First Line Study of Tamibarotene in Combination for Advanced Non-Small Cell Lung Cancer

Inclusion Criteria: * Subjects must be at least 18 years of age * Subjects must have pathological findings consistent with primary non-small cell lung cancer of any histology. * Subjects must have either stage IIIB with pleural effusion or IV NSCLC with radiographically measurable disease (RECIST 1.1 criteria). Women non-smokers with stage IV NSCLC should be screened for EGFR mutation and if positive be excluded from the study and placed on an EGFR kinase inhibitor. * Subjects must have an ECOG Performance Status ≤2. * If corticosteroids are required for controlling cerebral edema, subjects must be on a stable dose for at least 1 week. * Subjects must have recovered from any toxicity of prior therapies. * Subjects must be at least 4 weeks removed from surgery or radiation therapy. * Subjects must have a life expectancy of at least 12 weeks. * Subjects must have adequate bone marrow function (defined as an absolute neutrophil count of ≥1500 cells/mm3 and platelet count ≥100,000 cells/mm3), liver function with total bilirubin ≤2.0 mg/dL, and serum creatinine ≤1.5 x institutional ULN. * Subjects must be able to understand and be willing to sign a written informed consent document. * Tamibarotene, as with all retinoids, is teratogenic. Therefore, female subjects of childbearing potential must agree to use 2 effective methods of contraception (hormonal, barrier method of birth control, or abstinence) and sexually-active male subjects must agree to use an effective method of contraception (hormonal or barrier method of birth control or abstinence) while participating in this study and for six months afterwards. Women of childbearing potential must have a negative pregnancy test ≤1 week prior to registration. * Subjects must be able to swallow tablets. * If available, tumor specimens must be submitted for immunohistochemistry analyses with their pathology reports. Exclusion Criteria: * Subjects who have received or are currently receiving chemotherapy or antibody therapy, or are enrolled in another treatment clinical trial. * Subjects with a coagulopathy or bleeding disorder. * Clinically evident congestive heart failure \>class II of the New York Heart Association (NYHA) guidelines. * Serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute arrhythmia or ventricular arrhythmias classified as Lown III, IV or V. * History or signs of active coronary artery disease with or without angina pectoris (i.e. myocardial infarction with 6 months prior to enrollment, uncontrolled angina, electrocardiographic evidence of acute ischemia). * Subjects who have a serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol or may not be able to comply with the safety monitoring requirements of the study. * HIV-positive subjects; however, subjects will not be routinely screened for HIV. * Subjects who are allergic to any of the intended chemotherapies. * Female subjects who are pregnant or breast-feeding. * Active, clinically significant serious infection requiring treatment with antibiotics, antivirals, or antifungals. * Subjects with peripheral neuropathy ≥grade 2 * Prior systemic treatment for locally advanced or metastatic disease (exception below): Prior adjuvant chemotherapy for Stage I-III or combined modality chemotherapy-radiation for locally advanced disease allowed if completed \>12 months prior to randomization. * Subjects with brain metastases are only eligible if treated and neurologically stable with no ongoing requirement for corticosteroids, e.g., dexamethasone, for at least 2 weeks. * Subjects with hypertriglyceridemia (\>1000 mg/dL). * Subjects with elevated liver function tests if AST is ≥2.5x the institutional or central laboratory's upper limit of normal for subjects without liver metastases, or \>5x the institutional or central laboratory's upper limit of normal for subjects with liver metastases. * Subjects with HbA1c ≥8.0. * Subjects taking vitamin A either as a supplement or as part of a multivitamin unless there has been at least a 2 week washout. * Subjects using concomitant medications that are known inducers or inhibitors of CYP3A4 up to 14 days before Cycle 1 Day 1 (pimozide, diltiazem, erythromycin, clarithromycin, and quinidine, and amiodarone) should be excluded from the study. * Subjects whose tumors cannot be adequately measured per RECIST 1.1.