Adjuvant nivolumab treatment in stage II high-risk melanoma – A randomized, controlled, phase III trial with biomarker-based risk stratification (NivoMela)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Essen AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Jun 2020 → ongoing

Decision date (initial)

2024-08-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2023-509394-23-00

EudraCT number

2019-002276-13

ClinicalTrials.gov

NCT04309409

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

The primary objective of this trial is to determine efficacy of nivolumab in a biomarker-selected high-risk-enriched stage II melanoma patient
population in comparison to control receiving observation only in a 2 (Arm A=nivolumab) :1 (Arm B=observation) randomization, as
measured by Relapse-Free Survival (RFS). RFS is defined as the time from the date of registration until documented tumor recurrence date or date of death of any cause,
whichever occurs first. In addition, patients not being selected as highrisk in the biomarker test (= Arm C) and who will be observed as in Arm
B will be followed for RFS, too in order to evaluate the utility of the MelaGenix assay.

Secondary objectives 5

1. 1. To evaluate RFS rate at 12, 24, 36 and 60 months
2. 2. To evaluate distant metastasis-free survival (DMFS), melanomaspecific survival (MSS) and overall survival (OS) rates at 12, 24, 36 and 60 months
3. 3. Safety / toxicity, i.e. all adverse events ≥ Grade 3 according to CTCAE Version 5.0 criteria, that are definitely, probably, or possibly related to the administration of the investigational agent
4. 4. To evaluate the clinical utility/decision impact of the MelaGenix GEP score in stratifying patients for adjuvant therapy
5. In addition, patients not being selected as high-risk in the biomarker test (= Arm C) and who will be observed as in Arm B will be followed for DMFS and OS, too.

Conditions and MedDRA coding

Stage II melanoma arising from a primary cutaneous site after surgery therapy

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Histologically confirmed diagnosis of stage II (AJCCv8) melanoma arising from a primary cutaneous site after surgery therapy
2. Sentinel node biopsy without detection of melanoma deposits
3. Registration not later than 12 weeks after SNB procedure
4. Tumor tissue from primary tumor must be provided for biomarker analyses. In order to be registered, a patient must be classified by MelaGenix risk analysis.
5. Men and women at the age of 18 to 80 years
6. Signed written, informed consent
7. Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
8. Minimum life expectancy of five years excluding their melanoma diagnosis
9. ECOG performance status of 0-1
10. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to registration: o White blood cells (WBC) ≥ 2000/μL o Neutrophils ≥ 1500/μL o Platelets ≥ 100 x10^3/μL o Hemoglobin ≥ 9.0 g/dL o Serum creatinine ≤ 1.5xUL o Creatinine clearance (CrCl) ≥ 40mL/min (using the Cockcroft-Gault formula) o AST / ALT ≤ 3 x ULN o Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who may have total bilirubin < 3.0 mg/dL)
11. Negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) for women of childbearing potential (WOCBP) within 72 hours prior to registration. Women will be considered to be of childbearing potential unless surgically sterilized (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or being post-menopausal for at least 24 months or being amenorrheic for > 12 months and folliclestimulating hormone (FSH) levels ≥ 40 IU/L.
12. WOCBP and male patients with partners of childbearing potential must agree to always use a highly effective form of contraception according to CTFG during the course of this study and for at least 5 months after last dose of study medication (in Arm A only).

Exclusion criteria 21

1. History of primary uveal or mucosal melanoma
2. No access to sufficient tumor tissue of primary tumor
3. SNB procedure > 12 weeks before registration
4. Prior active malignancy within the previous 3 years except for locally curable cancers that have been apparently cured, such as: basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the prostate, cervix, or breast. Exception. Participants with a history of non-ulcerated cutaneous/acral primary melanoma <1 mm in depth with no nodal involvement are allowed in this trial
5. Prior or planned therapy with Interferon alpha, CTLA4 or PD-1 / PD-L1 antibodies
6. Use of any investigational or non-registered product (drug or vaccine) other than the study treatment
7. Administration of live vaccines within 4 weeks before start of study therapy
8. Any immunosuppressive therapy given within the past 30 days
9. Active psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures
10. Active immune deficiencies or significant autoimmune disease
11. Serious cardiac, gastrointestinal, hepatic or pulmonary disease which would reduce life expectancy to less than five years
12. Serious intercurrent illness, requiring hospitalization
13. Other serious illnesses, e.g., serious infections requiring antibiotics or bleeding disorders
14. The patient is known to be positive for Human Immunodeficiency Virus (HIV) or other active chronic infections (HBV, HCV) or has another confirmed or suspected immunosuppressive or immunodeficient condition
15. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
16. Hypersensitivity to the active substance or to any of the excipients
17. Participation in another clinical study within the 30 days before registration
18. For female patients: Pregnancy or breast-feeding
19. For WOCBP and male patients with partners of childbearing potential: Refusal or inability to use effective means of contraception
20. Lack of availability for clinical follow-up assessments
21. Legal incapacity or limited legal capacity

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Relapse / Recurrence-free survival (RFS) will be analyzed by stratified Cox regression. RFS is defined as the time from the date of registration until documented tumor recurrence date or date of death of any cause, whichever occurs first.

Secondary endpoints 6

1. RFS rate
2. Distant metastasis-free survival (DMFS) rate
3. Melanoma-specific survival (MSS) rate
4. Overall survival (OS) rate
5. AEs and clinical laboratory values
6. Clinical utility of the MelaGenix GEP score

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Essen AöR

Sponsor organisation

Universitaetsklinikum Essen AöR

Address

Hufelandstrasse 55, Holsterhausen Holsterhausen

City

Essen

Postcode

45147

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Essen AöR

Contact name

Prof. Dr. Dirk Schadendorf

Public contact point

Organisation

Universitaetsklinikum Essen AöR

Contact name

Prof. Dr. Dirk Schadendorf

Third parties 2

Locations

1 EU/EEA country · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications