Phase 3 Randomized Double-Blind Study of Tucidinostat and Nivolumab Versus Placebo and Nivolumab in Metastatic or Unresectable Melanoma
- Trial ID
- 2024-516914-39-00
- Protocol
- HBI-8000-303
- Sponsor
- Huyabio International LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate **Progression-free Survival (PFS)** in patients with metastatic or unresectable melanoma. This is defined as the time from randomization to either the first documented disease progression, as per the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) determined by the Blinded Independent Review Committee (BIRC), or death from any cause, whichever occurs first. This measure is clinically relevant as it provides insight into the efficacy of the treatment in delaying disease progression or death, which is crucial for patient prognosis and treatment planning.
Secondary objectives include:
- Comparing the **Objective Response Rate (ORR)** between the test and control arms, defined as the percentage of patients achieving a confirmed complete response (CR) or partial response (PR) according to RECIST 1.1, as determined by BIRC.
- Assessing **Overall Survival (OS)**, defined as the time from randomization to death from any cause, providing a direct measure of treatment impact on patient longevity.
- Evaluating **Safety**, defined by the incidence rate of adverse events, using the NCI-CTCAE v5.0 as a reference for grading severity and assessing causal relationships and outcomes from screening through the end of treatment safety follow-up visits.
Participants
The clinical trial involves a total of **140 participants** diagnosed with **metastatic or unresectable melanoma**. The study population includes both male and female subjects aged 12 years and older. Participants were selected based on specific inclusion criteria, such as having a histopathologically confirmed diagnosis of non-uveal, Stage III (unresectable), or Stage IV (metastatic) melanoma, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 for those aged 18 years and older, or a Lansky performance status of at least 80% for those aged 12-17 years. The trial does not include a vulnerable population. Participants' general health status is assessed through screening laboratory results, ensuring they meet the required hematology and biochemistry parameters. Lifestyle considerations such as diet and physical activity are not specified in the trial data. The selection process ensures that participants have not received prior anti-PD-1, anti-PD-L1, or other systemic therapies for unresectable or metastatic melanoma, with certain exceptions for previous treatments. The trial population is not limited by gender, as both male and female subjects are included. The sponsor has not provided additional information regarding lifestyle factors or other demographic details.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, controlled Phase III study designed to evaluate the efficacy of HBI-8000 combined with **nivolumab** versus placebo with nivolumab in patients with **metastatic or unresectable melanoma**. The primary objective is to assess **progression-free survival** (PFS), with secondary endpoints including **objective response rate** (ORR) and **overall survival** (OS). The trial is expected to run from September 2021 to March 2026, with a maximum treatment period of 24 months for participants.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histopathologically confirmed diagnosis of non-uveal, Stage III or IV melanoma, and a negative serum pregnancy test for women of childbearing potential. The screening phase will also involve testing for BRAF V600 mutation status and PD-L1 expression. Following randomization, participants will receive either the test or control treatment, with regular follow-up visits scheduled to monitor disease progression and treatment response according to the **Response Evaluation Criteria in Solid Tumors** (RECIST 1.1).
The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include disease progression, unacceptable toxicity, or withdrawal of consent. Participants are expected to be involved in the study for up to 24 months, with the possibility of early exit based on the aforementioned conditions. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.
Treatment
The clinical trial involves the administration of **Nivolumab**, marketed under the name **OPDIVO**, which is a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 10 mg/mL and is administered via **infusion**. The maximum daily dose is 480 mg, with a total maximum dose of 11,520 mg over a treatment period of up to 24 months. **Nivolumab** is a protein-based therapeutic agent developed by Bristol-Myers Squibb Pharma EEIG, and it is classified under the ATC code L01FF01. The administration schedule and participant compliance are closely monitored to ensure adherence to the dosing regimen.
Another experimental treatment in the study is **Tucidinostat**, also known by its sponsor product code **HBI-8000**. This medication is provided in the form of a **coated tablet** and is administered orally. The maximum daily dose for **Tucidinostat** is 30 mg, with a total maximum dose of 5,760 mg over a 24-month treatment period. **Tucidinostat** is a chemically synthesized compound developed by HUYABIO International. The study protocol includes measures to monitor participant compliance with the oral dosing schedule.
The trial also includes a control arm where participants receive a **placebo** in combination with **Nivolumab**. The placebo is administered in a manner consistent with the experimental treatments to maintain the double-blind nature of the study. The primary objective of the trial is to compare progression-free survival between the test and control arms, with disease progression assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as determined by an independent review committee.
Efficacy
Efficacy in this clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**, which is defined as the time from the date of randomization to the first date of documented disease progression according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as determined by the Blinded Independent Review Committee (BIRC), or the date of death due to any cause, whichever occurs first. Secondary endpoints include the **Objective Response Rate (ORR)**, defined as the percentage of patients with a best response of confirmed complete response (CR) or partial response (PR) as determined by the BIRC, and **Overall Survival (OS)**, defined as the time from randomization to the date of death due to any cause.
