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

This is a clinical study to compare the efficacy and safety of HBI-8000 combined with nivolumab to Placebo combined with nivolumab in patients with unresectable or metastatic melanoma. A separate open-label cohort of adults with new, progressive brain metastasis or adolescents with or without new progressive brain metastasis receive HBI-8000 combined with nivolumab.

This is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study of HBI-8000 or Placebo combined with nivolumab. Randomization of eligible patients will be stratified by PD-L1 expression (positive, ≥1% expression level versus negative, \<1% expression level) and LDH (normal versus elevated) in the main study. Adults with new, progressive brain metastasis, or adolescents with or without new progressive brain metastasis will be enrolled in a separate, non-randomized, open-label cohort to receive the combination of HBI-8000 and nivolumab.

In the main study, eligible patients will be randomized within the appropriate stratum at a 1:1 ratio to the Test arm or the Control arm. Study treatment will be initiated within 3 days of randomization.

A treatment cycle consists of 28 days. Patients will be treated with one of the following:

Test arm: HBI-8000 30 mg oral BIW + nivolumab IV at specific doses on specific days

Control arm: Placebo oral BIW + nivolumab IV at specific doses on specific days

The Study Treatment (HBI-8000 or Placebo) is administered approximately 30 minutes after a full meal.

The Study Treatment (HBI-8000 or Placebo) will be administered twice a week on the following days of every 28-day cycle:

* CxW1: Days 1, 4
* CxW2: Days 8, 11
* CxW3: Days 15, 18
* CxW4: Days 22, 25

Study treatment must commence within 3 days after randomization and continue up to 2 years or until disease progression (confirmed), unacceptable toxicity or patient withdrawal of consent.

In addition to Study Treatment, nivolumab is administered at specific doses on specific days as an intravenous infusion over approximately 30 minutes. Nivolumab will be administered on Day 1 of each cycle.

For non-randomized cohort for special population, eligible subjects will receive HBI-8000 30 mg oral BIW and nivolumab IV at specific doses on specific days, under the same schedule as described above. For adolescents weighing \< 40 kg, nivolumab will be dosed at specific doses every 4 weeks. Nivolumab will be administered on Day 1 of each cycle.

Eligibility Criteria:
Inclusion Criteria:

1. Histopathologically confirmed diagnosis of non-uveal, Stage III (unresectable), or Stage IV (metastatic) melanoma according to AJCC staging system (8th edition).
2. Known BRAF V600 mutation status or consent to BRAF V600 mutation testing before randomization.
3. Tumor tissue available for PD-L1 testing at central lab or local laboratory; results must be obtained prior to randomization. In the event when archived tumor tissue is not available, new tumor biopsy or historical PD-L1 test results may be used for randomization, however tumor tissue, either taken previously or newly acquired, must be provided for central biomarker confirmation for final data analyses.

   PD-L1 expression level is required for randomization. In order to be randomized, a patient must be classified as PD-L1 positive or PD-L1 negative according to the following criteria:
   * PD-L1 positive (≥ 1% tumor cell membrane staining in a minimum of a hundred evaluable tumor cells) vs
   * PD-L1 negative (\< 1% tumor cell membrane staining in a minimum of a hundred evaluable tumor cells).

   Note: If an insufficient amount of tumor tissue is available prior to the start of the screening phase, patients must consent to allow the acquisition of additional tumor 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 the lesion 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× slice thickness (when slice thickness is \>5 mm)
   * Pathologically enlarged lymph node: ≥15 mm in short axis by CT (when slice thickness 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 unresectable or metastatic melanoma, except for the following, provided that the patient has recovered from all treatment-related toxicities:

   * BRAF mutation targeting therapy \> 4 weeks before administration of Study Treatment.
   * Adjuvant or neoadjuvant therapy with PD-1 or PD-L1 inhibitors or anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) is allowed if disease progression/or recurrence had occurred at least 6 months after the last dose of neoadjuvant/adjuvant therapy and prior to receiving the first dose on this study and no clinically significant immune related toxicities leading to treatment discontinuation were observed
   * Adjuvant interferon therapy must have been completed \> 6 weeks before administration of Study Treatment
8. Any prior radiotherapy or minor surgery must be completed at least 2 weeks and 1 week respectively before Day 1 dosing and recovered from all treatment related toxicities
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 erythropoietic growth 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 metastases present (patients with documented bone metastases: alkaline phosphatase \<5 x ULN), 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 female capable of becoming pregnant) and all males (due to potential risk of drug exposure through the ejaculate) must agree to use adequate birth control measures from study start, 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 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, 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 agents targeting T-cell co-stimulation or immune checkpoint pathways for unresectable or metastatic melanoma.
3. Recipient of solid organ transplant.
4. History of a cardiovascular illness including: congestive heart failure (New York Heart Association Grade III or IV); unstable angina or myocardial infarction within the previous 6 months prior to first dose of Study Treatment; or symptomatic cardiac arrhythmia despite medical management. QT interval corrected by heart rate using QTcF \>450 ms in males or \>470 ms in females, or congenital long QT syndrome.
5. Uncontrolled hypertension, systolic blood pressure (SBP) \>160 mmHg or diastolic blood pressure (DBP) \>100 mmHg.
6. Patients with new, active, or progressive brain metastases or leptomeningeal disease with except when considered for a separate special open-label cohort.
7. History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolled peptic ulcer, or bowel resection that affects absorption of orally administered drugs.
8. Active, known, or suspected autoimmune disease, except for Type I diabetes mellitus, hypothyroidism requiring only hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic therapy.
9. Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.
10. Known history of testing positive for HIV, known AIDS.
11. Hepatitis B surface antigen positive or hepatitis C antibody positive. Further investigation per institutional practices may be performed to exclude active infection.
12. Patients with a condition requiring chronic systemic treatment with either corticosteroids (\>10 mg daily prednisone or equivalents) or other immunosuppressive medications within 14 days before administration of Study Treatment. Inhaled or topical steroids, or adrenal replacement dose of corticosteroids at dose ≤ 10 mg/day prednisone equivalent are permitted.
13. Use of another investigational agent (drug or vaccine not marketed for any indication) within 28 days or before administration of Study Treatment. If the investigational agent is a monoclonal antibody then within 3 months before administration of Study Treatment
14. Pregnant or breast-feeding women.
15. Have a history of any other malignancy unless in remission for 2 years or locally curable cancers that have been treated with curative intent with no evidence of recurrence, 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 specific antigen (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 of planned Cycle 1 Day 1. Inactivated viral vaccines or vaccines based upon subviral component are allowed; however intranasal influenza vaccines (e.g. Flu-Mist) are not allowed. COVID-19 vaccination should be administered at least 7 days before Cycle 1 Day 1.
19. Underlying medical conditions that, in the Investigator's opinion, will make the administration of Study Treatment hazardous or obscure the interpretation of toxicity determination or AEs.
20. Patients with a history of or active interstitial lung disease (ILD) or non-infectious pneumonitis.
21. Patients with prior organ or hematopoietic cell transplant (HCT), including allogeneic 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 the Study Treatment.
24. Patients who take drugs that prolong the QT interval or cause torsades de pointes or produce significant ventricular dysrhythmias.
25. Patients that are unwilling or unable to comply with procedures required in this protocol.