Efficacy and Safety Study of a New Therapeutic Strategy in the Treatment of Extended-Disease Small-Cell Lung Cancer

Exclusion Criteria

• •The patient has experienced any Grade 3-4 gastrointestinal bleeding within 3 months prior to first dose of protocol therapy.
• •The patient has a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to first dose of protocol therapy.
• •Symptomatic brain metastases or spinal cord compression (CT or MRI of the head is required within 4 weeks prior to registration) requiring immediate radiotherapy for palliation. Asymptomatic patients with treated or untreated CNS lesions are eligible, provided that all of the following criteria are met:
• •A. Presence outside the CNS of measurable disease per RECIST v1.1 B. No history of intracranial hemorrhage, spinal cord hemorrhage or heorrhagic intracranial lesions C. No stereotactic radiotherapy or whole brain radiotherapy within 14 days prior to initiation of study treatment or neurosurgical resection within 28 days prior to initiation of study treatment D. Concurrent therapy of corticosteroids ≤ 10 mg of oral prednisone or equivalent and/or anticonvulsant therapy at a stable dose E. Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla or spinal cord) F. No evidence of interim progression between completion of CNS directed therapy (if administered) and initiation of study treatment
• •History of leptomeningeal disease
• •Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) Patients with indwelling catheters (e.g., Pleurocath) are allowed.
• •Uncontrolled or symptomatic hypercalcemia (ionized calcium \> 1.5 mmol/L, calcium \> 12 mg/dL or corrected calcium \> ULN)
• •Active tubercolosis
• •Significant traumatic injury or radiotherapy involving an extensive field within the last 4 weeks prior to first dose of study treatment or anticipation of the need for major surgery during study treatment. Palliative radiotherapy to a limited field is allowed if concluded at least 2 weeks prior enrolment.
• •The patient experienced hemoptysis (defined ≥ one-half teaspoon of bright red blood per episode) within 2 months prior to first dose of protocol therapy or with radiographic evidence of intratumor cavitation.
• •Other malignancies (previous or current), except for adequately treated in situ carcinoma of the uterine cervix, basal or squamous cell carcinoma of the skin, localized prostate cancer surgically treated with curative intent or ductal carcinoma in situ treated surgically treated with curative intent or if previous malignancy was more than 5 years prior and there are no signs or symptoms of recurrence
• •The patient has experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy.
• •The patient has uncontrolled or poorly-controlled hypertension (\>150 mmHg systolic or \> 100 mmHg diastolic for \>4 weeks) despite standard medical management. Anti-hypertensive therapy to achieve these parameters is allowable.
• •Prior history of hypertensive crisis or hypertensive encephalopathy
• •Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to registration
• •The patient has a prior history of gastrointestinal or non-gastrointestinal fistula as well as gastrointestinal perforation (within 6 months of first dose of protocol therapy) or risk factors for perforation.
• •The patient has a serious or non-healing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy.
• •Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
• •Major surgery (including open biopsy) within 28 days prior to first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 7 days prior to the first dose of protocol therapy. The patient has elective or planned major surgery to be performed during the course of the clinical trial.
• •Prior allogeneic stem cell or solid organ transplantation
• •Patients with any underlying medical condition that might be aggravated by treatment or which cannot be controlled i.e. patients with active serious infection, diabetes mellitus, pericardial effusion.
• •Concomitant treatment with any other anti-cancer drug
• •Treatment with any other investigational agent, or participation in another clinical trial within 30 days prior to starting study treatment
• •Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications
• •Active, known or suspected autoimmune disease. Subjects with hypothyroidism only requiring hormone replacement, type I diabetes or autoimmune skin disorders not requiring systemic treatments are permitted to enroll.
• •Patient has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
• •Active infection requiring therapy.
• •Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), Hepatitis B (HBV) or Hepatitis C (HCV)
• •History of idiopathic pulmonary fibrosis, including pneumonitis, drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• •Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, CD137 agonists.
• •Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 \[IL-2\]) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment.
• •Any condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of registration. Steroid doses of ≤ 10 mg daily prednisone equivalent are permitted.
• •History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
• •History of allergies or hypersensitivity to any study drugs or study drug components.
• •The patient is pregnant or breast-feeding