderzoek zijn verkregen, zullen waardevolle informatie opleveren voor het plannen van verdere prospectieve klinische onderzoeken naar anti-PD-1 en andere immunotherapieën bij NSCLC, zowel in de perioperatieve als in de gevorderde ziektesetting. Uiteindelijk is het zeer wenselijk om prospectieve biomarkers van respons en toxiciteit te ontdekken, zodat patiënten met NSCLC die er het meest waarschijnlijk baat bij zullen hebben, een anti-PD-1-behandeling kunnen krijgen, en omgekeerd het risico op toxiciteit en ineffectieve behandeling voor patiënten die dat wel zijn, minimaliseren. waarschijnlijk niet profiteren.
Studie Overzicht
Toestand
Conditie
Studietype
Inschrijving (Geschat)
Fase
- Fase 2
Contacten en locaties
Studie Locaties
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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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Deelname Criteria
Geschiktheidscriteria
Leeftijden die in aanmerking komen voor studie
Accepteert gezonde vrijwilligers
Beschrijving
Inclusiecriteria:
- Vroeg stadium IB-IIIA, operabele niet-kleincellige longkanker, bevestigd in weefsel
- Longfunctiecapaciteit die de voorgestelde longoperatie kan verdragen
- Eastern Cooperative Oncology Group (ECOG) Prestatiestatus van 0-1
- Beschikbaar weefsel van primaire longtumor
Uitsluitingscriteria:
- Aanwezigheid van lokaal gevorderde, niet-operabele of gemetastaseerde ziekte
- Deelnemers met een actieve, bekende of vermoede auto-immuunziekte
- Voorafgaande behandeling met een geneesmiddel dat zich richt op co-stimulatieroutes van T-cellen (zoals checkpoint-remmers)
Andere in het protocol gedefinieerde opname-/uitsluitingscriteria kunnen van toepassing zijn
Studie plan
Hoe is de studie opgezet?
Ontwerpdetails
- Primair doel: Behandeling
- Toewijzing: Niet-gerandomiseerd
- Interventioneel model: Opdracht voor een enkele groep
- Masker: Geen (open label)
Wapens en interventies
Deelnemersgroep / Arm |
Interventie / Behandeling |
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Experimenteel: 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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Experimenteel: 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 elke drie weken
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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Experimenteel: 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 elke drie weken
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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Experimenteel: 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 elke drie weken
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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Wat meet het onderzoek?
Primaire uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
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MPR (Major Pathological Response) rate
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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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Secundaire uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
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MPR (Major Pathological response) rate in 2 subgroups patients (PD-L1 <1%, and 1-49%) in Arm B
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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%)
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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)
Tijdsspanne: 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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Andere uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
|---|---|---|
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pCR rate
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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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Medewerkers en onderzoekers
Medewerkers
Publicaties en nuttige links
Studie record data
Bestudeer belangrijke data
Studie start (Werkelijk)
Primaire voltooiing (Geschat)
Studie voltooiing (Geschat)
Studieregistratiedata
Eerst ingediend
Eerst ingediend dat voldeed aan de QC-criteria
Eerst geplaatst (Werkelijk)
Updates van studierecords
Laatste update geplaatst (Werkelijk)
Laatste update ingediend die voldeed aan QC-criteria
Laatst geverifieerd
Meer informatie
Termen gerelateerd aan deze studie
Aanvullende relevante MeSH-voorwaarden
- Neoplasmata per site
- Neoplasmata
- Ziekten van de luchtwegen
- Longziekten
- Neoplasmata van de luchtwegen
- Thoracale neoplasmata
- Longneoplasmata
- Carcinoom, bronchogeen
- Bronchiale neoplasmata
- Carcinoom, niet-kleincellige long
- Aminozuren, peptiden en eiwitten
- Eiwitten
- Organische chemicaliën
- Therapeutica
- Antilichamen, monoklonaal, gehumaniseerd
- Antilichamen, monoklonaal
- Antilichamen
- Immunoglobulinen
- Immunoproteïnen
- Bloedeiwitten
- Serum -globulines
- Globulines
- Anorganische chemicaliën
- Chloorverbindingen
- Stikstofverbindingen
- Coördinatiecomplexen
- Platinumverbindingen
- Nivolumab
- Carboplatine
- Cisplatine
- Drugstherapie
- 130-nm albumine-gebonden Paclitaxel
Andere studie-ID-nummers
- CTONG 1804
Plan Individuele Deelnemersgegevens (IPD)
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