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

Unresectable or Metastatic Melanoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04674683
• Other study ID #: HBI-8000-303
• Status: Recruiting
• Phase: Phase 3
• Start date: August 12, 2021
• Est. completion date: October 2025

Study information

• Verified date: July 2023
• Source: HUYABIO International, LLC.
• Contact: M Tawashi
• Phone: 1-858-209-1695
• Email: mtawashi[@]huyabio.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a phase 3 study to compare the efficacy and safety of HBI-8000 or Placebo combined with nivolumab on patients with unresectable or metastatic melanoma and eligible patients who are not adolescents or patients with new, progressive brain metastasis will be stratified by PD-L1 expression and LDH level.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 480
• Est. completion date: October 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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. 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 from an unresectable or metastatic site is available prior to the start of the Screening Phase, patients must consent to allow the acquisition of additional tumor tissue for assessment of the biomarker.

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

5. ECOG performance status =1 for age =18 years, Lansky performance score =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 for PD-L1 testing) 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-CTLA-4) is allowed if disease progression/or recurrence occurred at least 6 months after the last dose 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. 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; 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.

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

5. Patients with new, active, or progressive brain metastases or leptomeningeal disease with except when considered for a separate special open-label cohort described in protocol Section 5.3 or "Inclusion of Patients with Progressive Brain Metastasis" section in the protocol synopsis.

6. History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolled peptic ulcer, or bowel resection that affects absorption of orally administered drugs.

7. 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.

8. Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.

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

10. Hepatitis B surface antigen positive or hepatitis C antibody positive. Further investigation per institutional practices may be performed to exclude active infection.

11. 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.

12. Use of another investigational agent (drug or vaccine not marketed for any indication) 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

13. Pregnant or breast-feeding women.

14. Second 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
• Carcinoma in situ of the cervix treated with curative intent
• Prostate cancer treated with curative intent with serum prostate specific antigen (PSA) < 2.0 ng/mL

15. Patients with medical conditions requiring administration of strong cytochrome P450 (CYP), CYP3A4 Inducers and Inhibitors.

16. Uncontrolled adrenal insufficiency or active chronic liver disease.

17. 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.

18. 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.

19. Unwilling or unable to comply with procedures required in this protocol.

Related Conditions & MeSH terms

• Brain Neoplasms
• Melanoma
• Neoplasm Metastasis
• Progressive Brain Metastasis
• Unresectable or Metastatic Melanoma

Intervention

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.
• 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.

