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

A Multicenter, Randomized, Double-Blind Phase 3 Study of HBI-8000 Combined With Nivolumab Versus Placebo With Nivolumab in Patients With Unresectable or Metastatic Melanoma Not Previously Treated With PD-1 or PD-L1 Inhibitors

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Unresectable or Metastatic Melanoma; Progressive Brain Metastasis
• Intervention / Treatment: Drug: HBI-8000 in combination with nivolumab; Drug: Placebo in combination with nivolumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 450
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Brisbane, Australia
    • Royal Brisband and Women's Hospital
  • Liverpool, Australia
    • Liverpool Hospital
  • Nedlands, Australia
    • Affinity Clinical Research
  • Tweed Heads, Australia
    • Tweed Hospital
  • Waratah, Australia
    • Calvary Mater Newcastle
  • New South Wales
    • Wahroonga, New South Wales, Australia
      • Sydney Adventist Hospital
  • Queensland
    • Buderim, Queensland, Australia, 4556
      • University of the Sunshine Coast
    • South Brisbane, Queensland, Australia
      • Icon Cancer Centre Wesley
  • Victoria
    • Ballarat, Victoria, Australia
      • Ballarat Health Services
    • Shepparton, Victoria, Australia
      • Goulburn Valley Health
• Austria
  • Graz, Austria, 8036
    • Medical University of Graz Department of Dermatology and Venerology
  • Innsbruck, Austria, 6020
    • Univ.-Lkinik für Dermatologie, Venerologie und Allergologie
• Belgium
  • Brasschaat, Belgium, 2930
    • AZ Klina
  • Brussels, Belgium, 1200
    • Cliniques Universitaires
  • Ghent, Belgium, 9000
    • AZ Maria Middelares
  • Hasselt, Belgium, 3500
    • Jessa Ziekenhuis
  • Liège, Belgium, 4000
    • Hospital de La Citadelle
  • Ottignies, Belgium, 1340
    • Clinique Saint-Pierre
• Brazil
  • Estado de Bahia
    • Salvador, Estado de Bahia, Brazil, 41950-610
      • Ensino e Terapia de Inovação Clίnica AMO-ETICA
  • Paraná
    • Curitiba, Paraná, Brazil, 81520-060
      • Hospital Erasto Gaertner - Liga Paranaense de Combate ao Câncer,
    • Londrina, Paraná, Brazil, 86015-520
      • Hospital do Cancer de Londrina
  • Rio Grande do Sul
    • Centro, Rio Grande do Sul, Brazil, 99010-080
      • Hospital São Vicente de Paulo
    • Lajeado, Rio Grande do Sul, Brazil, 95900-010
      • Hospital Bruno Born
    • Porto Alegre, Rio Grande do Sul, Brazil, 90850-170
      • Centro Gaúcho Integrado de Oncologia, Hematologia
    • Santa Cruz do Sul, Rio Grande do Sul, Brazil, 96810-110
      • Hospital de Clίnίcas de Porto Alegre
    • São Cristóvão, Rio Grande do Sul, Brazil, 98700-000
      • Oncosite-Centro de Pesquisa Clίnica em Oncologia
  • São Paulo
    • Barretos, São Paulo, Brazil, 14784-400
      • Hopital de Câncer de Barretos-Fundação Pio XII
    • Jaú, São Paulo, Brazil, 17210-080
      • Fundação Doutor Amaral Carvalho
    • Santo André, São Paulo, Brazil, 09060-650
      • CEPHO-Centro de Estudos e Pesquisas de Hematologia e Oncologia
    • São José do Rio Preto, São Paulo, Brazil, 15090-000
      • Fundação Faculdade Regional de Medicina de São José do Rio Preto
    • São Paulo, São Paulo, Brazil, 01246-000
      • Instituto do Cancer do Estado de São Paulo - "Octavio Frias de Oliveira"-ICESP
• Czechia
  • Olomouc, Czechia, 77900
    • Fakultni nemocnice Olomoue
  • Ostrava-Poruba, Czechia, 70852
    • Fakultni nemocnice Ostrava Kozni oddeleni
  • Prague, Czechia, 10034
    • Fakultní nemocnice Královské Vinohrady
• France
  • Besançon, France
    • CHU de Besancon - Hopital Jean Minjoz
  • Boulogne-Billancourt, France
    • Hôpital Ambroise Paré
  • Dijon, France
    • CHU de Dijon, Service de dermatologie
  • La Tronche, France
    • Chu Grenoble Alpes
  • Lille, France
    • CHRU Lille - Hôpital Claude Huriez, Clinique de Dermatologie
  • Marseille, France, 13385 Cedex 05
    • Hôpital La Timone
  • Paris, France
    • Hopital Saint-Louis
  • Pierre-Bénite, France
    • Centre Hospitalier Lyon Sud
  • Rouen, France, 76031
    • CHU de Rouen-Hôpital
  • Villejuif, France
    • Institut Gustave Roussy, Service de Dermatologie
• Germany
  • Berlin, Germany, 10117
    • Charite Universitaetsmedizin Berlin - Campus Charite Mitte
  • Berlin, Germany, 13585
    • Vivantes Klinikum Spandau, Dermatologie und Allergologie
  • Cologne, Germany, 50937
    • Universitaetsklinikum Koeln, Dermatologie und Venerologie,
