CAN-2409 Plus Prodrug With Standard of Care Immune Checkpoint Inhibitor for Stage III/IV NSCLC

Prior treatment

• Patients receiving vascular endothelial growth factor (VEGF) inhibitors (including bevacizumab, ramucirumab) within the past 2 months or five half-lives, whichever is longer
• Patients must have no concurrent malignancy requiring treatment (except squamous or basal cell skin cancers)

Other illness

• Patients with a history of severe immune related adverse events related to ICI
• Patients who require ongoing therapy with disease-modifying antirheumatic drugs (DMARDs), immunomodulators or systemic immunosuppressive drugs including systemic corticosteroids (\>10 mg prednisone per day or equivalent) - premedication for ICI or chemotherapy is allowed
• Patients with a history of active autoimmune disease requiring treatment in the past 2 years
• Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active hepatitis, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients who are known to be HIV positive
• Patients with a history of hypersensitivity or allergic reactions to valacyclovir or acyclovir
• Patients with significant heart disease (New York Heart Association Functional Classification III or IV)
• Patients with known interstitial lung diseases (ILDs) requiring active therapy (Radiographic fibrosis not requiring therapy is allowed)

Lab values

• Patients with known EGFR mutation, ALK fusion, or ROS1 fusion positive NSCLC, or that are receiving tyrosine kinase inhibitor (TKI) agents/ALK/ROS1 inhibitors

Other

• Women who are pregnant, lactating or intend to become pregnant during the study
• Patients with continuous oxygen dependence \>2L/min at rest
• Tumor impinging on a neurovascular structure such that inflammation in the site may put patient at risk of compromise as determined by the investigator
• Patients with uncontrolled brain metastases as per investigator
• Patients with liver metastases involving more than half of the liver
• Patients without contrast enhanced imaging at baseline or those with contraindication to the use of contrast.
• Patients who are pregnant, breastfeeding, or plan to become pregnant.

• Patients with Stage III/IV NSCLC on first line treatment with anti-PD-1/PD-L1 (ICI) +/- chemotherapy for their current stage of disease and fits into one of the following cohorts as determined by investigator, preferably as per RECIST 1.1: Cohort 1) have persistent but stable disease at least 18 weeks after starting ICI treatment, or Cohort 2) have radiographic progressive disease at least 18 weeks after starting ICI treatment
• RECIST evaluable disease including a lesion that is amenable to injection
• Able and willing to undergo a pre-treatment and on-treatment biopsies, if feasible
• ECOG Performance status of 0 or 1
• 18 years of age or older
• Granulocyte count (ANC) ≥ 1,000/mm3
• Hemoglobin ≥ 8 g/dl (patients may be transfused to meet this criterion)
• Platelets ≥ 75,000/mm3
• Total bilirubin ≤ 1.5 x upper limit of normal, except for patients with known Gilbert disease who must have total bilirubin ≤ 3 x upper limit of normal
• SGOT (AST) ≤ 5x upper limit of normal and if elevated, not clinically significant such that ICI can continue
• INR no more than 0.2 above upper limit of normal and aPTT not \>1.2 x upper limit of normal, and value is acceptable for patient to undergo injection procedure. If on anti-coagulation, it must be clinically acceptable to hold anti-coagulation for the injection procedures per investigator discretion
• Serum creatinine \< 2mg/dl and calculated creatinine clearance \> 30ml/min
• Clinically stable and able to continue ICI for at least the 12-week treatment period
• Within 6 months of enrollment, no change of ICI therapy or prior interruptions of more than 4 weeks of current ICI
• Patients should not have received focal therapy (e.g., radiotherapy) at more than three different sites of disease within 12-months prior to enrollment
• Patients must give study specific informed consent prior to enrollment and any study specific procedures