Combination Study of SV-BR-1-GM With Retifanlimab

This is an open-label, phase I/II double arm study of the SV-BR-1-GM regimen in combination with retifanlimab in patients with metastatic or locally recurrent breast cancer who have failed standard therapy.

Patients will receive the SV-BR-1-GM regimen with combination immunotherapy. There will be an initial evaluation of the combination of the SV-BR-1-GM regimen with retifanlimab every 3 weeks. If this is found to be safe and well tolerated in a cohort of at least 12 patients (dose-limiting toxicities (DLTs) in less than 30% of the patients evaluated), then an expansion cohort of up to 24 patients will be treated with that combination. These will be randomized to two regimens differing in the timing of retifanlimab administration as noted below.

The SV-BR-1-GM regimen consists of:

• Pre- SV-BR-1-GM cyclophosphamide 2-3 days prior to SV-BR-1-GM inoculation
• SV-BR-1-GM inoculation on day 0
• Interferon - at the inoculation sites 2 (±1) day post-SV-BR-1-GM

Combination therapy with retifanlimab (anti-PD-1) will be given per one of two randomized treatment arms as follows:

The SV-BR-1-GM regimen with retifanlimab will be administered every 3 weeks (± 3 days), except when approved by the Investigator in consultation with the Medical Monitor. Note that hormonal therapy (e.g., aromatase inhibitors) is permitted if ongoing, but may be added while the patient is on this study only with the Medical Monitor's approval (e.g. for hormone receptor positive patients who are deriving clinical benefit but have not achieved a CR after >6 cycles of therapy).

Following the initial cohort, an expansion cohort of 24 patients will be randomized 1:1 into two arms with differences in initial treatment sequences: original sequence and alternative sequence. The original sequence arm will receive treatment in the same schedule as the initial cohort. Subjects in the alternative sequence will skip retifanlimab in Cycle 1, and resume retifanlimab on Day 2±1 at Cycle 2. Starting Cycle 3, retifanlimab can be administered either on Day -2/-3, Day 0 or Day 2±1. Patients will be screened to ensure they fulfill the enrollment criteria. Screening must be performed within 30 days of initiating therapy. Imaging studies must be performed within 30 days of initiating therapy for the initial 12 patients, and within 14 days for the expansion cohort (randomized portion), unless approved by the Sponsor. For subjects in expansion cohort participating in the substudy, the CD8 attenuation CT scan cannot be used for the baseline image. However, patients can be immediately scanned after the low dose attenuation scan. In the expansion cohort randomized portion of the trial, imaging must be performed within 14 days of the start of study treatment. Patients will be evaluated every 3 weeks during the study, including all safety assessments. Imaging studies will be performed every 8-12 weeks during study participation.

Pharmacodynamic assessments, including evaluation of the immune response to SV-BR-1-GM will also be performed during screening visit (substudy only), during Cycle 1, every 8-12 weeks and End of Treatment. Subsequent periodic assessments will be every 8-12 weeks from the first periodic assessment. Patients who develop progressive disease may remain on treatment for up to 6 weeks to obtain a confirmatory scan per iRECIST; or as long as the Investigator feels they are deriving clinical benefit with Medical Monitor approval. For patients who come off treatment, a final assessment will be carried out 2-4 weeks following the last dose of SV-BR-1-GM, including all safety assessments. Off-treatment subjects will continue to be followed for survival analysis every 3 months (e.g., by phone call) for at least 5 years or until death.

For the CD8 ImmunoPET sub-study, ten (10) patients will be recruited from select invited sites only, and will undergo CD8 ImmunoPET evaluation at baseline and following 3 cycles of SV-BR-1-GM therapy.