Oncolytic MG1-MAGEA3 With Ad-MAGEA3 Vaccine in Combination With Pembrolizumab for Non-Small Cell Lung Cancer Patients

This is a Phase 1/2, open-label, dose-escalation trial of Ad MAGEA3 and MG1-MAGEA3 in combination with pembrolizumab in patients with NSCLC (histological subtype of squamous and non-squamous NSCLC). In Phase 1, patients who have progressed after treatment with a platinum-based regimen and/or PD-1/PD-L1 targeted antibody therapy will be enrolled. In Phase 2, only patients who have progressed after treatment regimen containing PD-1/PD-L1 targeted antibody therapy will be enrolled. In the Phase 1 portion of the study, MG1-MAGEA3 treatment will be escalated in a sequential dose-escalating design. In the Phase 2 portion of the study, MG1-MAGEA3 treatment will be at the maximum tolerated dose (MTD) or the maximum feasible dose (MFD). The Ad-MAGEA3 and pembrolizumab dose is fixed in both the Phase 1 and Phase 2 portions of the trial. Phase 1 Enrollment Cohorts 1 through 5: Three patients will be treated at each dose level unless a dose-limiting toxicity (DLT), as defined below, is observed. Patients will be observed for a DLT through Day 29. After enrollment of the first patient in each cohort, 2 additional patients will be enrolled after the initial patient reaches Day 29 without experiencing a DLT. Treatment with MG1-MAGEA3 will proceed to the next dose level if 0 of 3 patients experiences a DLT. If one of the first 3 patients experiences a DLT, additional patients will be enrolled until a second patient experiences a DLT (which defines the toxic dose) or until 6 total patients have been treated, whichever comes first. If a second DLT is not experienced within that cohort, dose escalation may continue. If 2 DLTs are observed within a cohort, enrollment into the cohort will cease and the dose level immediately preceding that dose will be determined as the MTD. Ad-MAGEA3 will be administered by intramuscular (IM) injection at a dose level of 2 x 1011 virus particles (VP) on Day 1. MG1-MAGEA3 will be administered by intravenous (IV) infusion at escalating dose levels on Day 15 and Day 18. In Cohorts 1 through 5, patients will receive pembrolizumab at a dose of 200 mg IV on Day 22, and every 3 weeks thereafter until confirmed radiographic progression or unmanageable toxicity. Cohort 6: Upon determination of the MTD/MFD (safety assessment) in Cohorts 4-5, the treatment regimen will next be optimized such that pembrolizumab will begin on Day 1 (concurrent treatment). The Day 15 and Day 18 doses of MG1-MAGEA3 will be the doses defined as the MTD/MFD in either Cohort 4 or5. Specifically, the regimen evaluated in Cohort 6 is as follows: * Day 1: Patients will receive 2 x 1011 VP IM of Ad-MAGEA3 and 200 mg IV of pembrolizumab (the Pembrolizumab will be continued every 3 weeks \[Q3W\]). * Day 15: Patients will receive IV MG1-MAGEA3 at the MTD/MFD established for the first infusion from Cohort 4 or Cohort 5. * Day 18: Patients will receive IV MG1-MAGEA3 at the MTD/MFD established for the second infusion from Cohort 4 or Cohort 5. * Three patients will be treated according to the dose schedule above unless a DLT is observed between Day 1 and Day 29, at which time three additional patients will be enrolled onto this cohort. If 2 DLTs occur within these six patients treated in Cohort 6, this cohort will be stopped and a new Cohort will be initated again with patients treated concurrently with pembrolizumab but with a 0.5 log lower dose of MG1-MAGEA3 than used in Cohort 6 for the Day 15 and Day 18 doses. Phase 2 Enrollment Phase 2 enrollment will commence upon completion of dose escalation and determination of the MTD/MFD. In Stage 1 of the 2-Stage design, 18 evaluable patients will be treated at the MTD/MFD (this will include patients treated at the MTD/MFD in Phase 1 who meet Phase 2 inclusion criteria). If 1 or more patients respond, the study may continue to Stage 2, and an additional 14 evaluable patients will be enrolled for a total of 32 evaluable patients. A patient will be defined as being evaluable for the primary endpoint (EPPE) and included in the Simon 2-stage study design if they are seronegative to adenovirus Type 5, the virus used in the prime. Preliminary data from two other Turnstone Ad/MG1-MAGEA3 trials indicates that patients without pre-existing anti-adenovirus antibodies (seronegative) prior to treatment have a greater likelihood of generating MAGEA3 specific T-cell responses than those that are seropositive at baseline. Therefore, this study is designed to primarily determine the response rate and clinical outcome for this homogenous population of Ad5 seronegative patients whom are most likely to benefit from Ad/MG1-MAGEA3 treatment. However, there is a small subset of seropositive patients who developed significant anti-MAGEA3 T-cell responses after Ad/MG1-MAGEA3 treatment. In addition, the presence of Ad5 seropositivity would not be expected to have any significant impact on the potential benefit of MG1-MAGEA3 tumor oncolysis. Therefore, exploratory data on clinical and immune response in the Ad5 seropositive population will be conducted and the study will enroll both Ad5 seronegative and positive patients. It is anticipated that approximately half of the patients enrolled will be seronegative to Ad5, therefore Stage 1 of the Simon 2-stage design above will enroll approximately 18 patients and Stage 2 will enroll approximately 14 patients. Total study enrollment is projected to be between 2 and 100 patients. Safety Committee: Prior to each dose level increase or the initiation of Phase 2, a safety committee composed of independent voting members and treating physician(s) will review toxicity and other relevant data to determine suitability of dose escalation or expansion with regards to patient safety. Interim assessments of toxicity will be conducted throughout the trial to monitor for safety trends and identify any new or increased toxicity not previously associated with the IPs.