Locations

Country	Name	City	State
Australia	Ballarat Health Services	Ballarat	Victoria
Australia	Royal Brisband and Women's Hospital	Brisbane
Australia	University of the Sunshine Coast	Buderim	Queensland
Australia	Liverpool Hospital	Liverpool
Australia	Affinity Clinical Research	Nedlands
Australia	Goulburn Valley Health	Shepparton	Victoria
Australia	University of the Sunshine	Sippy Downs	Queensland
Australia	Icon Cancer Centre Wesley	South Brisbane	Queensland
Australia	Tweed Hospital	Tweed Heads
Australia	Sydney Adventist Hospital	Wahroonga	New South Wales
Australia	Calvary Mater Newcastle	Waratah
Austria	Medical University of Graz Department of Dermatology and Venerology	Graz
Austria	Univ.-Lkinik für Dermatologie, Venerologie und Allergologie	Innsbruck
Belgium	AZ Klina	Brasschaat
Belgium	Cliniques Universitaires	Brussels
Belgium	AZ Maria Middelares	Ghent
Belgium	Jessa Ziekenhuis	Hasselt
Belgium	Jessa Ziekenhuis	Hasselt
Belgium	Hospital de la Citadelle	Liège
Belgium	Clinique Saint-Pierre	Ottignies
Brazil	Hopital de Câncer de Barretos-Fundação Pio XII	Barretos	Sao Paulo
Brazil	Hospital São Vicente de Paulo	Centro	Rio Grande Do Sul
Brazil	Hospital Erasto Gaertner - Liga Paranaense de Combate ao Câncer,	Curitiba	Paraná
Brazil	Fundação Doutor Amaral Carvalho	Jaú	São Paulo
Brazil	Hospital Bruno Born	Lajeado	Rio Grande Do Sul
Brazil	Hospital do Câncer de Londrina	Londrina	Paraná
Brazil	Centro Gaúcho Integrado de Oncologia, Hematologia	Porto Alegre	Rio Grande Do Sul
Brazil	Ensino e Terapia de Inovação Cl?nica AMO-ETICA	Salvador	Bahia
Brazil	Hospital de Cl?n?cas de Porto Alegre	Santa Cruz Do Sul	Rio Grande Do Sul
Brazil	CEPHO-Centro de Estudos e Pesquisas de Hematologia e Oncologia	Santo André	São Paulo,
Brazil	Oncosite-Centro de Pesquisa Cl?nica em Oncologia	São Cristóvão	Rio Grande Do Sul
Brazil	Fundação Faculdade Regional de Medicina de São José do Rio Preto	São José Do Rio Preto	São Paulo
Brazil	Instituto do Cancer do Estado de São Paulo - "Octavio Frias de Oliveira"-ICESP	São Paulo
Czechia	Fakultni nemocnice Olomoue	Olomouc
Czechia	Fakultni nemocnice Ostrava Kozni oddeleni	Ostrava-Poruba
Czechia	Fakultni nemocnice Kralovske Vinohrady	Prague
France	CHU de Besançon - Hôpital Jean MINJOZ	Besançon
France	Hôpital Ambroise Paré	Boulogne-Billancourt
France	CHU de Dijon, Service de dermatologie	Dijon
France	CHU Grenoble Alpes	La Tronche
France	CHRU Lille - Hôpital Claude Huriez, Clinique de Dermatologie	Lille
France	Hôpital La Timone	Marseille
France	Hôpital Saint-Louis	Paris
France	Centre Hospitalier Lyon Sud	Pierre-Bénite
France	CHU de Rouen-Hôpital	Rouen
France	Institut Gustave Roussy, Service de Dermatologie	Villejuif
Germany	Charite Universitaetsmedizin Berlin - Campus Charite Mitte	Berlin
Germany	Vivantes Klinikum Spandau, Dermatologie und Allergologie	Berlin
Germany	Universitaetsklinikum Carl Gustav Carus TU Dresden, Klinik und Poliklinik f. Dermatologie	Dresden,
Germany	Helios Klinikum Erfurt, Dermatologie und Allergologie	Erfurt
Germany	Universitatsklinikum Essen Klinik fur Dermatologie Studienambulanz	Essen
Germany	Universitaetsklinikum Freiburg, Klinik fuer Dermatologie und Venerologie	Freiburg
Germany	Universitaetsklinikum Heidelberg, NCT-Dermatoonkologie	Heidelberg
Germany	Universitaetsklinikum Koeln, Dermatologie und Venerologie,	Koeln
Germany	Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie	Leipzig
Germany	Universitaetsklinikum Schleswig Holstein - Campus Luebeck	Luebeck
Germany	Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz, Hautklinik	Mainz
Germany	Universitaetsklinikum Mannheim, Klinik f. Dermatologie, Venerologie, Allergologle,	Mannheim
Germany	Studienzentrum Dermao-Onkologie, Universitaetsklinikum Tuebingen	Tuebingen
Italy	IRCCS Giovanni Paolo II Oncologia Medica	Bari
Italy	Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi IRCCS	Bologna
Italy	Fondazione IRCCS CA'Granda Ospedale Maggiore Policlinico-Oncologia Medica	Milan	Milano
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milan	Milano
Italy	Humanitas Istituto Clinico Catanese, U.O. Oncologia Medica	Misterbianco
Italy	Istituto Nazionale Tumori Fondazione G. Pascale, Oncologia Medica e Terapia Innovativa	Napoli
Italy	Azienda Ospedaliero Universitaria Policlinico Paolo Giaccone - U.O. Oncologia Medica	Palermo
Italy	A.O.S. Maria della Misericordia, Oncologia Medica	Perugia
Italy	Fondazione Policlinico Universitario Agostino Gemelli IRCCS	Roma
Italy	A.O.U Senese Policlinico Santa Maria alle Scotte-UOC Immunoterapia Oncologica	Siena
Italy	Policlinico G.B. Rossi-Borgo Roma-Centro Ricerche Cliniche di Verona	Verona
Japan	National Hospital Organization Osaka National Hospital	Chuo Ku	Osaka
Japan	National Hospital Organization Kyushu Cancer Center	Fukuoka
Japan	The Cancer Institute Hospital of JFCR	Koto-Ku	Tokho
Japan	Shinshu University Hospital	Matsumoto	Nagano
Japan	Shizuoka Cancer Center	Nagaizumi-cho	Sunto-gun
Japan	Niigata Cancer Center Hospital	Niigata
Japan	Okayama University Hospital	Okayama
Japan	Osaka Prefectural Hospital Organization Osaka International Cancer Institute	Osaka
Korea, Republic of	Chungnam National University Hospital	Daejeon	Jung-gu
Korea, Republic of	National Cancer Center	Goyang-si	Gyeonggi-do
Korea, Republic of	Chonnam National University Hwasun Hospital	Hwasun	Jeollanam-do
Korea, Republic of	Cha University Bundang Medical Center	Seongnam-si	Gyeonggi-do
Korea, Republic of	Kangbuk Samsung Hospital	Seoul	Gyeonggi-do
Korea, Republic of	Severance Hospital Yonsei University Health System	Seoul
Korea, Republic of	Severance Hospital Younsei University Health System,	Seoul	Gyeonggi
New Zealand	Auckland City Hospital	Auckland
New Zealand	Waikato Hospital	Hamilton
New Zealand	Tauranga Hospital	Tauranga
Puerto Rico	Hospial Oncologico, Puerto Rico Medical Center	Rio Piedras
Singapore	National Cancer Centre	Singapore
South Africa	Excellentis Clinical Trial Consultants	George	Western Cape
South Africa	The Medical Oncology Centre of Rosebank	Johannesburg	Gauteng
South Africa	Cape Town Oncology Trials Cape Gate Oncology Centre	Kraaifontein	Western Cape
South Africa	Curo Oncology	Pretoria	Gauteng
South Africa	Wilgers Oncology Centre	Pretoria	Gauteng
South Africa	Cancercare Rondebosch Oncology	Rondebosch	Western Cape
South Africa	West Rand Oncology Centre Flora Clinic	Roodepoort	Gauteng
Spain	Catalan Institute of Oncology	Barcelona
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	ICO Badalona-Hospital Universitari Germans Trias I Pujol	Barcelona
Spain	Centro Integral Oncologico Clara Campal	Madrid
Spain	Hospital Universitario Clinico San Carlos	Madrid
Spain	Hospital Universitario Fundación Jimenez Diaz	Madrid
Spain	MD Anderson Cancer Center	Madrid
Spain	Hospital Regional Universitario de Málaga	Málaga
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Hospital Universitario Miguel Servet	Zaragoza
United Kingdom	Nuffield Health Wessex Hospital	Eastleigh	Hampshire
United Kingdom	Edinburgh Cancer Center Western General Hospital	Edinburgh
United States	AnMed Health	Anderson	South Carolina
United States	Comprehensive Blood and Cancer Center	Bakersfield	California
United States	St. Vincent - Frontier Cancer Center	Billings	Montana
United States	Boca Raton Regional Hospital, Lynn Cancer Institute	Boca Raton	Florida
United States	St Louis Cancer Care	Bridgeton	Missouri
United States	Gabrail Cancer Center Research	Canton	Ohio
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	St. Elizabeth Healthcare	Edgewood	Kentucky
United States	Inova Schar Cancer Institute	Fairfax	Virginia
United States	Frederick Memorial Healthcare System	Frederick	Maryland
United States	Southeastern Medical Oncology Center	Goldsboro	North Carolina
United States	Goshen Center for Cancer Care	Goshen	Indiana
United States	Memorial Regional Hospital	Hollywood	Florida
United States	Baptist MD Anderson Cancer Center	Jacksonville	Florida
United States	AMR Kansas City	Kansas City	Missouri
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Carolina Blood and Cancer Care Associates	Lancaster	South Carolina
United States	Baptist Health Lexington	Lexington	Kentucky
United States	Froedtert Hospital, Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Orlando Health	Orlando	Florida
United States	Innovative Clinical Research Institute (ICRI)	Pasadena	California
United States	Ascension Sacred Heart Medical Oncology	Pensacola	Florida
United States	Thomas Jefferson University Medical Oncology Clinic	Philadelphia	Pennsylvania
United States	Emad Ibrahim, MD, INC	Redlands	California
United States	Kaiser Permanente Oncology Research	Riverside	California
United States	Medisearch Clinical Trials	Saint Joseph	Missouri
United States	Utah Cancer Specialists	Salt Lake City	Utah
United States	California Cancer Associates for Research and Excellence, Inc. (cCARE)	San Marcos	California
United States	Moffitt Cancer Center	Tampa	Florida
United States	Renovatio Clinical	The Woodlands	Texas
United States	Toledo Clinic Cancer Center	Toledo	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
HUYABIO International, LLC.	Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Brazil,  Czechia,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  New Zealand,  Puerto Rico,  Singapore,  South Africa,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Other Outcome Measures	Duration of Response (DoR) defined as the time from the first date of PR or better as determined by BIRC to the first date of PD or death from any cause.	Assessed up to 48 months
Other	Other Outcome Measures	Disease Control Rate (DCR) defined as the percentage of patients enrolled in each study arm with best overall response of CR, PR or stable disease (SD) as determined by BIRC.	Assessed up to 48 months
Primary	Primary Outcome	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
Primary	Primary Outcome	Progression-free Survival (PFS) defined as the time 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	Secondary Outcome	Overall Survival (OS) defined as the time from date of randomization to the date of death due to any cause.	From date of randomization to death due to any cause, assessed up to 48 months
Secondary	Secondary Outcome	Safety defined as incidence rate of adverse events (AEs), severity (CTCAE v.5.0), causal relationship assessment, and outcomes of reported AEs.	From date of randomization until the end of study, assessed up to 48 months

External Links

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