A phase II clinical trial of neoadjuvant treatment with Ivonescimab and chemotherapy for stage IIA-IIB-IIIA and IIIB (T3N2) non-small cell lung cancer (NSCLC) patients

Who can take part

• Previously untreated patients with histologically- or cytologically- documented NSCLC who present stage IIA, IIB, IIIA and IIIB (only T3N2) disease (according to the 9th version of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology)
• For male patients with female partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception that results in a low failure rate [< 1% per year] when used consistently and correctly, and to continue its use for 3 months after the last dose of trial treatment. Male patients should not donate sperm during this study and for at least 6 months after the last dose of trial treatment
• Oral contraception should always be combined with an additional contraceptive method because of a potential interaction with the study drugs. The same rules are valid for male patients involved in this clinical study if they have a partner of childbirth potential. Male patients must always use a condom
• Women who are not postmenopausal (≥ 12 months of non−therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 8 days prior to initiation of study drug
• Patients capable of proper therapeutic compliance and accessible for correct follow-up
• Presence of at least one measurable lesion by CT-SCAN, as defined by RECIST v1.1
• Patients with a life expectancy ≥12 weeks
• PET scan and brain CT or brain MRI at baseline to confirm the absence of distant disease
• Bronchoscopy must be done within 3 months of enrolment. Positive mediastinal lymph nodes by PET scan must be confirmed histologically within 3 months before enrolment by mediastinoscopy, EBUS, EUS or fibrobronchoscopy
• ECOG (Performance status) 0-1
• Adequate hematologic and organ function defined by the following laboratory results obtained within 14 days prior to enrolment: o Neutrophils ≥ 1.5 x109 /L without granulocyte colony-stimulating factor support. o Lymphocyte count ≥ 0.5 x109 /L o Platelet count ≥ 100 x109 /L without transfusion. o Haemoglobin ≥ 10.0 g/dL. o Prothrombin or aPTT ≤ 1.5 × upper limit of normal (ULN). This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose. o AST, ALT, GGT and alkaline phosphatase ≤ 2.5 × ULN o Serum bilirubin ≤ 1.5 × ULN. Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled. o Serum creatinine ≤ 1.5 × ULN or creatinine clearance of ≥50ml/min (based on the Cockcroft Gault formula). o Urine protein ˂2+ or 24h urine protein quantification ˂1.0g
• All patients are notified of the investigational nature of this study and signed a written informed consent in accordance with institutional and national guidelines, including the Declaration of Helsinki prior to any trial-related intervention
• Adequate lung function: predicted postoperative Forced Expiratory Volume in 1 second (ppo FEV1) >40% of normal volume and predicted postoperative Diffusion Capacity of the Lungs for Carbon Monoxide (ppo DLCO) >40% of normal value. In case any of these values are below 40%, oxygen consumption test should be done, and if the value is above 15 ml/kg/min or above 30% predicted, the patient can be considered operable
• Patients aged ≥ 18 years at the time of study entry
• For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception that results in a low failure rate (< 1% per year) when used consistently and correctly, and to continue its use for 6 months after the last dose of trial treatment. Such methods include: combined (estrogen and progestogen containing) hormonal contraception, progestogen-only hormonal contraception associated with inhibition of ovulation together with another additional barrier method always containing a spermicide, intrauterine device (IUD): intrauterine hormone-releasing system (IUS), bilateral tuba occlusion, vasectomized partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence. Female patients should not donate oocytes during this study and for at least 6 months after the last dose of trial treatment

Who cannot take part

• Severe infections within 4 weeks prior to being included in the study, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
• Major surgical procedures other than for diagnosis within 28 days prior to inclusion or anticipation of need for a major surgical procedure during the course of the study
• Active or prior history of inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis, or chronic diarrhea)
• Treatment with any other investigation agent with therapeutic intent within 28 days prior to initiation of study treatment
• Live vaccine or live attenuated vaccine within 4 weeks prior to planned randomization, or if scheduled to receive a live vaccine or live attenuated vaccine during the study period. Inactivated vaccines are permitted
• Weight loss >10% within the previous 3 months
• Patients that receive previous treatment with antineoplastic drugs, chest radiotherapy, or previous surgery for lung cancer
• Patients with other active malignancy requiring concurrent intervention and/or concurrent treatment with other investigational drugs or anti-cancer therapy
• Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrolment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• History of major diseases before randomization, specifically: a. Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association [NYHA] classification ≥ grade 2) or unstable vascular disease (eg, aortic aneurysm at risk of rupture, Moyamoya disease) that required hospitalization within 12 months prior to randomization, or other cardiac impairment that may affect the safety evaluation of the study drug (eg, poorly controlled arrhythmias, myocardial ischemia) b. History of esophageal gastric varices, severe ulcers, wounds that do not heal, abdominal fistula, intra-abdominal abscesses, or acute gastrointestinal bleeding within 6 months before randomization c. History of any grade arterial thromboembolic event, Grade 3 and above venous thromboembolic event, as specified in National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 12 months prior to randomization d. Acute exacerbation of chronic obstructive pulmonary disease within 4 weeks before randomization e. History of perforation of the gastrointestinal tract and/or fistula, history of gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection) within 6 months prior to randomization
• Patients with medical, mental, neurological or psychological condition which in the opinion of the investigator would not permit the patient to understand the patient information sheet or comply with study procedures
• Patients with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required during the study period
• Patients with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement or unexpected conditions of recurrence in the absence of an external trigger are allowed to be included
• Pleural or pericardial effusion, both will be considered indicative of metastatic disease unless proven otherwise. Patients with pleural effusion not visible on chest-X-ray or too small to perform diagnostic puncture safely may be included
• History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, idiopathic pneumonitis, Interstitial lung disease (ILD) or evidence of active pneumonitis on baseline chest CT scan
• Patients with significant pulmonary hypertension (meaning pulmonary artery pressure (mPAP above 30 mmHg, evaluated by echocardiography or right heart catheterization)
• Poorly controlled hypertension with repeated systolic blood pressure ≥ 150mmHg or diastolic blood pressure ≥ 100mmHg after oral antihypertensive therapy
• Patients with positive tests for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible only if they are negative for HBV DNA (vaccinated patients are excluded). Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA
• Active tuberculosis
• Patients with sensitizing mutation or an amplification in the epidermal growth factor receptor (EGFR) gene or any variety of alterations of ALK oncogene. This information has to be available before including the patient in the study
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications
• Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic cardiac dysfunction or unstable vascular disease (unstable angina, congestive heart failure, myocardial infarction within the previous year or cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects). Patients with a significant cardiac history, even if controlled, must have a LVEF > 50% within 12 weeks prior to randomization
• History of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to randomization, including but not limited to: a. Hemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots). Note: transient hemoptysis associated with diagnostic bronchoscopy is allowed. b. Nasal bleeding / epistaxis (bloody nasal discharge is allowed). c. Current use of prophylactic or full-dose anticoagulants or anti-platelet agents for therapeutic purposes that are not stable prior to randomization is not allowed. The use of full-dose anticoagulants is permitted as long as the international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits according to the medical standard of the enrolling institution
• Patients with history of HIV infection who meet one or more of the following criteria: a. CD4+ count <350 cells/μL b. Viral load >50 copies/μL (local lab assessment) c. Not receiving antiretroviral therapy d. Receiving established antiretroviral therapy for less than 4 weeks prior to the start of trial treatment e. History of AIDS-defining opportunistic infections within 12 months prior to start of trial treatment 15. Note: Patients with a history of HIV who do not meet any of the criteria above are eligible to participate but the patient must be under the care of a HIV/Infectious Diseases specialist, or an HIV/Infectious Diseases specialist must be consulted prior to inclusion
• Known STK-11 ligand alterations, MDM2 amplifications or ROS1 translocations
• Patients with uncontrolled comorbidities that may affect clinical trial compliance
• Women who are pregnant or in the breastfeeding period
• Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the study