Phase II Study of Platinum (Cisplatin/Carboplatin)and Polymeric Micelles Paclitaxel(Pm-Pac) With Ivonescimab in First Line Metastatic Squamous NSCLC.

Official title

Ivonescimab Combined With Polymeric Micelles Paclitaxel(Pm-Pac) and Platinum (Cisplatin/Carboplatin) as First-line Treatment for Patients With Advanced Squamous NSCLC: A Multicenter, Open-label, Single-arm Clinical Study.

Overview

This is a prospective, single-arm, multi-center, phase Ⅱ trial to evaluate the efficacy and safety of Polymeric Micelles paclitaxel(pm-Pac), platinum (cisplatin/carboplatin) in combination with Ivonescimab as first-line treatment in metastatic squamous NSCLC patients.

Interventions

• Drug Ivonescimab 20mg/kg intravenous every 3 weeks
  Ivonescimab(20mg/kg) combined with paclitaxel polymeric micelles (≤300mg/㎡) and platinum(cisplatin 75mg/㎡or carboplatin AUC5) IV every 3 weeks for 4 cycles.If patient assessment is of clinical benefit, maintenance therapy with ivonescimab or plus polymeric micelles paclitaxel(≤230mg/m\^2) can be continued based on investigator's evaluation and patient's own choice until disease progression or unacceptable toxicity. Ivonescimab is administered first, followed by paclitaxel polymeric micelles and

Primary outcome measures

• progression-free survival [Time frame: From the start of treatment until disease progression or death (assessed up to 24 months)]

Secondary outcome measures (5)

• Objective Response Rate [Time frame: Every 6 weeks (RECIST 1.1) until progression (up to 24 months)]
• Disease Control Rate [Time frame: From the first dose of study drug to the first date of documentation of disease progression or death whichever occurred first, up to approximately 2 years]
• Duration of Response [Time frame: From date of first documented confirmed CR or PR until date of first documentation of PD or death whichever occurred first, up to approximately 2 years]
• Overall Survival [Time frame: From the date of first dose of study drug until date of death from any cause (up to approximately 5 years )]
• Incidence of Adverse Events [Time frame: From first dose until 30 days after the last dose, up to approximately 2 years.]

Eligibility criteria

Inclusion criteria

• Written informed consent must be signed before implementing any trial-related procedures;
• Age ≥18 years old;
• Patients with histologically or cytologically confirmed metastatic or recurrent (stage IV) squamous NSCLC (International Association for the Study of Lung Cancer and American Joint Committee on Classification of Cancer, 8th Edition TNM staging), inoperable or inappropriate for radical concurrent chemoradiotherapy, and without previous systemic treatment；. Patients with mixed histology (example adenosquamous) are allowed if there is squamous component in the specimen. PD-L1 immunohistochemical results is required before enrollment.

5.According to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), there is at least one measurable lesion.

6.Have not received any previous systemic antitumor therapy for advanced/metastatic diseases. Participants who have previously received platinum-based adjuvant/neoadjuvant chemotherapy, or radical chemoradiotherapy for advanced disease are allowed to enroll if the interval between disease progression or recurrence and the end of the last chemotherapy treatment is at least 6 months.

7.ECOG score: 0-1 8.Expected survival time > 3 months 9.Normal organ function, patients should meet the following laboratory indicators:

