This is an open-label, non-randomized, single-center, phase II study to evaluate the efficacy, toxicity and, tolerability of pre-specified dose attenuated chemotherapy regimens in lung cancer patients with comorbidities.

This is an open-label, non-randomized, single-center, phase II study to evaluate the efficacy, toxicity and, tolerability of pre-specified dose attenuated chemotherapy regimens in lung cancer patients with comorbidities. The investigator will indicate the rationale(s) for dose modification based on the subgroups of patients listed in the protocol. Patients may fit into multiple subgroups and this is accounted for in the prospectively defined dose reduction level as listed in the protocol. Prespecified doses by chemotherapeutic agent and dose level adjustment based on patient characteristics and comorbidities are listed in the protocol. Analyses will be stratified by treatment group 1-3 based on the treating physician's selected therapy.

Inclusion Criteria:

• Must have histologically or cytologically confirmed stage IV (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 fit into at least one of the subgroups of patients as defined in section 3.3.
• Patients must have planned therapy with a regimen that includes at least one cytotoxic agent as listed in Table 1 (e.g. platinum, taxane, anti-metabolite, vinca alkaloid, podophylotoxin, camptothecin, lurbinectidin etc).
• Must have measurable disease as per RECIST criteria 1.1.
• History of treated or untreated asymptomatic 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
• Stable doses of anti-seizure medications are allowed if CNS disease has been treated and is stable. Treatment of CNS disease can include surgery, radiation or response to prior systemic therapy.
• May have received prior therapy for lung cancer. There is no limit on the number of prior therapies.
• Age > 18 years
• ECOG performance status of 0-3
• Ability to understand and willingness to sign a written informed and 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.
• 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.
• 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 as outlined in section 4.4 from the start of trial treatment, for the course of the study and 6 months after the last dose of study treatment.

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 PS 3 and hepatic or renal dysfunction.
• 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 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.