Study Comparing Investigational Drug HBI-8000 + Nivolumab vs. Placebo + Nivolumab in Patients With Advanced Melanoma

Inclusion Criteria:

1. Histopathologically confirmed diagnosis of non-uveal, Stage III (unresectable), orStage IV (metastatic) melanoma according to AJCC staging system (8th edition).

2. Known BRAF V600 mutation status or consent to BRAF V600 mutation testing beforerandomization.

3. Tumor tissue available for PD-L1 testing at central lab or local laboratory; resultsmust be obtained prior to randomization. In the event when archived tumor tissue isnot available, new tumor biopsy or historical PD-L1 test results may be used forrandomization, however tumor tissue, either taken previously or newly acquired, mustbe provided for central biomarker confirmation for final data analyses. PD-L1 expression level is required for randomization. In order to be randomized, apatient must be classified as PD-L1 positive or PD-L1 negative according to thefollowing criteria:

• PD-L1 positive (≥ 1% tumor cell membrane staining in a minimum of a hundredevaluable tumor cells) vs

• PD-L1 negative (< 1% tumor cell membrane staining in a minimum of a hundredevaluable tumor cells). Note: If an insufficient amount of tumor tissue is available prior to the start ofthe screening phase, patients must consent to allow the acquisition of additionaltumor tissue for performance of biomarker analyses.

4. Males or females 12 years of age or older.

5. ECOG performance status ≤1 for age ≥18 years, Lansky performance status ≥80% for age 12 to 17 years.

6. At least one measurable lesion defined by RECIST 1.1 criteria, (separate from thelesion to be used for tumor tissue collection) not counting brain metastasis with:

• Longest diameter ≥10 mm by CT (when slice thickness is ≤5 mm); or ≥ 2× slicethickness (when slice thickness is >5 mm)

• Pathologically enlarged lymph node: ≥15 mm in short axis by CT (when slicethickness is ≤5 mm)

• Clinical: ≥10 mm (that can be accurately measured with calipers).

7. Have not received anti-PD-1, anti-PD-L1 or other systemic therapy for unresectableor metastatic melanoma, except for the following, provided that the patient hasrecovered from all treatment-related toxicities:

• BRAF mutation targeting therapy > 4 weeks before administration of StudyTreatment.

• Adjuvant or neoadjuvant therapy with PD-1 or PD-L1 inhibitors or anti-cytotoxicT lymphocyte-associated protein 4 (anti-CTLA-4) is allowed if diseaseprogression/or recurrence had occurred at least 6 months after the last dose ofneoadjuvant/adjuvant therapy and prior to receiving the first dose on thisstudy and no clinically significant immune related toxicities leading totreatment discontinuation were observed

• Adjuvant interferon therapy must have been completed > 6 weeks beforeadministration of Study Treatment

8. Any prior radiotherapy or minor surgery must be completed at least 2 weeks and 1week respectively before Day 1 dosing and recovered from all treatment relatedtoxicities

9. Screening laboratory results within 14 days prior to randomization:

• Hematology: WBC ≥3000/μL, neutrophils ≥1500/μL, platelets ≥100 × 103/μL,hemoglobin ≥10.0 g/dL independent of transfusion. The use of erythropoieticgrowth factor to achieve hemoglobin (Hgb) ≥ 10 g/dl is acceptable.

• The CrCL≥ 30 mL/min using Cockcroft-Gault formula.

• AST and ALT ≤3 × ULN, alkaline phosphatase ≤2.5 × ULN unless bone metastasespresent (patients with documented bone metastases: alkaline phosphatase <5 xULN), bilirubin ≤ 1.5 × ULN (unless known Gilbert's disease where it must be ≤ 3 × ULN), serum albumin ≥ 3.0 g/dL).

10. Negative serum pregnancy test at baseline for women of childbearing potential.

11. Females of childbearing potential (non-surgically sterile or premenopausal femalecapable of becoming pregnant) and all males (due to potential risk of drug exposurethrough the ejaculate) must agree to use adequate birth control measures from studystart, during the study and for 5 months after the last dose of Study Drug.Acceptable methods of birth control in this trial include two highly effectivemethods of birth control (as determined by the Investigator; one of the methods mustbe a barrier technique) or abstinence.