  • Dresden, Germany, 01307
    • Universitaetsklinikum Carl Gustav Carus TU Dresden, Klinik und Poliklinik f. Dermatologie
  • Erfurt, Germany, 99089
    • Helios Klinikum Erfurt, Dermatologie und Allergologie
  • Essen, Germany
    • Universitatsklinikum Essen Klinik fur Dermatologie Studienambulanz
  • Freiburg im Breisgau, Germany, 79104
    • Universitaetsklinikum Freiburg, Klinik fuer Dermatologie und Venerologie
  • Heidelberg, Germany, 69120
    • Universitaetsklinikum Heidelberg, NCT-Dermatoonkologie
  • Leipzig, Germany, 04103
    • Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie
  • Lübeck, Germany, 23538
    • Universitaetsklinikum Schleswig Holstein - Campus Luebeck
  • Mainz, Germany, 55131
    • Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz, Hautklinik
  • Mannheim, Germany, 68167
    • Universitaetsklinikum Mannheim, Klinik f. Dermatologie, Venerologie, Allergologle,
  • Tübingen, Germany, 72076
    • Studienzentrum Dermao-Onkologie, Universitaetsklinikum Tuebingen
• Italy
  • Bari, Italy, 70124
    • IRCCS Giovanni Paolo II Oncologia Medica
  • Bologna, Italy, 40138
    • Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi IRCCS
  • Misterbianco, Italy, 95045
    • Humanitas Istituto Clinico Catanese, U.O. Oncologia Medica
  • Napoli, Italy, 80131
    • Istituto Nazionale Tumori Fondazione G. Pascale, Oncologia Medica e Terapia Innovativa
  • Palermo, Italy, 90127
    • Azienda Ospedaliero Universitaria Policlinico Paolo Giaccone - U.O. Oncologia Medica
  • Roma, Italy, 00168
    • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
  • Siena, Italy, 53100
    • A.O.U Senese Policlinico Santa Maria alle Scotte-UOC Immunoterapia Oncologica
  • Verona, Italy, 37134
    • Policlinico G.B. Rossi-Borgo Roma-Centro Ricerche Cliniche di Verona
  • Milano
    • Milan, Milano, Italy, 20133
      • Fondazione IRCCS Istituto Nazionale dei Tumori
    • Milan, Milano, Italy, 20122
      • Fondazione IRCCS CA'Granda Ospedale Maggiore Policlinico-Oncologia Medica
  • Perugia
    • Perugia, Perugia, Italy, 06132
      • A.O.S. Maria della Misericordia, Oncologia Medica
• Japan
  • Fukuoka
    • Fukuoka, Fukuoka, Japan, 811-1395
      • National Hospital Organization Kyushu Cancer Center
  • Nagano
    • Matsumoto, Nagano, Japan, 390-8621
      • Shinshu University Hospital
  • Niigata
    • Niigata, Niigata, Japan, 951-8566
      • Niigata Cancer Center Hospital
  • Okayama-ken
    • Okayama, Okayama-ken, Japan, 700-8558
      • Okayama University Hospital
  • Osaka
    • Chuo Ku, Osaka, Japan, 540-0006
      • National Hospital Organization Osaka National Hospital
    • Osaka, Osaka, Japan, 541-8567
      • Osaka Prefectural Hospital Organization Osaka International Cancer Institute
  • Sunto-gun
    • Nagaizumi-cho, Sunto-gun, Japan, 411-8777
      • Shizuoka Cancer Center
  • Tokho
    • Kōtoku, Tokho, Japan, 135-8550
      • The Cancer Institute Hospital Of JFCR
• New Zealand
  • Auckland, New Zealand
    • Auckland City Hospital
  • Hamilton, New Zealand
    • Waikato Hospital
  • Tauranga, New Zealand, 3112
    • Tauranga Hospital
• Puerto Rico
  • Puerto Rico
    • Rio Piedras, Puerto Rico, Puerto Rico, 00935
      • Hospial Oncologico, Puerto Rico Medical Center
• Singapore
  • Singapore, Singapore, 169610
    • National Cancer Centre
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2196
      • The Medical Oncology Centre of Rosebank
    • Pretoria, Gauteng, South Africa, 0081
      • Wilgers Oncology Centre
    • Pretoria, Gauteng, South Africa, 0084
      • Curo Oncology
    • Roodepoort, Gauteng, South Africa, 1709
      • West Rand Oncology Centre Flora Clinic
  • Western Cape
    • George, Western Cape, South Africa, 6529
      • Excellentis Clinical Trial Consultants
    • Kraaifontein, Western Cape, South Africa, 7570
      • Cape Town Oncology Trials Cape Gate Oncology Centre
    • Rondebosch, Western Cape, South Africa, 7700
      • Cancercare Rondebosch Oncology
• South Korea
  • Seoul, South Korea, 03722
    • Severance Hospital Yonsei University Health System
  • Gyeonggi-do
    • Goyang-si, Gyeonggi-do, South Korea, 10408
      • National Cancer Center
    • Seongnam-si, Gyeonggi-do, South Korea, 13496
      • CHA University Bundang Medical Center
    • Seoul, Gyeonggi-do, South Korea, 03722
      • Severance Hospital Younsei University Health System,
  • Jeollanam-do
    • Hwasun, Jeollanam-do, South Korea, 58128
