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

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.

Eligibility Criteria:
Inclusion Criteria:

1. 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
2. RECIST evaluable disease including a lesion that is amenable to injection
3. Able and willing to undergo a pre-treatment and on-treatment biopsies, if feasible
4. ECOG Performance status of 0 or 1
5. 18 years of age or older
6. Granulocyte count (ANC) ≥ 1,000/mm3
7. Hemoglobin ≥ 8 g/dl (patients may be transfused to meet this criterion)
8. Platelets ≥ 75,000/mm3
9. 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
10. SGOT (AST) ≤ 5x upper limit of normal and if elevated, not clinically significant such that ICI can continue
11. 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
12. Serum creatinine \< 2mg/dl and calculated creatinine clearance \> 30ml/min
13. Clinically stable and able to continue ICI for at least the 12-week treatment period
14. Within 6 months of enrollment, no change of ICI therapy or prior interruptions of more than 4 weeks of current ICI
15. Patients should not have received focal therapy (e.g., radiotherapy) at more than three different sites of disease within 12-months prior to enrollment
16. Patients must give study specific informed consent prior to enrollment and any study specific procedures

Exclusion Criteria:

1. Patients with a history of severe immune related adverse events related to ICI
2. 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
3. Patients with a history of active autoimmune disease requiring treatment in the past 2 years
4. 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
5. Women who are pregnant, lactating or intend to become pregnant during the study
6. Patients who are known to be HIV positive
7. Patients with a history of hypersensitivity or allergic reactions to valacyclovir or acyclovir
8. Patients with significant heart disease (New York Heart Association Functional Classification III or IV)
9. Patients with continuous oxygen dependence \>2L/min at rest
10. Tumor impinging on a neurovascular structure such that inflammation in the site may put patient at risk of compromise as determined by the investigator
11. Patients with uncontrolled brain metastases as per investigator
12. Patients with liver metastases involving more than half of the liver
13. Patients with known EGFR mutation, ALK fusion, or ROS1 fusion positive NSCLC, or that are receiving tyrosine kinase inhibitor (TKI) agents/ALK/ROS1 inhibitors
14. Patients with known interstitial lung diseases (ILDs) requiring active therapy (Radiographic fibrosis not requiring therapy is allowed)
15. Patients receiving vascular endothelial growth factor (VEGF) inhibitors (including bevacizumab, ramucirumab) within the past 2 months or five half-lives, whichever is longer
16. Patients must have no concurrent malignancy requiring treatment (except squamous or basal cell skin cancers)
17. Patients without contrast enhanced imaging at baseline or those with contraindication to the use of contrast.
18. Patients who are pregnant, breastfeeding, or plan to become pregnant.