12. Have the ability to understand and the willingness to sign a written informedconsent document, comply with study scheduled treatment, visits and assessments.

Exclusion Criteria:

1. History of ≥ Grade 3 hypersensitivity reactions to monoclonal antibodies.

2. Previous treatment with a PD-1, PD-L1, PD-L2, CTLA-4 inhibitor, or any other agentstargeting T-cell co-stimulation or immune checkpoint pathways for unresectable ormetastatic melanoma.

3. Recipient of solid organ transplant.

4. History of a cardiovascular illness including: congestive heart failure (New YorkHeart Association Grade III or IV); unstable angina or myocardial infarction withinthe previous 6 months prior to first dose of Study Treatment; or symptomatic cardiacarrhythmia despite medical management. QT interval corrected by heart rate usingQTcF >450 ms in males or >470 ms in females, or congenital long QT syndrome.

5. Uncontrolled hypertension, systolic blood pressure (SBP) >160 mmHg or diastolicblood pressure (DBP) >100 mmHg.

6. Patients with new, active, or progressive brain metastases or leptomeningeal diseasewith except when considered for a separate special open-label cohort.

7. History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolledpeptic ulcer, or bowel resection that affects absorption of orally administereddrugs.

8. Active, known, or suspected autoimmune disease, except for Type I diabetes mellitus,hypothyroidism requiring only hormone replacement, or skin disorders (such asvitiligo, psoriasis, or alopecia) not requiring systemic therapy.

9. Active uncontrolled bacterial, viral, or fungal infection requiring systemictherapy.

10. Known history of testing positive for HIV, known AIDS.

11. Hepatitis B surface antigen positive or hepatitis C antibody positive. Furtherinvestigation per institutional practices may be performed to exclude activeinfection.

12. Patients with a condition requiring chronic systemic treatment with eithercorticosteroids (>10 mg daily prednisone or equivalents) or other immunosuppressivemedications within 14 days before administration of Study Treatment. Inhaled ortopical steroids, or adrenal replacement dose of corticosteroids at dose ≤ 10 mg/dayprednisone equivalent are permitted.

13. Use of another investigational agent (drug or vaccine not marketed for anyindication) within 28 days or before administration of Study Treatment. If theinvestigational agent is a monoclonal antibody then within 3 months beforeadministration of Study Treatment

14. Pregnant or breast-feeding women.

15. Have a history of any other malignancy unless in remission for 2 years or locallycurable cancers that have been treated with curative intent with no evidence ofrecurrence, such as:

• Basal or squamous cell skin cancer

• Superficial bladder cancer

• Carcinoma in situ of cervix or breast

• Incidental prostate cancer

• Non melanomatous skin cancer

• Prostate cancer treated with curative intent with serum prostate specificantigen (PSA) < 2.0 ng/mL

16. Patients with medical conditions requiring administration of strong cytochrome P450 (CYP), CYP3A4 Inducers and Inhibitors with no alternative therapy.

17. Uncontrolled adrenal insufficiency or active chronic liver disease.

18. Has received approved live vaccine/live attenuated vaccines within 30 days ofplanned Cycle 1 Day 1. Inactivated viral vaccines or vaccines based upon subviralcomponent are allowed; however intranasal influenza vaccines (e.g. Flu-Mist) are notallowed. COVID-19 vaccination should be administered at least 7 days before Cycle 1Day 1.

19. Underlying medical conditions that, in the Investigator's opinion, will make theadministration of Study Treatment hazardous or obscure the interpretation oftoxicity determination or AEs.

20. Patients with a history of or active interstitial lung disease (ILD) ornon-infectious pneumonitis.

21. Patients with prior organ or hematopoietic cell transplant (HCT), includingallogeneic HCT.

22. Patients with known sensitivity to any of the ingredients of the Study Treatment.

23. Patients who received radiation therapy within 14 days of the first dose of theStudy Treatment.

24. Patients who take drugs that prolong the QT interval or cause torsades de pointes orproduce significant ventricular dysrhythmias.

25. Patients that are unwilling or unable to comply with procedures required in thisprotocol.