The purpose of this study is to test the safety and tolerability of PMD-026 in patients with metastatic breast cancer. PMD-026 is a targeted oral agent designed to kill tumor cells in metastatic breast cancer.

Combination with fulvestrant (Part 3):

This study will enroll RSK2+, HR+, and human epidermal growth factor receptor 2 negative (HER2-) patients to evaluate PMD-026 in combination with a standard dose and schedule of fulvestrant. Fulvestrant will be dosed per the package insert in combination with PMD-026 at the RP2D determined in the monotherapy phase of the study. Up to 20 patients will be enrolled with locally advanced or metastatic HR+/HER2- breast cancer previously treated with a CDK4/6 inhibitor in combination with endocrine therapy.

Inclusion Criteria, Combination with fulvestrant (Part 3):

• RSK2 positive from available archival or fresh tumor tissue (FFPE).
• Histologically or cytologically diagnosed HR+, HER2-
• ESR1 wild type
• Diagnosis of adenocarcinoma of the breast with evidence of either locally advanced disease not amendable to resection or radiation with curative intent or metastatic disease not amendable to curative therapy
• Must be appropriate candidates for endocrine therapy
• Previously received at least 1 line of endocrine therapy for MBC or had recurrence while on adjuvant endocrine therapy for locally advanced breast cancer
• Discontinued endocrine therapy at least 15 days prior to first dose of PMD-026
• At least 1 measurable target lesion as defined by RECIST v1.1
• Progression on or after treatment with a CDK4/6 inhibitor in combination with endocrine therapy inhibitor in the locally advanced or metastatic setting
• Adequate hematologic, hepatic, and renal function as assessed by laboratory parameters
• Toxicity related to prior therapy resolved to at least Grade 1 (alopecia excepted) or to at least Grade 2 with prior approval of the Medical Monitor

Exclusion Criteria, Combination with fulvestrant (Part 3):

• Prior chemotherapy
• ESR1 mutations
• ≤14 days from biological or investigational therapy
• Presence of visceral crisis or uncontrolled visceral disease for which chemotherapy would be indicated
• Central nervous system metastases, unless appropriately treated and neurologically stable
• History of leptomeningeal metastases
• Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy
• Known hepatitis B or hepatitis C infection
• Known HIV-positive with CD4+ cell counts <350 cells/μL
• Known HIV-positive with a history of an AIDS-defining opportunistic infection
• History of clinically significant cardiovascular abnormalities, including QTcF interval >460 msec (using Fridericia's formula)