The study consists of 2 parts. Part 1 is dose escalation and will first administer SY-5609 alone to participants with select advanced solid tumors and then in combination with fulvestrant to participants with HR positive, HER2-negative breast cancer. Part 2 is a dose expansion and will first administer SY-5609 in combination with gemcitabine and then SY-5609 in combination with gemcitabine and nab-paclitaxel in participants with pancreatic ductal adenocarcinoma (PDAC) .

Inclusion Criteria:

1. Age ≥ 18 years
2. Advanced Solid Tumors for which standard curative or palliative measures do not exist or are no longer effective (Group 1 only).
3. Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. Participants must have failed prior treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor in combination with hormonal therapy in a previous line of therapy (Group 2 only).
4. Participants with histologically or cytologically confirmed PDAC with measurable metastatic lesion(s) (Groups 3 and 4 only).
5. Participants must have at least 1 measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
6. All toxicities (except alopecia) from prior cancer treatments must have resolved to ≤ Grade 1 before enrollment.
7. For women of childbearing potential (WCBP): negative serum β human chorionic gonadotropin pregnancy test within 1 week before the first dose of SY 5609
8. Adequate organ and marrow function
9. Participants must be willing and able to comply with all aspects of the protocol
10. Participants must provide written informed consent before any study-specific screening procedures.
11. Albumin ≥ 3.0 grams/deciliters (g/dL) (Groups 3 and 4 only).

Exclusion Criteria:

1. Chemotherapy or limited field radiotherapy within 2 weeks, wide field radiotherapy within 4 weeks, or nitrosoureas or mitomycin C within 6 weeks before entering the study

2. Major surgery within 2 weeks before starting the study treatment, or not recovered to baseline status from the effects of surgery received > 2 weeks prior

3. Received any other investigational agents within 4 weeks before enrollment, or < 5 half-lives since completion of previous investigational therapy, whichever is shorter

4. Received previous noncytotoxic, US Food and Drug Administration-approved anticancer agent within previous 2 weeks, or < 5 half-lives since completion of previous therapy, whichever is shorter

5. Known brain metastases or carcinomatous meningitis

6. Immunocompromised participants with increased risk of opportunistic infections

7. Participants with known active or chronic hepatitis B or active hepatitis C infection. Participants with a history of hepatitis C virus (HCV) infection who have completed curative therapy for HCV at least 12 weeks before Screening and have a documented undetectable viral load at Screening are eligible for enrollment.

8. Baseline QT interval corrected (QTc) with Fridericia's method > 480 milliseconds

   • NOTE: criterion does not apply to participants with a right or left bundle branch block (QTc interval)

9. Female participants who are pregnant or breastfeeding

10. History of clinically significant cardiac disease or clinically relevant uncontrolled cardiac risk factors

11. Uncontrolled intercurrent illness.

12. Poorly controlled ascites requiring paracentesis within 1 month prior to entering the study. (Groups 3 and 4 only)