CDX-301, CDX-1140, and Stereotactic Body Radiation Therapy versus Standard Therapy the Treatment of Advanced Non-Small Cell Lung Cancer

Inclusion Criteria

• Histologically proven NSCLC, not classically deemed to be amenable to curative therapy based on disease extent at the time of diagnosis or disease progression after the initial diagnosis
• Age >= 18 years
• Prior treatment with at least two lines of systemic therapy for advanced NSCLC, including one line of platinum-based combination chemotherapy * Treatment with concurrent chemotherapy and immunotherapy can count as two lines of therapy for the purposes of study eligibility.
• Radiological assessment within 21 days prior to study entry demonstrating measurable disease that includes at least one pulmonary or extrapulmonary lesion >= 1 cm in greatest dimension that would be amenable to SBRT and at least one measurable lesion that would be outside of the SBRT treatment fields
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Both men and women enrolled in this trial must agree to use adequate birth control measures during the trial and for at least 90 days after last receipt of study therapy. Patients and/or partners who are surgically sterile or postmenopausal are exempt from this requirement.
• Hemoglobin >= 9.0 g/dL (within 21 days prior to first study drug administration [Arm 1] or within 21 days prior to study registration [Arm 2])
• Absolute neutrophil count >= 1.5 x 10^9/L (within 21 days prior to first study drug administration [Arm 1] or within 21 days prior to study registration [Arm 2])
• Platelet count >= 100 x 10^9/L (within 21 days prior to first study drug administration [Arm 1] or within 21 days prior to study registration [Arm 2])
• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance (by Cockcroft-Gault formula) > 60 mL/min (within 21 days prior to first study drug administration [Arm 1] or within 21 days prior to study registration [Arm 2])
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (within 21 days prior to first study drug administration [Arm 1] or within 21 days prior to study registration [Arm 2])
• Total bilirubin =< 2.0 x ULN (except patients with Gilbert’s syndrome, who must have a total bilirubin =< 3.0 mg/dL) (within 21 days prior to first study drug administration [Arm 1] or within 21 days prior to study registration [Arm 2])
• Negative SARS-CoV-2 (COVID-19) polymerase chain reaction (PCR) test (within 21 days prior to first study drug administration [Arm 1] or within 21 days prior to study registration [Arm 2]) * COVID-19 testing may be repeated periodically based on institutional policies and must be repeated for any subject with unexplained signs (e.g., imaging findings, fever) or symptoms (e.g., anosmia) concerning for COVID-19 infection or with recent known exposure to COVID-19.

Exclusion Criteria

• Prior therapy with any anti-CD40 antibody or FLT3 ligand
• Less than 21 days between registration and the last receipt of chemotherapy, targeted cancer therapy, immunotherapy, radiotherapy (excluding palliative radiotherapy), or major surgery.
• Untreated central nervous system metastases. Patients with a history of brain metastases must have had no central nervous system (CNS)-directed therapy within the past 60 days and radiological assessment within 30 days of study entry demonstrating a lack of progressive CNS disease. Patients without a history of brain metastases and without symptoms suggestive of brain metastasis do not require staging imaging of the brain prior to study enrollment.
• Known mutation/amplification in FLT3
• Ongoing or recent (within 21 days prior to study entry) use of high dose oral corticosteroids (>= 2 mg of dexamethasone daily or equivalent) or inhaled corticosteroids. Intranasal and/or intraarticular corticosteroid use is permitted.
• History of non-infectious pneumonitis or any ongoing pneumonitis
• History of allogeneic organ transplant or active autoimmune disease
• Other active malignancy for which systemic therapy (excluding hormonal therapy for breast or prostate cancer) is indicated.
• History of myocardial infarction, cerebral vascular accident, thrombosis, or pulmonary embolus within 12 months prior to study registration.
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements as judged by the treating physicians
• Active infection requiring systemic therapy, known human immunodeficiency virus (HIV) infection, or positive test for hepatitis B surface antigen or hepatitis C (antibody screen and if positive confirmed by ribonucleic acid [RNA] analysis). If positive results are not indicative of a true active or chronic infection, the patient can be enrolled after discussion with, and agreement by, the principal investigator.
• Receipt of a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed.
• Subjects who are not ambulatory or ambulate using a walker are not eligible for the objective activity monitoring component of this study.