NIVOLUMAB for Unresectable melanoma | Metastatic melanoma

Stratification factors

• PD-L1 expression status (PD-L1 positive ≥1% vs PD-L1 negative <1%)
• BRAF V600 mutation status / testing status

Inclusion criteria

• {"criterion_text":"-Histopathologically confirmed diagnosis of non-uveal, Stage III (unresectable), or Stage IV (metastatic) melanoma according to AJCC staging system (8th edition).\n-Negative serum pregnancy test at baseline for women of childbearing potential (WOCBP).\n-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\n-Have the ability to understand and the willingness to sign a written informed consent document, comply with study scheduled treatment, visits and assessments.\n-Known BRAF V600 mutation status or consent to BRAF V600 mutation testing before randomization.\n-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.\n-Males or females 12 years of age or older\n-Eastern Cooperative Oncology Group (ECOG) performance status ≤1 for age ≥18 years, Lansky performance status ≥80% for age 12-17 years.\n-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)\n-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\n-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.\n-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."}

Exclusion criteria

• {"criterion_text":"-History of ≥ Grade 3 hypersensitivity reactions to monoclonal antibodies.\n-Known history of testing positive for human immunodeficiency virus (HIV), known acquired immunodeficiency syndrome (AIDS).\n-Hepatitis B surface antigen positive or hepatitis C antibody positive. Further investigation per institutional practices may be performed to exclude active infection.\n-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.\n-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\n-Pregnant or breast-feeding women.\n-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\n-Patients with medical conditions requiring administration of strong cytochrome P450 (CYP) 3A4 Inducers and Inhibitors with no alternative therapy.\n-Uncontrolled adrenal insufficiency or active chronic liver disease.\n-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.\n-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.\n-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.\n-Patients with a history of or active interstitial lung disease (ILD) or non-infectious pneumonitis.\n-Patient with prior organ or hematopoietic cell transplant (HCT), including allogeneic HCT.\n-Patients with known sensitivity to any of the ingredients of the Study Treatment.\n-Patients who received radiation therapy within 14 days of the first dose of the Study Treatment.\n-Patients who take drugs that prolong the QT interval or cause torsades de pointes or produce significant ventricular dysrhythmias.\n-Patients that are unwilling or unable to comply with the procedures required in this protocol.\n-Recipient of solid organ transplant.\n-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.\n-Uncontrolled hypertension, systolic blood pressure (SBP) >160 mmHg or diastolic blood pressure (DBP) >100 mmHg.\n-Patients with new, active, or progressive brain metastases or leptomeningeal disease, except when considered for a separate open label cohort for special population\n-History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolled peptic ulcer, or bowel resection that affects absorption of orally administered drugs.\n-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.\n-Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy."}

Primary endpoints

• {"endpoint_text":"-The primary endpoint of this study is Progression Free Survival PFS. (PFS) is defined as the time (in days) from the date of randomization to the first date of documented progression as determined by the BIRC, or the date of death due to any cause, whichever occurs first.","definition_or_measurement_approach":"PFS is defined as the time (in days) 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. Progression assessment by RECIST 1.1 with BIRC review."}

Secondary endpoints

• {"endpoint_text":"-Objective Response Rate (ORR) The ORR is defined as the percentage of patients enrolled in each arm with a best response of confirmed CR or PR as determined by the BIRC","definition_or_measurement_approach":"ORR defined as percentage of patients with confirmed complete response (CR) or partial response (PR) per RECIST 1.1 as determined by Blinded Independent Review Committee (BIRC)."}
• {"endpoint_text":"-Overall Survival (OS) The OS is defined as the time from randomization date to the date of death due to any cause.","definition_or_measurement_approach":"OS measured as time from randomization to death from any cause."}
• {"endpoint_text":"-To compare, between Test and Control arms: Safety defined as the incidence rate of adverse events. 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 at the time of screening through to the completion of the end of treatment safety follow up visits.","definition_or_measurement_approach":"Safety assessed as incidence and severity of adverse events graded using NCI-CTCAE v5.0, including assessment of causal relationship and outcomes from screening through end-of-treatment safety follow-up visits."}

Belgium

Earliest CTIS Part Ii Submission Date

14-10-2024

Latest Decision Or Authorization Date

22-10-2024

Processing Time Days

8

Number Of Sites

2

Number Of Participants

3

Czechia

Earliest CTIS Part Ii Submission Date

14-10-2024

Latest Decision Or Authorization Date

23-10-2024

Processing Time Days

9

Number Of Sites

4

Number Of Participants

17

France

Earliest CTIS Part Ii Submission Date

14-10-2024

Latest Decision Or Authorization Date

25-10-2024

Processing Time Days

11

Number Of Sites

11

Number Of Participants

21

Italy

Earliest CTIS Part Ii Submission Date

14-10-2024

Latest Decision Or Authorization Date

28-10-2024

Processing Time Days

14

Number Of Sites

9

Number Of Participants

32

Spain

Earliest CTIS Part Ii Submission Date

14-10-2024

Latest Decision Or Authorization Date

12-11-2024

Processing Time Days

29

Number Of Sites

12

Number Of Participants

51

Germany

Earliest CTIS Part Ii Submission Date

14-10-2024

Latest Decision Or Authorization Date

02-04-2025

Processing Time Days

170

Number Of Sites

16

Number Of Participants

61

Primary sponsor

Full Name

Huyabio International LLC

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

WCG Clinical Inc.

Responsibilities

Data Entry

Name

IQVIA Limited

Responsibilities

Multiple study operational activities (codes 1,11,12,2,8) and subcontracting with IVRS vendor (code 15)

Name

Medidata Solutions International Limited

Responsibilities

Sponsor duty code 7

Name

eResearchTechnology GmbH

Responsibilities

Imaging

Third parties

• {"country":"United States","full_name":"WCG Clinical Inc.","duties_or_roles":"Data Entry","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Medidata Solutions International Limited","duties_or_roles":"Sponsor duty code 7","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"Sponsor duties codes: 1, 11, 12, 15 (Subcontracting with IVRS vendor), 2, 8","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"eResearchTechnology GmbH","duties_or_roles":"Imaging","organisation_type":"Pharmaceutical company"}