Phase 1 Study of a Self-amplifying RNA Vaccine (ITI-5000) in Stage 2-3 Triple Negative Breast Cancer

This will be a phase 1, FIH, multicenter, open-label, two-part, ascending dose study to evaluate the safety, tolerability, and immune response of the ITI-5000 vaccine in adult participants with TNBC (stage 2-3). The study will be divided into 2 parts: in Part A, participants will receive the ITI-5000 vaccine as a single agent in the post-adjuvant setting, and in Part B, participants will receive the ITI-5000 vaccine in combination with standard of care adjuvant therapy. Part A will be divided into 2 dose level cohorts - Cohort 1A conducted at the dose of 1 μg (low dose) per vaccination and Cohort 2A conducted at the dose of 10 μg (high dose) per vaccination. In Part A, three vaccinations of ITI-5000 will be administered with a 28-day interval. The first 3-6 participants will be enrolled sequentially, with the first participant designated as a sentinel participant who will be monitored for 28 days after receiving the first ITI-5000 vaccination before subsequent participants are enrolled. If 0/3 participants experience a DLT, Cohort 2A may proceed. If 1/3 of the participants experience a DLT, the cohort will expand to include 3 additional participants (total of 6). If ≥2/6 participants experience a DLT, the dose will be considered not tolerable, and the cohort will be stopped. At the conclusion of each cohort, the safety review committee (SRC) will review safety signals and determine a rationale for dose escalation, de-escalation, or potential intermediate doses to be evaluated. The SRC will also determine the dose to be evaluated in Cohort 3A and Part B. The MTD will be evaluated in Cohort 3A which will enroll up to 15 participants who did not achieve pathological complete response (pCR) following neoadjuvant therapy. This expansion will allow further assessment of safety and immunogenicity in a participant population that is at high risk of disease recurrence. Part B will evaluate the MTD of ITI-5000 in combination with standard of care (SOC) adjuvant therapy among participants who did not achieve a pathological complete response (pCR) following neoadjuvant therapy. A safety lead-in group comprising 3 participants will be enrolled at the beginning of Cohort 1B and 2B to assess the safety of the combination treatment. Unlike Part A, no sentinel participant will be required, as the safety of ITI-5000 alone will already have been established in Part A. The safety lead-in will provide an early evaluation of the tolerability of the combination regimen before enrolling additional participants. Cohort 1B will enroll up to 20 participants with BRCA1/2 mutation who did not achieve pathological complete response (pCR) following neoadjuvant therapy. Three doses of ITI-5000 will be administered in the adjuvant setting with a 21-day interval in combination with standard of care (pembrolizumab 200 mg Q3 weeks or 400 mg Q6 weeks and olaparib as per FDA approved label and currently accepted guidelines). Cohort 2B will enroll up to 20 participants with wild-type BRCA1/2 who did not achieve pCR following neoadjuvant therapy. Three doses of ITI-5000 will be administered in the adjuvant setting with a 21-day interval in combination with standard of care (pembrolizumab 200 mg Q3 weeks or 400 mg Q6 weeks and capecitabine as per FDA approved label and currently accepted guidelines). Following SRC review of the safety lead-in participants, an expansion cohort of up to 17 additional participants will be enrolled in both Cohorts 1B and 2B, bringing Part B to a total of up to 40 participants (up to 20 participants per cohort). After all Part B participants have completed the Follow-up #1 visit, the SRC will meet to guide further clinical development of ITI-5000. The final analysis will take place after the end of the study. In both Part A and Part B, participants will undergo 3 main study periods: a screening period, a treatment period (also named study vaccination period) with 3 study visits during which each participant will receive a total of 3 ITI-5000 vaccinations: 28 days