A Study of HBI-8000 (Tucidinostat) With Pembrolizumab in Non-Small Cell Lung Cancer

Inclusion Criteria

1. Adults at least 18 years of age.
2. Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
3. Histopathologically confirmed diagnosis of NSCLC PD-L1 expression TPS ≥1% as determined by an FDA-approved test.
4. Have at least one measurable target lesion as defined by RECIST v.1.1.
5. Have not received immune checkpoint inhibitor therapy or more than one regimen of chemotherapy for advanced or metastatic disease. Subjects who have previously received immune checkpoint inhibitor therapy in the adjuvant or neoadjuvant setting may be allowed if disease progression occurred \>6 months after the last dose and no clinically significant immune related toxicities leading to treatment discontinuation were observed.
6. Prior adjuvant or neoadjuvant systemic therapy with chemotherapy, EGFR or ALK mutation directed therapy must have been completed \>4 weeks before Cycle 1 Day 1 (C1D1) dosing and recovered from all treatment related toxicity.
7. Any prior palliative radiotherapy or minor surgery must be completed at least 2 weeks and 1 week respectively before C1D1 dosing and recovered from all treatment related toxicities.
8. Adequate major organ functions at baseline as evidenced by laboratory findings within 14 days prior to C1D1 study drug administration as defined below:

   1. White blood cells (WBC) ≥3000/μL, neutrophils ≥1500/μL, platelets ≥100×103/μL, hemoglobin ≥9.0 g/dL, independent of transfusion.
   2. Serum creatinine ≤1.5 mg/dL, normal electrolytes, phosphorus, and calcium.
   3. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN), alkaline phosphatase ≤2.5 × ULN unless bone metastases present, bilirubin ≤1.5 × ULN (unless known Gilbert's disease where it must be ≤3 × ULN) and serum albumin ≥3.0 g/dL.
   4. Thyroid stimulating hormone (TSH) within normal limits.
9. Life expectancy ≥12 weeks.
10. A negative serum pregnancy test at baseline for women of childbearing potential (WOCBP).
11. Women of childbearing potential. (WOCBP), non-surgically sterile or premenopausal female capable of becoming pregnant and men (due to potential risk of drug exposure through the ejaculate) must agree to use an acceptable method of contraception while enrolled on this study, and for a period of 5 months following the last dose of treatment. Acceptable methods of birth control in this trial include 2 highly effective methods of birth control (as determined by the Investigator; one of the methods must be a barrier technique) or abstinence.
12. Have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

1. History of Grade ≥3 hypersensitivity reactions to monoclonal antibodies.
2. History of a cardiovascular illness including: QT interval corrected by heart rate using Fridericia's correction formula (QTcF) \>450 ms in male or \>470 ms in female, congenital long QT syndrome, congestive heart failure (New York Heart Association Grade III or IV) (Protocol Appendix 2); unstable angina or myocardial infarction within the previous 6 months; or symptomatic cardiac arrhythmia despite medical management.
3. Uncontrolled hypertension, systolic blood pressure (SBP) \>160 mmHg or diastolic blood pressure (DBP) \>100 mmHg.
4. Central nervous system metastasis or leptomeningeal disease except when treatment for brain metastasis is completed \>14 days prior to C1D1 and stable for ≥4 weeks on \<10 mg daily prednisone or equivalent.
5. History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolled peptic ulcer disease or bowel resection that affects absorption of orally administered drugs.
6. Recurrent pleural effusion requiring repetitive palliative thoracentesis within 3 months prior to study entry, except for subjects with a pleurex port.
7. Active, known, or suspected autoimmune disease, or history of immune-mediated toxicity leading to treatment discontinuation, except for type I diabetes mellitus, hypothyroidism only requiring hormone replacement or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic therapy.
8. Active pneumonitis, history of non-infectious pneumonitis that required treatment with steroids, or history of interstitial lung disease.
9. Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.
10. Known history of testing positive for human immunodeficiency virus (HIV), known acquired immunodeficiency syndrome (AIDS).
11. Active hepatitis B (hepatitis B surface antigen \[HBVsAg\] positive), or hepatitis C (HCV antibody test or serum hepatitis C ribonucleic acid \[RNA\] positive).
12. Received approved live vaccines within 30 days of planned C1D1. Inactivated viral vaccines or vaccines based on subviral component are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are not allowed. COVID-19 vaccination should be administered \>7 days before C1D1.
13. Any condition requiring chronic systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications, or steroids use within 14 days of study drug administration. Inhaled or topical steroids are permitted.
14. Use of other investigational agent (drug not marketed for any indication) within 28 days or at least 5 half-lives (whichever is shorter) before study drug administration.
15. Pregnant or breast-feeding women.
16. Second malignancy unless in remission for 2 years; subjects with non-melanomatous skin cancer, carcinoma in situ of the cervix treated with curative intent, or curatively treated prostate cancer with prostate-specific antigen (PSA) \<2.0 ng/mL can be included.
17. Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events.
18. Unwilling or unable to comply with procedures required in this protocol.