The purpose of this study is to evaluate the safety and establish the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of ION537 when administered by intravenous infusion in patients with advanced solid tumors.

This is a single center, open label, non-randomized, Phase 1, two-part study of ION537 in up to 102 participants. Part 1 of the study consists of sequential cohort, dose escalation in patients with advanced solid tumors. Part 2 is dose expansion in patients with molecularly selected advanced solid tumors. In total, the study includes up to 102 participants. The study will consist of a 30-day screening period, a treatment period consisting of sequential consecutive treatment cycles (each cycle will be of 28 days) and a post-treatment follow-up period of at least 28 days following the last dose of study drug.

Inclusion Criteria:

1. Males and females ≥ 18 years old
2. Participants must have histological diagnosis of local advanced (primary or recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent
3. Participants must be in need of systemic treatment for their cancer and either are refractory to or have failed treatment with, are intolerant to or have refused, or are not otherwise a candidate, in the opinion of the Investigator, for any of the currently available established therapies
4. Participants must have available a fresh or recent tumor tissue sample from a diagnostic biopsy/surgery or a metastatic tumor biopsy;
5. Participants must have measurable disease by response evaluation criteria in solid tumors (RECIST) v1.1; or participants may have bone metastatic disease evaluable by Prostate Cancer Working Group 2 (PCWG2) for participants with metastatic castration-resistant prostate cancer (mCRPC), or according to the tumor evaluation criteria best suited and accepted for the tumor type being evaluated
6. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
7. Participants must be willing and able to comply with the scheduled visits, treatment plan, laboratory tests and other specified study procedures

Exclusion Criteria:

1. Known history or positive test for human immunodeficiency virus (HIV), hepatitis C virus (HCV) or chronic hepatitis B virus (HBV) infection.
2. Active infection requiring intravenous (IV) antibiotics
3. History of cerebrovascular accident (CVA), myocardial infarction or unstable angina within the previous 6 months before starting therapy.
4. Participants with uncontrolled Type I or II diabetes mellitus (DM); uncontrolled DM
5. Participants with prior anti-cancer therapy within 2 weeks prior to study enrollment or prior radiation therapy within 2 weeks prior to study enrollment.