A multicenter, single-arm, first-in-human study to investigate the safety, pharmacokinetics, and preliminary antitumor activity of PLX-61639 in participants with locally advanced or metastatic, relapsed/refractory, SMARCA4-deficient solid tumors who are intolerant of or have failed available, approved therapies.

The study will be conducted in 3 parts: dose escalation (Part 1), dose optimization (Part 2), and cohort expansion (Part 3). Each part of the study will consist of a Screening Phase lasting up to 28 days during which participants will be assessed for eligibility, a Treatment Phase beginning on Cycle 1 Day 1 and consisting of consecutive 28-day cycles, an End of Treatment Visit, and a Post-Treatment Follow-Up Phase.

Participants will receive their assigned dose of PLX-61639 administered orally, once daily until progression/relapse, intolerance, death, or withdrawal from study treatment by the Investigator or participant.

Key Inclusion Criteria:

• Participants with locally advanced or metastatic, relapsed/refractory, solid tumors harboring a SMARCA4 loss-of-function mutation that have progressed on, are intolerant of, or not otherwise candidates for available approved therapies
• Adequate liver bone marrow, coagulation, renal, and cardiopulmonary function
• Measurable disease per RECIST 1.1
• ECOG PS of 0 or 1

Key Exclusion Criteria:

• Germline SMARCA4 mutations
• Known SMARCA2 mutation or loss of expression
• Symptomatic CNS disease
• Prior treatment with another SMARCA2-directed therapy
• History of other malignancies
• Clinically significant heart disease
• Uncontrolled hypertension
• Prolongation of QT interval