• Blood routine test should meet the following criteria (no blood transfusion, no use of blood products, granulocyte colony-stimulating factor, or other hematopoietic growth factors within 7 days before blood routine test); White blood cell count ≥3.0x10\^9/L, absolute neutrophil count (ANC) ≥1.5x10\^9/L，Platelet count ≥100×10\^9/L Hemoglobin >9g/dL. If patients receive blood component transfusion (red blood cells, platelets, etc.) during the screening period, blood routine test should be performed again at an interval of 1 week to meet the above criteria before continuing screening.
• Blood biochemical examination must meet the following criteria: Total bilirubin ≤1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase (ALP) ≤2.5 times ULN (ALT, AST, or ALP≤ 5×ULN for patients with liver metastases, and ALP≤10×ULN for patients with bone metastases); Serum creatinine ≤1.5 times ULN and creatinine clearance (calculated using Cockcroft-Gault formula) ≥60 ml/min；
• Normal coagulation function, defined as international normalized ratio (INR) or prothrombin time (PT) ≤1.5 times ULN;
• Normal thyroid function, defined as thyroid stimulating hormone (TSH) within the normal range. Subjects with baseline TSH beyond the normal range, but total T3 (or FT3) and FT4 are within the normal range can also be enrolled;
• Myocardial zymogram within the normal range (if the investor judges that the simple laboratory result is not of clinical significance, the patient is allowed to be included); 10.For female patients of childbearing age, a negative urine or serum pregnancy test should be performed within 3 days before the first study drug administration (day 1 of cycle 1). If the urine pregnancy test result cannot be confirmed as negative, a blood pregnancy test is requested. Female patients who are not of childbearing age are defined as those who have been postmenopausal for at least 1 year or have undergone surgical sterilization or hysterectomy; 11.If there is a risk of conception, all patients (male or female) are required to use contraception throughout the treatment period until 180 days after the last study drug administration.

