| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or unresectable melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027481 |
| E.1.2 | Term | Metastatic melanoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Co-primary Objectives:
To compare, between Test (HBI-8000 + nivolumab) and Control (placebo + nivolumab) arms:
• Objective Response Rate (ORR), defined as the percentage of patients enrolled in each study arm with a best response of CR or PR according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), as determined by the blinded independent review committee (BIRC)
• Progression-free Survival (PFS), defined as the time from the date of randomization to the first date of documented progression as determined by BIRC, or the date of death due to any cause, whichever occurs first. |
|
| E.2.2 | Secondary objectives of the trial |
To compare, between Test and Control arms:
• Overall Survival (OS) defined as the time from the date of randomization to the date of death due to any cause.
• Safety defined as incidence rate of adverse events, severity (CTCAE), causal relationship assessment, and outcomes at the time of randomization until the end of study. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients may be entered in the study only if they meet all of the following 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 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 18 years of age or older.
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 for age ≥18 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 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)
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 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 occurred at least 6 months after the last dose 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.
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:
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.
Creatinine clearance (CrCL) ≥30 mL/min using Cockcroft-Gault formula Appendix 2.
b. [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.
10. Negative serum pregnancy test at baseline for women of childbearing potential (WOCBP).
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 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
12. Have the ability to understand and the willingness to sign a written informed consent document, comply with study scheduled treatment,
visits and assessments. |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria
Patients who fulfill any of the following criteria at Screening will not be eligible for admission into the study:
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; 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.
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, except when considered for a separate open label cohort for special population.
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 human immunodeficiency virus (HIV), known acquired immunodeficiency syndrome (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 (or equivalent) are permitted.
13. 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
14. Pregnant or breast-feeding women.
15. 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
16. Patients with medical conditions requiring administration of strong cytochrome P450 (CYP) 3A4 Inducers and Inhibitors.
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 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.
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 adverse events.
20. Patients with a history of interstitial lung disease (ILD) or noninfectious
pneumonitis.
21. Patient with prior organ or hematopoietic cell transplant (HCT),
including allogeneic
HCT.
22. Patients with known sensitivity to any of the ingredients of the
drug.
23. Patients who received radiation therapy within 28 days of the first
dose of the study
drug.
24. Patients who take drugs that prolong the QT interval or cause
torsades de pointes or produce significant ventricular
dysrhythmias.
25.Unwilling or unable to provide consent and comply with procedures required in this protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1.Primary Outcome [ Time Frame: From date of randomization until disease progression or unacceptable toxicity, assessed up to 48 months ]
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).
2.Primary Outcome [ Time Frame: From date of randomization to the earliest date of documented progressive disease (PD), assessed up to 48 months ]
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.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1.Overall Survival (OS) defined as the time from the date of randomization to the date of death due to any cause.
2. Safety defined as incidence rate of adverse events, severity (CTCAE), causal relationship assessment, and outcomes at the time of randomization until the end of study
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Open Label Cohort included |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 19 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 76 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| New Zealand |
| Singapore |
| Australia |
| Brazil |
| Japan |
| Korea, Republic of |
| South Africa |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Czechia |
| France |
| Germany |
| Italy |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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