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Efficacy and Safety of Iparomlimab and Tuvonralimab (QL1706) plus Docetaxel in patients with advanced lung squamous cell carcinoma resistant to prior PD-1/PD-L1 inhibitor therapy: A Phase Ⅱ Trial

Efficacy and Safety of Iparomlimab and Tuvonralimab (QL1706) plus Docetaxel in patients with advanced lung squamous cell carcinoma resistant to prior PD-1/PD-L1 inhibitor therapy: A Phase Ⅱ Trial

Kai Zhu 

Xingsheng Hu 

No. 17, Nanli, Panjiaohai, Chaoyang District, Beijing

No. 17, Nanli, Panjiaohai, Chaoyang District, Beijing

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

Yes

Ethics Committee of Lang Fang Campus of National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

Yong Wang

No.67 Huayuan Road, Economic and Technological Development Zone, Langfang, Hebei Province

National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

No. 17, Nanli, Panjiaohai, Chaoyang District, Beijing

Beijing Vlove Charity Foundation

Lung squamous cell carcinoma

Interventional study

2

Single arm 

1.Primary Objective: To evaluate the objective response rate (ORR) of Iparomlimab and Tuvonralimab (QL1706) plus Docetaxel in patients with advanced lung squamous cell carcinoma resistant to prior PD-1/PD-L1 inhibitor therapy. 2.Secondary Objectives: (1) To evaluate the disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS) of Iparomlimab and Tuvonralimab (QL1706) plus Docetaxel in patients with advanced lung squamous cell carcinoma resistant to prior PD-1/PD-L1 inhibitor therapy according to RECIST v1.1 criteria. (2) To evaluate the safety of Iparomlimab and Tuvonralimab (QL1706) plus Docetaxel in patients with advanced lung squamous cell carcinoma resistant to prior PD-1/PD-L1 inhibitor therapy. 3.Exploratory Objectives: (1) To explore the efficacy evaluation based on iRECIST criteria. (2) To explore biomarkers associated with the efficacy, safety, and prognosis of Iparomlimab and Tuvonralimab (QL1706) plus Docetaxel in patients with advanced lung squamous cell carcinoma resistant to prior PD-1/PD-L1 inhibitor therapy.

1. Combined administration period: Each 3-week (21-day) period constitutes one cycle. There are a total of 4 cycles. On the first day of each cycle (D1), the following are administered intravenously in sequence: (1) Epalrestat Voroxylin Antibody (5mg/kg, intravenous infusion for 30-60 minutes). The instructions in the manual should be followed. First, administer Epalrestat Voroxylin Antibody, and then administer the chemotherapy drug 30 minutes after the Epalrestat Voroxylin Antibody infusion is completed. The dose of Epalrestat Voroxylin Antibody cannot be adjusted; only the administration can be suspended or permanently terminated. (2) Docetaxel (75mg/m2, intravenous infusion for 60 minutes). After 30 minutes of the Epalrestat Voroxylin Antibody infusion, administer the preventive medication, and then administer the chemotherapy drug. The dose of Docetaxel can be adjusted according to the patient's condition. 2. Monotherapy maintenance period: After the four cycles of combined administration, if the subject does not experience an endpoint event, they enter the monotherapy maintenance period. Each 3-week (21-day) period constitutes one cycle. On D1, administer intravenously: Epalrestat Voroxylin Antibody (5mg/kg, intravenous infusion for 30-60 minutes), or use other immunotherapy regimens. The specific infusion method should be carried out in accordance with the instructions and SOP. The dose of Epalrestat Voroxylin Antibody cannot be adjusted; only the administration can be suspended or permanently terminated. 

1. Voluntary signing of a written informed consent form (ICF); 2. Age >= 18 years at enrollment, gender not restricted; 3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1; 4. Expected survival period >= 3 months; 5. According to the International Association for the Study of Lung Cancer and the American Joint Committee on Cancer 8th edition of the lung cancer TNM staging classification, having histological or cytological confirmed incurable locally advanced (stage IIIA/IIIB/IIIC) or metastatic (stage IV) lung squamous cell carcinoma; 6. Only received one PD-1/PD-L1 inhibitor (including combined with one platinum-based double-drug chemotherapy), and after receiving PD-1/PD-L1 inhibitor (combined or not combined with chemotherapy) with clinical benefit, the disease progressed, including the following groups of patients: For patients with advanced lung squamous cell carcinoma who received only immunotherapy and achieved CR and PR (without duration limit), and SD >= 6 months, and then experienced disease progression; For patients with advanced lung squamous cell carcinoma who received chemotherapy combined with immunotherapy with clinical benefit PFS >= 3 months before disease progression can be enrolled; For patients who received a full course of immunotherapy and experienced PD after the last immunotherapy can be enrolled; Patients who received only immunotherapy as neoadjuvant treatment, those with recent response of CR/PR or postoperative pathology indicating complete pathological response (pCR)/major pathological response (MPR), regardless of whether they received adjuvant immunotherapy, can be enrolled if they have recurrence within 6 months after the last immunotherapy; For patients who received neoadjuvant treatment with chemotherapy combined with immunotherapy, only if the pathological assessment reaches pCR/MPR, regardless of whether they received adjuvant immunotherapy, can be enrolled if they have recurrence within 6 months after the last immunotherapy. (Notes: a) For patients in the neoadjuvant or adjuvant stage who received platinum-based chemotherapy treatment, if disease progression or recurrence occurs within 6 months after treatment, this treatment plan will be regarded as a platinum-based chemotherapy for locally advanced or metastatic lung squamous cell carcinoma; b) For patients in the neoadjuvant or adjuvant stage who received PD-1/PD-L1 inhibitor treatment, if disease progression or recurrence occurs within 6 months after treatment, this treatment plan will be regarded as PD-1/PD-L1 inhibitor treatment for locally advanced or metastatic lung squamous cell carcinoma; c) Patients who progressed after first-line PD-1/PD-L1 inhibitor treatment and then progressed with platinum-based chemotherapy can be enrolled; d) Patients who progressed after first-line platinum-based chemotherapy treatment and then progressed with immunotherapy monotherapy can be enrolled); 7. If the previous driver gene status is unknown, no corresponding test is required before enrolling in this study, and it is regarded as negative. 8. The subject must have at least one measurable lesion (according to RECIST v1.1 definition), and the lesion is suitable for repeated accurate measurement. If progression is confirmed, the previously untreated area without radiotherapy or the measurable lesion after non-local treatment can be selected as the target lesion. The enlarged lesion after radiotherapy or local treatment can also be selected as the target lesion. The freshly extracted tumor lesion should be completed within 1 month before screening and judged by the investigator to have no bleeding or other related risks. 9. The following requirements are used to determine good organ function: Hematology (no use of any blood component and cell growth factor support treatment within 7 days of starting the study) i. Absolute neutrophil count ANC >= 1.5 × 10^9/L (1,500/mm^3) ii. Platelet count >= 100 × 10^9/L (100,000/mm^3); iii. Hemoglobin >= 90 g/L. Kidneys: i. The calculated value of creatinine clearance rate * (CrCl) is >= 50 mL/min * The CrCl will be calculated using the Cockcroft-Gault formula (Cockcroft-Gault formula) CrCL (mL/min) = {(140 - age) × weight (kg) × F} / (SCr (mg/dL) × 72) Where F for males is 1 and for females is 0.85; SCr = serum creatinine ii. Urine protein < 2+ or 24-hour (h) urine protein quantification < 1.0 g. Liver: i. Serum total bilirubin (TBil) <= 5 × ULN ii. AST and ALT <= 2.5 × ULN iii. Serum albumin (ALB) >= 28 g/L Coagulation function: International normalized ratio (INR) and activated partial thromboplastin time (APTT) <= 1.5 × ULN. Cardiac function: Left ventricular ejection fraction (LVEF) >= 50%. 10. For fertile female subjects, a urine or serum pregnancy test must be conducted 3 days before the first administration of the drug (if the urine pregnancy test result cannot be confirmed as negative, a serum pregnancy test must be performed, and the serum pregnancy result shall prevail), and the result must be negative. If a fertile female subject has sexual intercourse with an unsterilized male partner, the subject must start using an acceptable contraceptive method from the screening and must agree to continue using the contraceptive method for 120 days after the last administration of the study drug; regarding whether to stop the contraception after this time point, it should be discussed with the investigator. 11. If an unsterilized male subject has sexual intercourse with a fertile female partner, the subject must start using an effective contraceptive method from the screening until the 120th day after the last administration of the study drug; regarding whether to stop the contraception after this time point, it should be discussed with the investigator; regarding whether to stop the contraception after this time point, it should be discussed with the investigator. 12. The subject is willing and able to comply with the scheduled visits, treatment plans, laboratory tests, and other requirements of the study.

Tumor-related characteristics and treatment 1. Histological or cytological pathology confirms the presence of small cell cancer components, or any driver gene-positive lung squamous cell carcinoma. 2. Subjects who have experienced disease progression after PD-1/PD-L1 inhibitor treatment and continue to use the original PD-1/PD-L1 inhibitor for 2 times or less can be enrolled. Subjects who continue to use other immunosuppressants for >= 2 times will be excluded; subjects who have previously received anti-CTLA-4 treatment are excluded. 3. Exclude those who have previously used docetaxel. 4. Exclude subjects who have received systemic treatment >= 2 lines. 5. Exclude subjects who received the last systemic anti-tumor treatment (chemotherapy, immunotherapy) within 3 weeks before the first administration. 6. Exclude subjects who received the following treatments within 2 weeks before the first administration: TKI treatment, hormone anti-tumor treatment, palliative local treatment for non-target lesions, non-specific immunomodulatory treatment (such as interleukin, interferon, thymosin, tumor necrosis factor, etc., excluding IL-11 used for treating thrombocytopenia); subjects who received traditional Chinese medicine or herbal medicine with anti-tumor indications within 1 week before the first administration. 7. Exclude subjects who have received radiotherapy to the radiation field that has involved the heart (such as chest radiotherapy, etc.). 8. Subjects with tumor invasion surrounding important blood vessels or with obvious necrosis and cavities, and the investigator determines that entering the study will cause bleeding risk. 9. Anti-tumor biological therapy or major surgery within 3 weeks before the administration of the first study drug. 10. Exclude subjects whose imaging shows tumor invasion of surrounding important organs and blood vessels (such as heart and pericardium, trachea, esophagus, aorta, superior vena cava, etc.) or with the risk of developing esophageal-tracheal fistula or esophageal-pulmonary fistula. 11. Have symptomatic central nervous system metastasis; for patients with asymptomatic brain metastases or stable symptoms after treatment of brain metastases and >= 2 weeks since the last administration, as long as all of the following criteria are met, they can participate in this study: no brainstem, midbrain, pons, cerebellum, medulla oblongata, spinal cord metastasis or spinal cord compression; no history of intracranial hemorrhage; more than 2 weeks have passed since stopping hormone treatment before the first administration; no obvious edema around the brain metastasis lesion; the long diameter of the brain metastasis lesion is > 1.5 cm. 12. Subjects who have experienced any of the following situations during PD-1/PD-L1 inhibitor treatment in the past: - Experienced grade 3 or above immune-related adverse reactions (irAE) caused by PD-1/PD-L1 inhibitor treatment (excluding endocrine system-related irAE), resulting in permanent discontinuation of treatment, grade 2 immune-related cardiac toxicity, or any grade of neurological or ocular irAE. - Before the screening of this study, all adverse events during the previous PD-1/PD-L1 inhibitor treatment have not been completely resolved to grade 1 or have subsided (excluding alopecia and sensory nerve lesions). For subjects with >= 2 grade 2 adverse endocrine events, if the condition is stable after appropriate alternative treatment and there are no symptoms, they are allowed to be enrolled (for example, if clinical symptoms are well controlled and the daily dose of prednisone or equivalent <= 10mg, patients with grade 2 adrenal insufficiency or grade 2 hypothyroidism related to previous anti-tumor treatment can be enrolled). Adverse events requiring the use of other immunosuppressants besides glucocorticoids in the subjects, or recurrence of adverse events during the previous immunotherapy, necessitating the systematic use of glucocorticoids again. Previous medical history and comorbidities 1. Other than lung squamous cell carcinoma, had active malignant tumors within 3 years prior to enrollment. This includes subjects who had other malignant tumors that were cured by local treatment, such as basal or skin squamous cell carcinoma, superficial bladder cancer, cervical or breast carcinoma in situ, etc. 2. Had active autoimmune diseases that required systemic treatment in the past 2 years (such as treatment with disease-modifying drugs, corticosteroids, or immunosuppressants) (excluding irAE caused by PD-1/PD-L1 inhibitors). Alternative treatments (such as thyroid hormone, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) are not considered as systemic treatment. 3. Had a history of immunodeficiency; those with positive HIV antibody test; those currently using systemic corticosteroids or other immunosuppressants for a long time. 4. Known active pulmonary tuberculosis (TB), subjects suspected of having active TB, need clinical examination to rule out; known active syphilis infection. 5. Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation. 6. Had a history of non-infectious pneumonia/interstitial lung disease requiring systemic glucocorticoid treatment or currently having non-infectious pneumonia. 7. Had a severe infection within 4 weeks before the first administration, including but not limited to those with complications requiring hospitalization, sepsis, or severe pneumonia; had active infection that received systemic anti-infective treatment within 2 weeks before the first administration (excluding antiviral treatment for hepatitis B or hepatitis C). 8. Uncontrolled chronic hepatitis B patients or chronic hepatitis B virus (HBV) carriers with HBV DNA > 1000 IU/mL, and active hepatitis C patients should be excluded. Non-active hepatitis B surface antigen (HBsAg) carriers, stable hepatitis B patients treated and in remission (HBV DNA < 1000 IU/mL), and cured hepatitis C patients can be enrolled. For HCVAb positive subjects, only those with negative HCV RNA test results are eligible to participate in the study. Known human immunodeficiency virus (HIV) infection history (i.e., positive HIV antibody test), known active syphilis infection. 9. Had brainstem, meningeal metastasis, spinal cord metastasis or compression 10. Had active central nervous system (CNS) metastatic lesions; subjects with previously treated brain metastases (such as surgery, radiotherapy), if clinically stable for at least 2 weeks after the first administration of the study drug (counting from the start of administering the study drug), and the use of corticosteroids was stopped 3 days before the administration of the study drug, then allowed to enroll; asymptomatic subjects with untreated, non-symptomatic brain metastases (i.e., no neurological symptoms, no need for corticosteroids, no obvious brain metastasis lesion with a long diameter > 1.5 cm, no obvious edema around the brain metastasis lesion) can enroll. 11. Subjects with uncontrollable need for repeated drainage of pleural effusion, pericardial effusion or ascites (subjects without the need for effusion drainage or with a drainage frequency of less than 1 time per month can enroll); 12. There are currently uncontrolled coexisting diseases, including but not limited to symptomatic congestive heart failure (classified as grade 2 or above according to the New York Heart Association functional classification), unstable angina pectoris, acute myocardial ischemia, poorly controlled arrhythmias, decompensated cirrhosis, nephrotic syndrome, uncontrolled metabolic disorders, severe active peptic ulcer disease or gastritis, and current hypertension with systolic blood pressure >= 160 mmHg or diastolic blood pressure >= 100 mmHg after oral antihypertensive drug treatment. Or mental disorders/situations that may limit the subject's compliance with the study requirements or affect the subject's ability to provide written informed consent. 13. Previous history of myocarditis, cardiomyopathy, or malignant arrhythmia. Within 12 months prior to the first administration, there was unstable angina pectoris, congestive heart failure, or vascular disease (such as aortic aneurysm requiring surgical repair or peripheral venous thrombosis) that required hospitalization, or other cardiac damage that may affect the safety evaluation of the study drug (such as poorly controlled arrhythmias, myocardial infarction or ischemia); within 6 months prior to the first administration, there was esophageal gastric varices, severe ulcers, unhealed wounds, gastrointestinal perforation, abdominal fistula, gastrointestinal obstruction, intra-abdominal abscess, or acute gastrointestinal bleeding history; within 6 months prior to the first administration, there had been any arterial thromboembolic event, NCIC CTCAE version 5.0 grade 3 or above venous thromboembolism, transient cerebral ischemia attack, cerebrovascular accident, hypertensive crisis or hypertensive encephalopathy; within 1 month prior to the first administration, there had been an acute exacerbation of chronic obstructive pulmonary disease. 14. History of severe bleeding tendency or coagulation dysfunction; within 1 month prior to the first administration, there was significant clinical significance of hemoptysis (defined as coughing or expectorating >= 1 teaspoon of blood or small blood clots or coughing blood without sputum, allowing those with blood in sputum to be enrolled). 15. Within 30 days prior to the first administration, received live vaccines (or attenuated live vaccines), or planned to receive live vaccines (or attenuated live vaccines) during the study period. 16. Within 30 days prior to the first administration, underwent major surgery or suffered severe trauma, or had a major surgical plan within 30 days after the first administration (determined by the investigator); within 3 days prior to the first administration, underwent minor local surgery (excluding peripherally inserted central catheterization). 17. Known allergy to any component of the study drug; known history of severe hypersensitivity reaction to other monoclonal antibodies. 18. Previous antitumor treatment toxicity has not been resolved, defined as toxicity not restored to NCIC CTCAE version 5.0 grade 0 or 1, or the level specified in the inclusion/exclusion criteria, except for hair loss and sensory nerve lesions. For subjects with irreversible toxicity and it is expected that the study drug administration will not aggravate the condition (such as hearing loss), they may be included in the study after consultation with the medical monitor. If the patient undergoes major surgery or > 30 Gy radiotherapy, they must have recovered from the toxicity and/or complications of the intervention and have not experienced radiation pneumonitis (except for long-term toxicities caused by special radiotherapy, where the subject may be included in the study after consultation with the medical monitor). 19. Past or current presence of any disease, treatment, or laboratory test abnormalities that may confound the study results, affect the subject's full participation in the study, or make participation in the study not in the best interests of the subject. 20. Local or systemic diseases not related to malignancy, or secondary diseases or symptoms of the tumor, which may lead to higher medical risks and/or uncertainty in survival period evaluation, such as tumor leukemia reaction (white blood cell count > 20 × 10^9/L), cachexia manifestations (such as known weight loss of more than 10% within 3 months before screening), etc. 21. Known to have a history of mental illness, drug abuse, alcoholism or drug addiction. 22. Pregnant or lactating women.

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