The trial involves a multicenter, randomized, double-blind Phase 3 study comparing 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. Efficacy parameters will be measured and collected at specified timepoints throughout the study, with the final data analysis incorporating central biomarker confirmation. The study is designed to ensure rigorous assessment of efficacy through validated criteria and independent review processes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histopathologically confirmed diagnosis of non-uveal, Stage III (unresectable), or Stage IV (metastatic) melanoma according to AJCC staging system (8th edition).
- Known BRAF V600 mutation status or consent to BRAF V600 mutation testing before randomization.
- Tumor tissue available for PD-L1 testing at central Laboratory 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.
- Males or females 12 years of age or older
- Eastern Cooperative Oncology Group (ECOG) performance status ≤1 for age ≥18 years, Lansky performance status ≥80% for age 12-17 years.
- At least one measurable lesion defined by RECIST 1.1 criteria separate from the lesion to be used for tumor tissue collection for PDL1 testing, not counting brain metastasis with: • Longest diameter ≥10 mm by computed tomography (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) (refer to Appendix 5)
- 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 recovered from all treatment related toxicities: a. BRAF mutation targeted therapy >4 weeks before administration of Study Treatment. b. Adjuvant or neoadjuvant therapy with PD-1 or PD-L1 inhibitors, anti- cytotoxic T lymphocyte-associated protein 4 (CTLA4) 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. c. Adjuvant interferon therapy must have been completed >6 weeks before administration of Study Treatment
- 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.
- Screening laboratory results within 14 days prior to randomization: a. Hematology: white blood cells (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 Hgb ≥10 g/dl is acceptable. b. CrCL ≥30 mL/min using Cockcroft-Gault formula Appendix 3 [Cockcroft and Gault, 1976]. c. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN), alkaline phosphatase ≤2.5 × ULN unless bone metastases present (patients with documented bone metastases: alkaline phosphatase <5 × ULN), bilirubin ≤1.5 × ULN (unless known Gilbert’s disease where it must be ≤3 × ULN), serum albumin ≥3.0 g/dL.
- Negative serum pregnancy test at baseline for women of childbearing potential (WOCBP).
- 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 an adequate method of contraception including a highly effective method and a barrier method during the study and for 5 months after the last dose of Study Drug. Highly effective contraception used by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Refer to Section 8.3 for details and definitions of WOCBP, postmenopausal females, and contraception guidance
- 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
- History of ≥ Grade 3 hypersensitivity reactions to monoclonal antibodies.
- 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.
- Recipient of solid organ transplant.
- 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 Fridericia’s correction formula (QTcF) >450 ms in male or >470 ms in female, or congenital long QT syndrome.
- Uncontrolled hypertension, systolic blood pressure (SBP) >160 mmHg or diastolic blood pressure (DBP) >100 mmHg.
- Patients with new, active, or progressive brain metastases or leptomeningeal disease, except when considered for a separate open label cohort for special population
- History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolled peptic ulcer, or bowel resection that affects absorption of orally administered drugs.
- 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.
- Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.
- Known history of testing positive for human immunodeficiency virus (HIV), known acquired immunodeficiency syndrome (AIDS).
- Hepatitis B surface antigen positive or hepatitis C antibody positive. Further investigation per institutional practices may be performed to exclude active infection.
- 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 (or equivalent) are permitted.
- Use of other investigational agent (drug or vaccine not marketed for any indication) within 28 days before administration of Study Treatment. If the investigational agent is a monoclonal antibody, then use within 3 months, before administration of Study Treatment
- Pregnant or breast-feeding women.
- 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
- Patients with medical conditions requiring administration of strong cytochrome P450 (CYP) 3A4 Inducers and Inhibitors with no alternative therapy.
- Uncontrolled adrenal insufficiency or active chronic liver disease.
- Has received approved live vaccine/ live attenuated vaccines within 30 days of planned Cycle 1 Day 1. Inactivated viral vaccines or vaccines based on subviral component are allowed; however intranasal influenza vaccines (e.g. Flu-Mist) are not allowed. Coronavirus disease 2019 COVID-19 vaccination should be administered at least 7 days before Cycle 1 Day 1.
- 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 adverse events.
- Patients with a history of or active interstitial lung disease (ILD) or non-infectious pneumonitis.
- Patient with prior organ or hematopoietic cell transplant (HCT), including allogeneic HCT.
- Patients with known sensitivity to any of the ingredients of the Study Treatment.
- Patients who received radiation therapy within 14 days of the first dose of the Study Treatment.
- Patients who take drugs that prolong the QT interval or cause torsades de pointes or produce significant ventricular dysrhythmias.
- Patients that are unwilling or unable to comply with the procedures required in this protocol.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Sept 2021 | 3 |
 Czechia | Not Recruiting | 01 Sept 2021 | 17 |
 France | Not Recruiting | 01 Sept 2021 | 21 |
 Germany | Not Recruiting | 01 Sept 2021 | 61 |
 Italy | Not Recruiting | 01 Sept 2021 | 32 |
 Spain | Not Recruiting | 01 Sept 2021 | 51 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 480 | 24 | PRD2941375 |
Tucidinostat | Test | COATED TABLET | ORAL USE | 30 | 24 | PRD11574132 |