Exclusion criteria

• Currently participating in interventional clinical research treatment;
• Has non-squamous histology NSCLC. Mixed tumors will be categorized by the predominant cell type; if small cell elements are present, the subject is ineligible; for non-small cell histology if there is any squamous element is present (example adenosquamous), the subject is eligible; the squamous element does not have to be predominant.
• Previously received immunotherapy, including immune checkpoint inhibitors (such as anti-PD-1 /L1 antibodies, anti-CTLA-4 antibodies, anti-LAG-3 antibodies, etc.), immune checkpoint agonists (such as: Subjects of ICOS, CD40, CD137, GITR, OX40 antibody, etc.), immune cell therapy, etc., any treatment targeting the immune mechanism of tumor action;
• known allergic or hypersensitive reactions to any investigational drug or any excipients thereof;
• Have a history of severe bleeding or coagulopathy; Clinically significant bleeding symptoms, including but not limited to gastrointestinal bleeding, hemoptysis (defined as coughing up or spitting up ≥1 TSP of blood or small blood clots or only coughing up blood with no sputum, allowing inclusion of blood in the sputum), nasal bleeding (excluding nosebleed and retractive rhinorrhea) within 1 month before first administration; Imaging during the screening period showed that the tumor surrounded important blood vessels or had obvious necrosis and voids, and the researchers determined that entering the study would cause bleeding risk. Central, squamous non-small cell lung cancer with cavities and a higher risk of bleeding as determined by the investigators; Received continuous antiplatelet or anticoagulant therapy within 10 days prior to initial administration;
• Tumor invasion of surrounding important organs and blood vessels (such as aorta, heart and pericardium, superior vena cava, trachea, esophagus, etc.) or esophagotracheal fistula or esophagopleural fistula risk;
• Subjects with uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (subjects who do not require drainage effusion or whose frequency of drainage is less than once per month can be enrolled);
• Patients with symptomatic brain metastases, meningeal metastases, or spinal cord compression;
• There is a history or current presence of non-infectious pneumonia/interstitial lung disease requiring systemic glucocorticoid therapy;
• Serious comorbidities such as a history of severe lung or heart disease, any arterial thrombosis, embolism, or ischemia within 6 months prior to treatment, such as myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic attack. A history of deep vein thrombosis, pulmonary embolism, or any other severe thromboembolism within the 3 months prior to enrollment (implantable intravenous port or catheter-derived thrombosis, or superficial venous thrombosis was not considered "severe" thromboembolism);
• History of autoimmune diseases, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with autoimmune related hypothyroidism receiving stable dose thyroid hormone replacement therapy were eligible to participate in the study. Patients with controlled type 1 diabetes following a stable insulin regimen were eligible to participate in the study.
• Active systemic infections, including tuberculosis (clinical diagnosis including clinical history, physical examination and imaging findings, and TB testing based on local medical practice), hepatitis B (known to be positive for HBV surface antigen (HBsAg), HBV DNA ≥1000cps/ml or the lower limit of its reference value), hepatitis C or human immunodeficiency virus (HIV antibody positive);
• A known mental illness or substance abuse condition that may affect compliance with the test requirements;
• There is a medical history, disease, treatment, or abnormal laboratory result that could interfere with the test results or prevent the subject from fully participating in the study, or the investigator believes that participation in the study is not in the subject's best interest.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Xiong A, Wang L, Chen J, Wu L, Liu B, Yao J, Zhong H, Li J, Cheng Y, Sun Y, Ge H, Yao J, Shi Q, Zhou M, Chen B, Han Z, Wang J, Bu Q, Zhao Y, Chen J, Nie L, Li G, Li X, Yu X, Ji Y, Sun D, Ai X, Chu Q, Lin Y, Hao J, Huang D, Zhou C, Shan J, Yang H, Liu X, Wang J, Shang Y, Mei X, Yang J, Lu D, Hu M, Wang ZM, Li B, Xia M, Zhou C. Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung PMID 40057343
• HARMONi-A Study Investigators; Fang W, Zhao Y, Luo Y, Yang R, Huang Y, He Z, Zhao H, Li M, Li K, Song Q, Du X, Sun Y, Li W, Xu F, Wang Z, Yang K, Fan Y, Liu B, Zhao H, Hu Y, Jia L, Xu S, Yi T, Lv D, Lan H, Li M, Liang W, Wang Y, Yang H, Jia Y, Chen Y, Lu J, Feng J, Liu C, Zhou M, Zhou J, Liu X, Zhou N, He M, Dong X, Chen H, Chen Y, Su H, Li X, Zhang Z, Yang L, Cheng Y, Chen L, Hou X, Zhang Y, Guo PMID 38820549
• Socinski MA, Nishio M, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodriguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kong S, Lee A, Coleman S, Zou W, McCleland M, Shankar G, Reck M. IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC. J Thorac Oncol. 2021 Nov;16(11):1909-1924. doi: PMID 34311108
• Boyd JA, Hubbs JL, Kim DW, Hollis D, Marks LB, Kelsey CR. Timing of local and distant failure in resected lung cancer: implications for reported rates of local failure. J Thorac Oncol. 2010 Feb;5(2):211-4. doi: 10.1097/JTO.0b013e3181c20080. PMID 19901853
• Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021 Jan;71(1):7-33. doi: 10.3322/caac.21654. Epub 2021 Jan 12. PMID 33433946
• Shi M, Gu A, Tu H, Huang C, Wang H, Yu Z, Wang X, Cao L, Shu Y, Wang H, Yang R, Li X, Chang J, Hu Y, Shen P, Hu Y, Guo Z, Tao M, Zhang Y, Liu X, Sun Q, Zhang X, Jiang Z, Zhao J, Chen F, Yu H, Zhang W, Sun J, Li D, Zhou J, Han B, Wu YL. Comparing nanoparticle polymeric micellar paclitaxel and solvent-based paclitaxel as first-line treatment of advanced non-small-cell lung cancer: an open-label, ran PMID 33130217
• Shi M, Sun J, Zhou J, Yu H, Yu S, Xia G, Wang L, Teng Y, Liu G, Yu C, Feng J, Shen Y. Phase I dose escalation and pharmacokinetic study on the nanoparticle formulation of polymeric micellar paclitaxel for injection in patients with advanced solid malignancies. Invest New Drugs. 2018 Apr;36(2):269-277. doi: 10.1007/s10637-017-0506-4. Epub 2017 Sep 4. PMID 28868573
• Zhao Y, Chen G, Chen J, Zhuang L, Du Y, Yu Q, Zhuang W, Zhao Y, Zhou M, Zhang W, Zhang Y, Wan Y, Li W, Song W, Wang ZM, Li B, Xia M, Yang Y, Fang W, Huang Y, Zhang L. AK112, a novel PD-1/VEGF bispecific antibody, in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC): an open-label, multicenter, phase II trial. EClinicalMedicine. 2023 Aug 3;62:102106. doi: 10 PMID 37593227

Identifiers

NCT: NCT07009925 · MShi

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