Inclusion Criteria:
1. Males and females ≥18 years of age who comprehend, are not incarcerated, are willing and able to provide consent by signing an ICF, and able to comply with scheduled visits, treatment schedule, and laboratory tests, including other requirements for the study
2. Histologically or cytologically documented locally advanced or metastatic solid tumor malignancy
3. Patients who have progressed on or after prior therapy and who are not eligible for available treatment options
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Has at least 1 measurable lesion per RECIST 1.1 criteria
6. Recovery from previous treatment related adverse events (TRAEs) to allow safety evaluations of SPX-303. Previous TRAEs include adverse drug reactions, and consequences of radiation, surgery, and other therapeutic modalities
7. Adequate hepatic function; bilirubin ≤1.5x upper limit of normal (ULN) (except for patients with Gilbert syndrome: ≤ 3xULN), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) ≤2.5 x ULN (≤5 x ULN if liver metastases present).
8. Adequate renal function as calculated (e.g. Cockroft Gault) creatine clearance (CrCl) ≥ 30 mL/min or 24-hour urine CrCl ≥ 30 mL/min.
9. Adequate hematological function: absolute neutrophil count (ANC) ≥1 x 10\^9/L; platelets ≥75 x 10\^9/L, hemoglobin ≥9 g/dL.
10. Patients with well controlled HIV infection (ie CD4+ count \>350 cells/uL and viral copies less than 400/mL after at least 4 weeks of ART) are eligible for the trial.
11. Adequate coagulation function: INR, PT and aPPT ≤ 1.5x ULN except for patients on anti-coagulation as long as PT, aPPT, or INR are within intended range.
12. Adequate cardiac function: Left Ventricular Ejection Fraction (LVEF) ≥ 45% by multi-gated acquisition (MUGA) or echocardiography (ECHO) scan.
13. Fridericia-corrected QT interval (QTcF) ≤480 msec.
14. Women of childbearing potential must have a negative pregnancy test and must agree to use of 2 different methods of acceptable contraception from screening until 4 months after the last dose of study drug. Acceptable methods of contraception are defined as those that result, alone or in combination, in a low failure rate (ie, less than 1% per year) when used consistently and correctly, such as surgical sterilization, an intrauterine device, hormonal contraception in combination with a barrier method or abstinence).
15. Males who are sexually active with a female partner of childbearing potential must agree to use a barrier contraception (eg, condom with spermicidal foam/gel/film/cream/suppository) from screening until 4 months following the last dose of study drug, in addition to their female partner using either an intrauterine device or hormonal contraception and continuing until 4 months following the last dose of study drug. This criterion may be waived for male patients who have had a vasectomy \>6 months before signing the ICF.
Exclusion Criteria:
1. History of prior malignancy, except for adequately treated in situ cancer, basal cell, or squamous cell skin cancer, or other cancers (eg, breast, prostate) for which the patient has been disease free for at least 3 years. Prostate cancer patients on active surveillance are eligible.
2. Active brain or leptomeningeal metastasis. Except patients with known brain metastases if they have been treated and MRI shows no evidence of progression for at least 8 weeks and require less than 10 mg/day prednisone/prednisolone or equivalent.
3. Treatment with anti neoplastic therapy ≤ 28 days or ≤ 5× elimination half life, whichever is shorter, before the first dose of study drug.
4. Major surgery requiring general anesthesia ≤ 28 days prior to dosing.
5. History of permanent discontinuation of prior IO therapy due to irAE.
6. Prior treatment targeting ILT2 and/or ILT4 or targeting HLA G.
7. Live or live attenuated vaccine ≤ 28days prior to dosing.
8. Immunosuppressive systemic medication, except topical corticosteroids or systemic corticosteroids at a dose level of ≤ 10 mg/d of prednisone/prednisolone or equivalent. Note: patients with adrenal insufficiency requiring hormonal replacement may receive higher dose of steroids.
9. Prior solid organ or bone marrow transplantation (except cornea transplantation).
10. History of clinically significant cardiovascular events (e.g. DVT ≤ 6 months, PE ≤ 12 months, MI or hospitalization for CHF ≤ 12 months, bleeding disorder or bleeding event ≤ 6 months, current clinically significant arrhythmia or unstable angina pectoris, current uncontrolled history of cerebrovascular accident in the past 6 months, current uncontrolled hypertension).