      • Chonnam National University Hwasun Hospital
  • Jung-gu
    • Daejeon, Jung-gu, South Korea, 35015
      • Chungnam National University Hospital
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic De Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain
    • Hospital De La Santa Creu I Sant Pau
  • Barcelona, Spain, 08908
    • Catalan Institute of Oncology
  • Barcelona, Spain, 08916
    • ICO Badalona-Hospital Universitari Germans Trias I Pujol
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz
  • Madrid, Spain
    • Hospital Universitario Clínico San Carlos
  • Madrid, Spain, 28050
    • Centro Integral Oncologico Clara Campal
  • Madrid, Spain, 28033
    • MD Anderson Cancer Center
  • Málaga, Spain, 29010
    • Hospital Regional Universitario de Málaga
  • Seville, Spain
    • Hospital Universitario Virgen Macarena
  • Zaragoza, Spain
    • Hospital Universitario Miguel Servet
• United Kingdom
  • Edinburgh, United Kingdom, EH4 2XU
    • Edinburgh Cancer Center Western General Hospital
  • Hampshire
    • Eastleigh, Hampshire, United Kingdom, SO53 2DW
      • Nuffield Health Wessex Hospital
• United States
  • California
    • Bakersfield, California, United States, 93309
      • Comprehensive Blood and Cancer Center
    • La Jolla, California, United States, 92037
      • UC San Diego Moores Cancer Center
    • Pasadena, California, United States, 91105
      • Innovative Clinical Research Institute (ICRI)
    • Redlands, California, United States, 92373
      • Emad Ibrahim, MD, INC
    • Riverside, California, United States, 92505
      • Kaiser Permanente Oncology Research
    • San Marcos, California, United States, 92069
      • California Cancer Associates for Research and Excellence, Inc. (cCARE)
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Boca Raton Regional Hospital, Lynn Cancer Institute
    • Hollywood, Florida, United States, 33021
      • Memorial Regional Hospital
    • Jacksonville, Florida, United States, 32207
      • Baptist MD Anderson Cancer Center
    • Orlando, Florida, United States, 32806
      • Orlando Health
    • Pensacola, Florida, United States, 32504
      • Ascension Sacred Heart Medical Oncology
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Indiana
    • Goshen, Indiana, United States, 46526
      • Goshen Center for Cancer Care
  • Kentucky
    • Edgewood, Kentucky, United States, 41017
      • St. Elizabeth Healthcare
    • Lexington, Kentucky, United States, 40503
      • Baptist Health Lexington
  • Maryland
    • Frederick, Maryland, United States, 21701
      • Frederick Memorial Healthcare System
  • Missouri
    • Bridgeton, Missouri, United States, 63044
      • St Louis Cancer Care
    • Kansas City, Missouri, United States, 64114
      • AMR Kansas City
    • Saint Joseph, Missouri, United States, 64506
      • MediSearch Clinical Trials
  • Montana
    • Billings, Montana, United States, 59102
      • St. Vincent - Frontier Cancer Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
    • Goldsboro, North Carolina, United States, 27534
      • Southeastern Medical Oncology Center
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center Research
    • Toledo, Ohio, United States, 43623
      • Toledo Clinic Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Medical Oncology Clinic
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • AnMed Health
    • Lancaster, South Carolina, United States, 29720
      • Carolina Blood and Cancer Care Associates
  • Texas
    • The Woodlands, Texas, United States, 77380
      • Renovatio Clinical
  • Utah
    • Salt Lake City, Utah, United States, 84106
      • Utah Cancer Specialists
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Inova Schar Cancer Institute
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Hospital, Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Test Arm; HBI-8000 30 mg oral BIW + nivolumab IV at specific doses on specific days	Drug: HBI-8000 in combination with nivolumab; Patients will take 30 mg of HBI-8000 orally approximately 30 minutes after a full meal, beginning on Day 1 and continue every 3 to 4 days on the BIW schedule. On Day 1 of each cycle nivolumab IV will be administered by intravenous infusion at specific doses on specific days in accordance with OPDIVO® manufacturer regional product information insert and the institution's prescribing practice. In adolescent patients with body weight < 40 kg, nivolumab will be dosed at specific doses on specific days.; Other Names: For HBI-8000: tudicdinostat; For nivolumab: OPDIVO®
