The primary objective of this study is to determine the recommended Phase 2 doses (RP2D(s)) and maximum tolerated dose (MTD) of PYX-201 in combination with pembrolizumab for participants with advanced solid tumors.

Inclusion Criteria

1. Histologically or cytologically confirmed advanced solid tumors, including first-line (1L) head and neck squamous cell carcinoma (HNSCC), advanced or metastatic triple negative breast cancer (TNBC), hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative breast cancer (HER2- BC), gastric cancer (GC), cervical cancer, and second-line and higher (2L+) HNSCC.
2. Male or non-pregnant, non-lactating female participants age ≥18 years.
3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1.
4. Participant must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.
5. Life expectancy of >3 months, in the opinion of the Investigator.
6. Adequate hematologic function.
7. Adequate hepatic function.
8. Adequate renal function.
9. Adequate coagulation profile.
10. Clinical sites must conduct fresh tumor biopsy or provide participant's archived tumor tissue sample.

Exclusion Criteria

1. Known additional malignancy that is progressing or has required active treatment within the past 2 years.
2. Have any active central nervous system (CNS) metastases and/or carcinomatous meningitis.
3. Significant cardiovascular disease within 6 months prior to start of study drug.
4. Evidence of an active systemic bacterial, fungal, or viral infection requiring treatment at the start of study drug.
5. Known active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS).
6. Failure to recover to Baseline severity or National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 Grade ≤1 from acute non-hematologic toxicity due to previous therapy, prior to Screening.
7. Participants with Grade >1 neuropathy of any grade per CTCAE v5.0 and/or receiving treatment for neuropathy at Screening.
8. History of uncontrolled diabetes mellitus.
9. Participants with immunodeficiency or active autoimmune disease that is contraindicated for pembrolizumab.
10. Participants with a history of (noninfectious) pneumonitis/interstitial lung disease (ILD) that required steroids or has current pneumonitis/ILD.
11. Prior solid organ or bone marrow progenitor cell transplantation.
12. Prior high-dose chemotherapy requiring stem cell rescue.
13. Previously received treatment with a programmed death-1 (PD-1)/L1 inhibitor any prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor.
14. Severe hypersensitivity (Grade ≥3) to pembrolizumab and/or any of its excipients and/or PYX-201 and/or any of its excipients.