This phase Ib/II trial studies how well cadonilimab combined with anlotinib and docetaxel work in treating patients with non-small cell lung cancer that is stage IV or has come back. Cadonilimab, a PD-1/CTLA-4 bispecific antibody, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Anlotinib can regulate tumor microenvironment. Docetaxel was used in standard of care chemotherapy for non-small cell lung cancer, work to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving cadonilimab, anlotinib and docetaxel together may work better in treating patients with non-small lung cancer compared to standard of care.
PRIMARY OBJECTIVES: 1. Dose discovery stage: evaluate the safety of cadonilimab combined with anlotinib and docetaxel in the treatment of locally advanced and metastatic NSCLC after failure of treatment with PD-L1/1 inhibitors and the recommended dose of anlotinib. 2. Dose expansion stage: evaluate the 6-month PFS rate of patients with locally advanced and metastatic NSCLC after failure of treatment with PD-L1/1 inhibitors by cadonilimab combined with anlotinib and docetaxel, which was evaluated by researchers based on RECIST v1.1. SECONDARY OBJECTIVES: 1. evaluate the objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), duration of response (DoR), time to response (TTR), and total survival (OS) of patients with locally advanced and metastatic NSCLC after failure of treatment with PD-L1/1 inhibitors with cadonilimab, anlotinib, and docetaxel. 2. evaluate the safety and tolerability of cadonilimab combined with arotinib and docetaxel in the treatment of locally advanced and metastatic NSCLC after failure of treatment with PD-L1/1 inhibitor. OUTLINE: This is a prospective, open, single-arm, multi-center, phase I b/II clinical study. All patients were confirmed Locally advanced (stage IIIB/IIIC) that cannot be resected by radical surgery and cannot accept radical synchronous/sequential radiotherapy and chemotherapy or metastatic (stage IV) NSCLC by histology or cytology. Patients must have progressed on at most a PD-1/L1 inhibitor and a platinum-based chemotherapy (combined or sequential, regardless of sequence), and at least two cycles of PD-1/L1 inhibitor (combined or non-combined chemotherapy) with clinical benefits (PFS ≥ 3 months). The study is divided into two parts. The first part is the dose discovery stage. The patients will receive a 21-day observation period of dose limiting toxicity (DLT). 3-6 subjects will be enrolled in each dose, and finally evaluate the safety and determine the recommended dose (RP2D) for phase II clinical study according to the "3+3" principle. We will continue to recruit 44 patients at the dose expansion stage.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Given IV, 10mg/kg Q3W
oral,6mg/8mg/10mg qd 2W/3W
Given IV, 60-75mg/m2 Q3W
lejie Cao
Hefei, Anhui, China
Jing Wang
Qingdao, Shandong, China
Zhuang Yu
Qingdao, Shandong, China
Shanghai Chest Hospital
Shanghai, Shanghai Municipality, China
Jianya Zhou
Hangzhou, Zhejiang, China
RP2D of anlotinib
Will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Overall toxicity incidence as well as toxicity profiles will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses. Proportion of acute and late toxicity will be reported, and 95% confidence intervals will be estimated using the Clopper-Pearson method.
Time frame: Up to 21 days after the first cycle of study treatment
6-month progression-free survival (PFS) rate
Will be determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will be reported and its 95% confidence intervals will be estimated using the Clopper-Pearson method. PFS rates of two patient groups stratified by binary biomarker (PD-L1 and KRAS status), respectively will be estimated with the Kaplan-Meier method and compared using the log-rank test, respectively. Cox proportional hazards models will be further used in the multivariable analyses to assess adjusted effect of PD-L1 and KRAS status on the patients' PFS after adjusting for other factors. Interaction terms between these factors will also be tested for statistical significance. The proportional hazards assumption will be evaluated graphically and analytically with regression diagnostics. Violations of the proportional hazards assumptions will be addressed by use of time-dependent covariates or extended Cox regression models.
Time frame: up to 6 months
Overall response rate
Will be determined per RECIST 1.1 and immune-modified Response Evaluation Criteria in Solid Tumors.
Time frame: Through study completion, an average of 1 year
Overall survival (OS)
OS and rates of two patient groups stratified by binary biomarker (PD-L1 and KRAS status), respectively will be estimated with the Kaplan-Meier method and compared using the log-rank test, respectively. Cox proportional hazards models will be further used in the multivariable analyses to assess adjusted effect of PD-L1 and KRAS status on the patients' OS after adjusting for other factors. Interaction terms between these factors will also be tested for statistical significance. The proportional hazards assumption will be evaluated graphically and analytically with regression diagnostics. Violations of the proportional hazards assumptions will be addressed by use of time-dependent covariates or extended Cox regression models.
Time frame: up to 10 years
Investigator assessed-progression-free survival (IA-PFS)
Will be estimated using the method of Kaplan-Meier. Median and landmark time-point estimates will be based on the Kaplan-Meier estimates. The average hazard ratio (HR) will be estimated using a Cox proportional hazards model. An assessment of the proportional hazards assumption will be performed and an assessment of the time-dependent HR will be done.
Time frame: From date of sub-study registration to date of first documentation of progression assessed by central review or symptomatic deterioration, or death due to any cause, assessed up to 3 years
Incidence of adverse events
Will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Overall toxicity incidence as well as toxicity profiles will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses. Proportion of acute and late toxicity will be reported, and 95% confidence intervals will be estimated using the Clopper-Pearson method.
Time frame: Up to 30 days after the last dose of study treatment
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