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

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

The purpose of this clinical trial is to evaluate the effects of adding CAN-2409 + prodrug for stage III/IV NSCLC patients who are on standard of care first line immune checkpoint inhibitor (ICI) treatment with evidence that the clinical response is inadequate. CAN-2409 is a viral immunotherapy approach that induces tumor-infiltrating T-cells and a consequent PD-L1 up-regulation. A combination of CAN-2409 added to standard of care (SOC) checkpoint inhibitors may lead to improved long-term outcomes for patients with NSCLC who have suboptimal response to ICI therapy.

This clinical trial evaluates the addition of CAN-2409 plus prodrug for stage III/IV NSCLC patients who are on standard of care first line ICI (anti-PD-1/PD-L1) but with evidence of suboptimal response (either disease progression or stable disease at time of study enrollment). CAN-2409 plus prodrug has been shown to increase the response rate to ICI in animal studies. Safety and tolerability of CAN-2409 plus prodrug has been demonstrated in clinical trials in over 950 patients with cancer, including cancers of the lung, pancreas, prostate, and brain. Initial proof of mechanism has been shown in non-small lung cancer, prostate cancer, high-grade glioma, and pancreatic cancer. The eligibility criterion in the current clinical trial is based on time on ICI and response status with cohorts as follows: Cohort 1A and 1B: patients with stable disease radiographically at least 18 weeks after starting ICI treatment and who are clinically stable Cohort 2A and 2B: patients with evidence of radiographic progression at least 18 weeks after starting ICI treatment but who are clinically stable. Cohort 3, which is now closed for enrollment, was for patients who had evidence of radiographic progression at least 9 weeks after starting ICI but who were clinically stable. The specific ICI treatment regimen is not specified to allow for different standard of care options with or without chemotherapy; for example, pembrolizumab alone, pembrolizumab plus chemotherapy, or atezolizumab/chemotherapy. In addition, it allows stage III patients after chemoradiation who may be on durvalumab as their standard of care. For example, a stage III patient may be eligible for cohort 2 if they have radiographic progression but are clinically stable 18 weeks after starting durvalumab. The release of Version 05 of the protocol increased enrollment numbers into Cohorts 1 and 2 (from target n=32 evaluable to n=40 evaluable), while closing Cohort 3. In Amendment 6, cohort 1B and 2B were initiated to evaluate a 3-dose regimen of CAN-2409 + prodrug. Adjustments to the sample size extended the anticipated primary completion date for this trial.

The study is a phase II prospective study to evaluate the safety and potential efficacy of CAN-2409 plus prodrug added to standard of care immune checkpoint inhibitor (ICI) therapy in stage III/IV NSCLC

Cohort 1A and 1B - persistent but stable disease at least 18 weeks after starting ICI treatment Cohort 2A and 2B - radiographic progressive disease at least 18 weeks after starting ICI treatment Cohort 3 - refractory disease defined as progressed by imaging at least 9 weeks after starting ICI treatment (CLOSED TO ENROLLMENT)

Two courses (Cohort 1A and Cohort 2A) or three courses (Cohort 1B and Cohort 2B) of CAN-2409 injection into an accessible involved tumor site followed by 14 days of prodrug (valacyclovir or acyclovir). For Cohort 1B, the third course is optional. All patients will continue standard of care immune checkpoint inhibitor with or without chemotherapy.

Tumor response as measured by RECIST criteria including overall response rate (ORR) and/or disease control rate (DCR)

Defined as time from date of first dose of CAN-2409 to death by any cause (OS-1). An additional OS will be defined as time from ICI treatment initiation to death due to any cause (OS-2).

Defined as time from date of first dose of CAN-2409 to post-treatment progression or death by any cause (PFS-1). An additional PFS estimate will be calculated from ICI treatment initiation (PFS-2).

Non-small Cell Lung Cancer Symptoms Assessment Questionnaire (NSCLC-SAQ) score after compared to before treatment. The lowest score possible is 0, and the highest score possible is 20. Higher score indicates more severe symptoms.

Inclusion Criteria: 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 Exclusion Criteria: 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 Women who are pregnant, lactating or intend to become pregnant during the study 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 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 with known EGFR mutation, ALK fusion, or ROS1 fusion positive NSCLC, or that are receiving tyrosine kinase inhibitor (TKI) agents/ALK/ROS1 inhibitors Patients with known interstitial lung diseases (ILDs) requiring active therapy (Radiographic fibrosis not requiring therapy is allowed) 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) 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.