Placebo Comparator: Control Arm; Placebo oral BIW + nivolumab IV at specific doses on specific days	Drug: Placebo in combination with nivolumab; Patients will take 30 mg of Placebo orally approximately 30 minutes after a full meal, beginning on Day 1 and continue every 3 to 4 days on the BIW schedule. On Day 1 of each cycle nivolumab IV at specific doses will be administered by intravenous infusion in accordance with OPDIVO® manufacturer regional product information insert and the institution's prescribing practice.; Other Names: For nivolumab: OPDIVO®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Outcome	Progression-free Survival (PFS) defined as the time (in days) from the date of randomization to the first date of documented disease progression as determined by BIRC, or the date of death due to any cause, whichever occurs first.	From date of randomization to the earliest date of documented progressive disease (PD), assessed up to 48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate	Objective Response Rate (ORR) defined as the percentage of patients enrolled in each study arm with a best response of Complete Response (CR) or Partial Response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), as determined by the blinded independent review committee (BIRC).	From date of randomization until disease progression or unacceptable toxicity, assessed up to 48 months
Overall Survival	Overall Survival (OS) defined as the time from randomization date to the date of death due to any cause.	From date of randomization to death due to any cause, assessed up to 48 months
Safety, defined as the incidence rate of AEs	Safety, defined as the incidence rate of AEs. The NCI-CTCAE v5.0 will serve as the reference document for choosing the appropriate terminology to grade the severity of AEs, and to assess the causal relationship and outcomes.	From date of screening until the end of study, assessed up to 48 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response	Duration of Response (DoR), defined as the time from the first date of objective response (PR or CR) according to RECIST 1.1 as determined by the BIRC to the first date of progressive disease (PD) or death from any cause.	Assessed up to 48 months
Disease Control Rate	Disease Control Rate (DCR), defined as the percentage of total patients enrolled in each study arm with a best response of CR, PR or SD according to RECIST 1.1, as determined by the BIRC.	Assessed up to 48 months
Time to Response	Time to Response (TTR), defined as the time from the date of randomization to the first date of documented objective response (CR or PR) as determined by the BIRC.	Assessed up to 48 months
Time to Progression	Time to Progression (TTP) defined as the time from the date of randomization to the first date of documented progression as determined by the BIRC. For patients with no PD, TTP will be considered censored at death or at the last evaluable imaging date.	Assessed up to 48 months

Collaborators and Investigators

• Sponsor: HUYABIO International, LLC.
• Collaborators: Bristol-Myers Squibb
• Investigators: Study Director: Gloria Lee, MD, PhD, HUYABIO International, LLC.

Publications and helpful links

Helpful Links

• U.S. FDA Resources
• MedlinePlus Genetics related topics: Melanoma
• MedlinePlus related topics: Melanoma
• Drug Information available for: Nivolumab
• Genetic and Rare Diseases Information Center resources: Neuroendocrine Tumor Neuroepithelioma

Study record dates

Study Major Dates

• Study Start (Actual): August 12, 2021
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: December 7, 2020
• First Submitted That Met QC Criteria: December 14, 2020
• First Posted (Actual): December 19, 2020

Study Record Updates

• Last Update Posted (Estimated): September 24, 2025
• Last Update Submitted That Met QC Criteria: September 18, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: melanoma; nivolumab; brain metastasis; HBI-8000
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Central Nervous System Neoplasms; Skin and Connective Tissue Diseases; Melanoma; Brain Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Nivolumab; HBI-8000
• Other Study ID Numbers: HBI-8000-303

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No