A Trial With Metronomic Low-dose Treosulfan, Pioglitazone and Clarithromycin Versus Standard Treatment in NSCLC

Inclusion Criteria:

• Signed Informed Consent Form

• Ability to comply with protocol

• Age ≥ 18 years

• Measurable disease, as defined by RECIST v1.1

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Life expectancy ≥ 12 weeks

• Histologically or cytologically confirmed locally advanced or metastatic (i.e., StageIIIB not eligible for definitive chemoradiotherapy, Stage IV, or recurrent) NSCLC (perthe Union Internationale Contre le Cancer/American Joint Committee on Cancer [UICC/AJCC] staging system);

• Disease progression during or following treatment with a prior platinum containingregimen for locally advanced, unresectable/inoperable or metastatic NSCLC or diseaserecurrence within 6 months of treatment with a platinum based adjuvant/neoadjuvantregimen

• No more than 2 cytotoxic chemotherapy regimens

• Patients that have progressed during or after treatment with EGFR Tyrosine KinaseInhibitor (TKI) in first line, or are intolerant to treatment with erlotinib,gefitinib, or another EGFR TKI may be included.

• Patients that have progressed during or after , or intolerant to treatment withcrizotinib or another ALK inhibitor

• The last dose of prior systemic anti-cancer therapy must have been administered ≥ 21days prior to randomization (≥ 14 days for vinorelbine or other vinca alkaloids orgemcitabine.)

• The last dose of treatment with any investigational agent must have ended ≥ 28 daysprior to randomization.

• Prior radiation therapy is allowed provided recovery from any toxic effects thereofand ≥ 7 days between the last fraction and randomization.

• Adequate hematologic and end organ function, defined by the following (max 14 daysprior study treatment): Absolute Neutrophil Count (ANC) ≥ 1500 cells/μL (withoutgranulocyte colonystimulating factor support within 2 weeks of sampling), White BloodCell (WBC) counts > 2,500/μL and < 15,000/μL, lymphocyte count ≥ 500/μL, Plateletcount ≥ 100,000/μL (without transfusion within 2 weeks of sampling), Hemoglobin ≥ 9.0g/dL. Transfusion or erythropoietic treatment is allowed.

• Liver function tests meeting one of the following criteria: Aspartate Transaminase (AST) or Alanine Transaminase (ALT) ≤ 2.5 × ULN, with normal alkaline phosphatase orAST and ALT ≤ 1.5 × ULN in conjunction with alkaline phosphatase > 2.5 × ULN; Serumbilirubin ≤ 1.0 × ULN. Patients with known Gilbert's disease must have serum bilirubinlevel ≤ 3 × ULN.

• Prothrombin Time - International Normalized Ratio (INR) and activated partialthromboplastin time (aPTT) ≤ 1.5 × ULN, without anticoagulants. Patients receivingtherapeutic anticoagulation must be on a stable dose for at least 1 week prior torandomization.

• For female patients of childbearing potential and male patients with partners ofchildbearing potential, agreement (by patient and/or partner) to use a highlyeffective form of contraception (e.g., surgical sterilization, a reliable barriermethod, birth control pills, or contraceptive hormone implants) and to continue itsuse for 6 months after the last dose of the combined modularized treatment.

• Patients must have recovered from all acute toxicities from previous therapy,excluding alopecia.

Exclusion Criteria: Cancer-Specific Exclusion Criteria

• Known active or untreated central nervous system (CNS) metastases.Patients with ahistory of treated asymptomatic CNS metastases are eligible, if they meet all of thefollowing criteria: No metastases to brain stem, midbrain, pons, medulla, cerebellum,or within 10 mm of the optic apparatus. Radiographic demonstration of improvement uponthe completion of CNS directed therapy and no evidence of interim progression betweenthe completion of CNS-directed therapy and the screening radiographic study

• History of intracranial hemorrhage

• Ongoing requirement for dexamethasone for CNS disease

• Stereotactic radiation or whole-brain radiation within 28 days prior to Cycle 1,Day 1

• Screening CNS imaging ≥ 4 weeks since completion of radiotherapy and ≥ 2 weeks sincediscontinuation of corticosteroids

• Spinal cord compression not definitively treated with surgery and/or radiation orpreviously diagnosed and treated spinal cord compression that has not been clinicallystable for ≥ 2 weeks prior to randomization

• Leptomeningeal disease

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures

• Uncontrolled tumor-related pain: patients requiring pain medication must be on astable regimen at study entry. Symptomatic lesions amenable to palliative radiotherapyshould be treated prior to enrolment. Asymptomatic metastatic lesions whose furthergrowth would likely cause functional deficits or intractable pain should be consideredfor loco-regional therapy prior to enrolment.

• Hypercalcemia (Ca > 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected serumcalcium > ULN) or symptomatic hypercalcemia requiring continuous bisphosphonatetherapy or denosumab. Patients who are receiving bisphosphonate therapy or denosumabspecifically to prevent skeletal events and without a history of clinicallysignificant hypercalcemia are eligible.

• Malignancies other than NSCLC within 5 years prior to randomization, with theexception of those with a negligible risk of metastasis or death and treated withcurative outcome General Exclusion Criteria

• History of idiopathic pulmonary fibrosis (including pneumonitis), history ofdrug-induced pneumonitis

• Serum albumin < 2.5 g/dL

• Patients with active hepatitis B or hepatitis C. Patients with past Hepatitis B Virus (HBV) infection or resolved HBV are eligible. Patients positive for Hepatitis C Virus (HCV) antibody are eligible only if Polymerase Chain Reaction (PCR) is negative forHCV Ribonucleic Acid (RNA).

• Significant uncontrolled concomitant disease that could affect compliance with theprotocol or interpretation of results, including significant liver disease

• Significant cardiovascular disease, such as myocardial infarction within 3 monthsprior to randomization, unstable arrhythmias, or unstable angina.

• Known left ventricular ejection fraction (LVEF) < 40%. Patients with known coronaryartery disease, congestive heart failure not meeting the above criteria, or LVEF < 50%must be on a stable medical regimen.

• Tuberculosis

• Severe infections within 4 weeks prior to randomization

• oral or intravenous antibiotics within 2 weeks prior to randomization

• Major surgical procedure within 4 weeks prior to randomization or expected need for amajor surgical procedure during the course of the study other than for diagnosis

• Prior treatment with nivolumab

• Grade ≥ 2 peripheral neuropathy as defined by the National Cancer Institute CommonTerminology Criteria for Adverse Events (NCI CTC AE) v4.0 criteria

• Patients undergoing dialysis or creatinine clearance <30 mL per minute,definedaccording to Modification of Diet in Renal Disease Study Criteria (MDRD)

• Patients with uncontrolled hypertension (Respiratory rate continuously > 140/90 mm Hg)

• Simultaneous treatment with another investigational agent or simultaneous anticancertreatment outside this trial Exclusion Criteria Related to Study Drugs

• Heart failure > New York Heart Association (NYHA) 1, QT prolongation, ventriculararrhythmias, torsade de pointes

• Creatinine > 1.5 mg/dL

• chronic hypopotassemia

• HIV infection requiring virostatic therapy

• past or current bladder cancer , patients with risk factors for bladder cancer (suchas exposure to aromatic amines or heavy tobacco smokers), or macrohematuria of unknownorigin

• Known gastrointestinal disorder, including malabsorption or active gastric ulcer, thatmight interfere with oral intake and absorption of study medication

• Autoimmune disease, symptomatic interstitial lung disease, systemic immunosuppression,prior therapy with T-cell costimulation or checkpoint targeted agent