Randomised, Multicentre, Multinational, Double-Blind Integrated Study to Compare the Pharmacokinetics, Efficacy, Safety, and Immunogenicity of MB11 (Proposed Nivolumab Biosimilar) Versus EU-/US-Opdivo in Subjects With Previously Untreated Advanced (Unresectable or Metastatic) Melanoma (LEON Study)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Mabxience Research S.L.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

30 Dec 2025 → ongoing

Decision date (initial)

2025-11-20

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

mAbxience Research S.L.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Pharmacodynamic, Pharmacokinetic, Efficacy, Therapy, Safety

To establish the PK bioequivalence between MB11 and EU-/US-Opdivo and to demonstrate similar efficacy between MB11 and Opdivo administered as first-line treatment in adult subjects with untreated, unresectable, or metastatic Stage III or Stage IV melanoma.

Secondary objectives 4

1. 1) To compare the efficacy of MB11 with Opdivo based on other efficacy parameters and timepoints over the study period
2. 2) To compare the PK profile of MB11 to that of Opdivo over the study period.
3. 3) To assess the safety and tolerability of MB11 as compared with that of Opdivo over the study period
4. 4) To assess the immunogenicity of MB11 as compared with Opdivo over the study period.

Conditions and MedDRA coding

Previously Untreated Advanced (Unresectable or Metastatic) Melanoma

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1. Age ≥18 years at the time of signing the informed consent (or adulthood where the legalage of majority in the country is established >18 years).
2. 2. Body weight ≥50 kg at baseline.
3. 3. Signed informed consent must be obtained before initiation of any study-specific procedures or treatment.
4. 4. ECOG performance status of 0 or 1.
5. 5. Life expectancy for at least 3 months.
6. 6. Untreated, histologically confirmed advanced unresectable Stage III or Stage IV melanoma, as per AJCC 8th Edition staging system. Prior melanoma systemic therapy for earlier stages is allowed for patients who have been disease-free for at least 1 year after end of therapy, except if therapy included use of prohibited medications. Prior use of immune therapies (adjuvant or neoadjuvant) is not allowed as per Exclusion Criteria #2.
7. 7. At least 1 measurable disease lesion by CT or MRI per RECIST v1.1 criteria.
8. 8. Tumour tissue from an unresectable or metastatic site of disease, collected within 90 days prior to randomisation, must be available and provided for PD-L1 testing. All samples must be classified as negative (<1%) or PD-L1 positive (≥1% to <5% or ≥5%). If only the old sample >90 days is available and there is no possibility of having a new biopsy sample, then the subject will be excluded
9. 9. In the case of prior palliative radiotherapy (on metastatic lesions), this must have been completed at least 2 weeks prior to the study drug administration. No adjuvant radiation therapies are allowed.
10. 10. Any BRAF mutation status is allowed (BRAF-mutated, BRAF wild-type or non-mutated, or BRAF status unknown).
11. 11. Adequate organ function (bone marrow, hepatic, renal, haematologic, endocrine, and coagulation function) should be demonstrated during the screening period. This is defined as: a. Haematologic function: absolute neutrophil count ≥1.5 × 109/L, platelets ≥100 × 109 /L, and haemoglobin ≥9 g/dL. ** Subjects should not have received RBC transfusion prior to 14 days before screening labs. b. Renal function: GFR (using CKD-EPI-2021) ≥ 60 mL/min/1.73 m2 . c. Liver function: total bilirubin level ≤1.5 × ULN (except subjects with Gilbert Syndrome, who can have total bilirubin <3.0 mg/dL), albumin level ≥LLN, AST/ALT ≤2.5 × ULN (≤5 × ULN for subjects with liver metastases). d. Endocrine function: TSH within normal limits. If TSH is not within normal limits, the subject may still be eligible if free T3 and free T4 are within normal limits. e. Coagulation: INR ≤ 1.5 and aPTT ≤1.5 × ULN unless the subject is receiving anticoagulant therapy. Subjects on anticoagulant therapy must be on a stable anticoagulation regimen and have an INR not above the target therapeutic range for the 14 days preceding the start of the study drug.
12. 12. Female subjects of childbearing potential and their partners, as well as male subjects with female partners of childbearing potential and their partners, must agree to adhere to the use of a highly effective method of contraception during the study and for at least 5 months after the last dose of nivolumab. Refer to Appendix 15.1 for contraception guidance.
13. 13. Non-fertile females can be included.

