Dose Attenuated Chemotherapy With or Without Immunotherapy or Targeted Therapy for the Treatment of Stage III or IV Lung Cancer in Patients with Comorbidities

Inclusion Criteria

• Must have histologically or cytologically confirmed stage IV (American Joint Committee on Cancer [AJCC] version 8) lung cancer (small cell or non-small cell). Patients with stage III disease who are not felt to be candidates for definitive therapy are also eligible
• Must meet criteria for one of the Dose Levels: * Age > 70 with Eastern Cooperative Oncology Group (ECOG) performance score (PS) = 0 AND/OR * HIV positive (+) AND OR * Have at least 1 risk criteria
• Patients must have planned therapy with a regimen that includes at least one cytotoxic agent (e.g. platinum, taxane, anti-metabolite, vinca alkaloid, podophyllotoxin, camptothecin, lurbinectedin etc) * Use of pemetrexed is prohibited if creatinine clearance (CrCl) is less than 30 mL/min.
• Must have measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1
• History of treated or untreated asymptomatic central nervous system (CNS) metastases are eligible, provided they meet all of the following criteria: * No ongoing requirement for corticosteroids as therapy for CNS disease * No stereotactic radiation or whole-brain radiation within 7 days prior to treatment initiation * Anti-seizure medications are allowed if seizure activity is controlled, and CNS disease has been treated and is stable per treating physician. Treatment of CNS disease can include surgery, radiation or response to prior systemic therapy
• May have received prior therapy for lung cancer, including prior cytotoxic therapy on this trial * A patient may subsequently enroll on this trial, if the next cytotoxic therapy planned is part of a different treatment category than any prior cytotoxic agent on this trial (i.e. patient was previously treated with platinum doublet chemotherapy plus immunotherapy in treatment group 1, now is planned to receive single agent chemotherapy +/- VEGFi in treatment group 3) *There is no limit on the number of prior therapies * Individuals may have received up to one cycle (21 days) of any of the study treatment regimens (i.e., platinum doublet plus immunotherapy [IO], platinum doublet with or without FDA approved combination therapy (not immunotherapy), single agent chemotherapy with or without a VEGFi). Such therapy must have been initiated within 21 days prior to enrollment. All screening procedures must be completed as outlined in the study calendar prior to patient being considered on study. ** Subjects must have progressed on tyrosine kinase inhibitor (TKI) monotherapy if chemotherapy is given in combination with a TKI (i.e. chemotherapy added after progression)
• Age >= 18 years
• ECOG performance status of 0-3
• Ability to understand and willingness to sign the written informed and Health Insurance Portability and Accountability Act (HIPAA) consent documents
• Females of child-bearing potential must be willing to use an effective method of contraception for the course of the study through at least 6 months after the last dose of study medication
• Males who are fertile and who have partners who are women of child-bearing potential (WOCBP) must agree to use effective method(s) of contraception from the start of trial treatment, for the course of the study and 6 months after the last dose of study treatment
• Patients with known HIV infection and are receiving combination antiretroviral therapy with a viral load <400 copies per mL at screening or CD4+ T-cell count >= 350 cell per μL at screening and no history of AIDS-defining opportunistic infection =< 12 months before first dose of study drug are eligible

Exclusion Criteria

• Patients receiving only a targeted agent (e.g. TKI, sotorasib etc.) or immunotherapy without a cytotoxic agent
• Patients currently receiving investigational agents for cancer
• Patients with ECOG performance status (PS) 3 and one of the following: severe hepatic or sever renal dysfunction: * Severe hepatic dysfunction is defined as total bilirubin (T. bili) > 1.5 - 3 x upper limit of normal (ULN) OR aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2.5 - 5 x ULN (no liver metastases). * Severe renal dysfunction is defined as creatinine clearance < 20 ml/min/1.73 m^2
• Clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
• Undergone major surgery within 28 days prior to first dose of study treatment. The patient has elective or planned major surgery to be performed during the course of the clinical trial
• Have not recovered from adverse events due to anticancer agents administered previously except neuropathy, alopecia or endocrinopathies that can be treated with replacement therapy. Physician’s discretion is allowed to decide which unresolved adverse events from previous therapy prohibit patient participation in this study
• Uncontrolled illness including, but not limited to, ongoing or active infection (other than chronic viral infections that are controlled, e.g. HIV, as described above), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (uncontrolled), cirrhosis, or psychiatric illness/ social situations that would limit compliance with the study requirements
• Patients with prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Leptomeningeal disease
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) * Indwelling catheters (e.g., PleurX®) are allowed
• Corrected serum calcium (Ca) > 12 mg/dl * Patients who are receiving hypocalcemic therapies (e.g. denosumab, bisphosphonates) who achieve appropriate serum calcium levels are eligible
• Pregnant or breast feeding. Patients must agree to comply with contraception requirements