This study tests an investigational cancer vaccine called ITI-5000 in people who have completed standard treatment for early-stage triple-negative breast cancer (TNBC).

ITI-5000 is a self-amplifying RNA (saRNA) vaccine that instructs the immune system to recognize and attack cancer cells expressing two proteins found on TNBC cells-HERV-K and CT83-fused with a molecule called LAMP-1 that helps the immune system respond more strongly. The vaccine is delivered inside lipid nanoparticles (LNPs), similar to other approved mRNA vaccines.

The study has two parts:

• Part A: Participants receive ITI-5000 alone at one of two dose levels (1 µg or 10 µg), given as an injection into the upper arm muscle every 28 days for 3 doses total. The goal is to find the safest dose.
• Part B: Participants receive ITI-5000 at the best dose identified in Part A, combined with an approved immunotherapy drug called pembrolizumab (Keytruda®), every 21 days for 3 doses total.

This is a Phase 1, first-in-human (FIH), multicenter, open-label, two-part, ascending-dose study . Part A evaluates ITI-5000 as a single agent using a modified 3+3 dose-escalation design across two sequential cohorts:

• Cohort 1: 1 µg (low dose) per vaccination
• Cohort 2: 10 µg (high dose) per vaccination

Each cohort begins with a sentinel participant monitored for 28 days after Vaccination #1 before additional participants are enrolled. The dose-limiting toxicity (DLT) observation window is Day 1-28 following Vaccination #1. If ≤1/6 participants experience a DLT, the dose is deemed tolerable and the cohort expands to further characterize safety and immunogenicity. The Safety Review Committee (SRC) reviews safety data between cohorts. After participants complete Part A, without dose-limiting toxicity, Part B will commence. Part B participants will receive ITI-5000 (dose selected after Part A) in combination with pembrolizumab. Pembrolizumab is administered per its FDA-approved label at either:

• 200 mg intravenously every 3 weeks (Q3W), or
• 400 mg intravenously every 6 weeks (Q6W)

Inclusion Criteria:

• Age: Adults aged 18 years or over.
• Consent: Provided a signed and dated informed consent form (ICF).
• Diagnosis: Histologically confirmed stage 2-3 triple-negative breast cancer (TNBC), defined as HER2-negative, ER-negative, and PgR-negative by immunohistochemistry. BRCA mutations are allowed.
• Prior Treatment: Completed all planned standard therapy (surgery, chemotherapy, radiation, and/or pembrolizumab as applicable) and be within 36 months of definitive surgery.
• Performance Status: ECOG performance status of 0 or 1.
• Organ Function: Adequate organ function at baseline (hematology, biochemistry, etc.).
• Cardiac Function: No significant ischemic heart disease or myocardial infarction within 3 months before vaccination #1; QTc ≤470 msec for females or ≤450 msec for males.
• Pregnancy: Women of childbearing potential must have a negative serum pregnancy test within 3 days before vaccination #1 and agree to use highly effective contraception during the study and for 123 (Part A) or 137 (Part B) days after last study drug.
• Compliance: Able to attend required study visits and follow-up.
• Understanding: Able to understand and provide signed informed consent per IRB/IEC guidelines.
• Vaccinations: Agrees not to receive routine vaccinations until at least 30 days after the last study vaccine.
• Alternative Therapies: Agrees not to use alternative therapies from the time of informed consent through 30 days following vaccination #3.

Exclusion Criteria:

• Part B only: Discontinued prior treatment with an immune checkpoint inhibitor (ICI) due to immune-related adverse events (irAEs).
• Recent Surgery/Therapy: Major surgery within 4 weeks before vaccination #1 or received cancer-directed therapy or investigational drug/device within 4 weeks or 5 half-lives before vaccination #1.
• Part B only: Received other PD-1/PD-L1 inhibitors (besides pembrolizumab) without proper washout.
• Toxicities: Unresolved toxicities from prior immunotherapy or chemotherapy (must be ≤ Grade 1 or baseline, or deemed irreversible and not worsened by immunotherapy).
• Medical Illness: Significant medical illness, underlying health condition, or abnormal laboratory finding increasing risk.
• Autoimmune Disease: Active autoimmune disease requiring immunosuppressive treatment within the last year.
• Pregnancy/Lactation: Female participants trying to conceive, pregnant, or lactating.
• Positive Pregnancy Test: Positive serum pregnancy test at screening or positive urine test at baseline.
• Other Trials: Concurrent participation in any other interventional clinical trial.
• Allergies: Known allergies to any components of the study vaccine.
• Anaphylaxis: History of anaphylaxis requiring medical intervention (including severe reactions to other mRNA vaccines).
• Cardiac History: History of stroke, transient ischemic attack, unstable angina, or myocardial infarction within 3 months prior to first dose.
• Myocarditis/Pericarditis: History of myocarditis or pericarditis.
• Heart Failure: Symptomatic congestive heart failure (NYHA Class III or IV), significant arrhythmia, or LVEF <45%.
• QT Risk: History of risk factors for torsade de pointes or use of QT-prolonging medications.
• Vaccines: Received mRNA or live virus vaccine within 28 days of planned vaccination #1 (flu and COVID boosters prohibited in that window).
• Prior Malignancy: Prior malignancy except adequately treated basal/squamous cell skin cancer, in situ cervical cancer, or disease-free for ≥3 years.
• Organ Transplant: History of organ transplant requiring immunosuppression; unstable HIV/AIDS.
• Hepatitis: Known active hepatitis B or C.
• Compliance: Unable or unwilling to comply with study schedule/procedures.
• Injection/Blood Draw: Contraindication to IM injections or blood draws.