Exclusion criteria 21

1. 1. Subjects receiving any prior systemic therapy for advanced, unresectable, or metastatic Stage III or Stage IV melanoma (except for palliative radiotherapy, in accordance with Inclusion Criteria #9).
2. 2. Subjects receiving any prior immunotherapy (regardless of the melanoma stage), such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-LAG or anti-CTLA-4 therapy (including ipilimumab or any other antibody or drug that specifically targets costimulation of T-cells or immune checkpoints) and/or BRAF-targeted therapy.
3. 3. Participation in another clinical study or treatment with another investigational agent within 4 weeks or 5 elimination half-lives prior to randomisation (whichever is longer)
4. 4. Brain metastases or leptomeningeal metastases. A negative brain imaging of less than 90 days prior to screening is required.
5. 5. Peritoneal melanomatosis.
6. 6. Ocular melanoma, mucosal melanoma and acral lentiginous melanoma.
7. 7. History of another malignancy or a concurrent malignancy. Exceptions include subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ.
8. 8. Active autoimmune disease that has required systemic treatment in the last 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin or physiological corticosteroid replacement therapy for pituitary or adrenal insufficiency [daily prednisone at a dose of ≤10 mg or equivalent]) is not considered a form of systemic treatment.
9. 9. Subjects with hyperthyroidism or hypothyroidism are excluded but those subjects who are stable on hormone replacement will be allowed.
10. 10. Any diagnosis of immunodeficiency, systemic steroid therapy (replacement therapy outlined in Exclusion Criteria #8, inhaled, intranasal, intraocular, or topical steroids are allowed) or any other form of immunosuppressive therapy within 7 days prior to the first dose of the study drug.
11. 11. Any major surgery (eg, hip or spine surgery) less than 28 days prior to the first dose of the study drug.
12. 12. Having received a solid organ/tissue allogeneic or haematopoietic transplant.
13. 13. History and/or current interstitial lung disease or pneumonitis (non-infectious) requiring oral or IV steroids or another immunosuppressive drug.
14. 14. Any active or previous infection requiring therapy (oral or systemic) within 30 days prior to the first dose of the study drug.
15. 15. Have received or are about to receive a live virus vaccination within 30 days prior to the first dose of the study drug. Seasonal flu and COVID-19 vaccines that do not contain live virus are permitted.
16. 16. Known active TB or untreated latent TB.
17. 17. Positive serology for human immunodeficiency virus (HIV 1/2), hepatitis B (HBsAg positive and/or HBcAb positive, and HBV DNA positive, refer to Section 8.3.2.1) or hepatitis C (HCVAb positive and HCV RNA positive). In addition, subjects with untreated positive serology for Strongyloides spp will be excluded.
18. 18. At the time of signing the informed consent, the subject is a regular user (including “recreational use”) of any illicit drug or have a recent history (within the past year) of substance abuse (including alcohol).
19. 19. Be pregnant or lactating or expecting to conceive during the study or up to 5 months after the last dose of the study drug.
20. 20. Immediate family member who is at the research site or sponsoring staff who is directlyninvolved in this study.
21. 21. Inability to comply with protocol procedures and/or any other acute or chronic medical condition that may increase the risk for the subject associated with study participation or study drug administration, that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Co-Primary Endpoints: - PK: • AUC0-336 between Cycle 1 and Cycle 2 (for Estimand 1a) • AUCss, between Cycle 8 and Cycle 9 (for Estimand 1b) - Efficacy, assessed by a BICR per RECIST v1.1:
2. • bOR where a responder must have achieved CR or PR while alive, prior to permanent treatment discontinuation, prior to use of other anti-cancer therapies and by 24 weeks after Day 1 (for the FDA Primary Estimand 2a and EMA Primary Estimand 2b)
3. Supportive efficacy endpoint (assessed by BICR per RECIST v 1.1): • Composite bOR where responder must be alive, able to remain on or resume treatment, and achieved CR or PR without use of other anti-cancer therapies up to 24 weeks after Day 1 (for Estimand 2c)

Secondary endpoints 4

1. Secondary efficacy endpoints assessed by BICR at the following time points post Day 1: • Composite OR at 10, 16, 24, 32, and 52 weeks • PFS at 24 and 52 weeks • DOR • OS at 24 and 52 weeks PK endpoints, not covered by the primary endpoints: • Cmax in Cycle 1 and Cycle 8 • Ctrough: Cycle 1 to EOT visit as per the SoE
2. Safety endpoints include (52 weeks from baseline [Day 1] and up to EOS) • Incidence, nature and severity of TEAE, including SAEs, SUSARs and AESIs over the study period. • Other safety endpoints as follows: o Absolute values and changes from baseline in: o Clinical laboratory assessments (haematology, clinical chemistry [including selected hormone panel], coagulation and urinalysis).
3. o Vitals signs parameters (systolic and diastolic blood pressure, pulse rate, respiratory rate, and body temperature). o Incidence of abnormalities in: o Clinical laboratory parameters o 12-lead ECG o Physical examination
4. Immunogenicity endpoints over the study include (time frame: 52 weeks from baseline [Day 1] as per SoE): • ADAs • NAbs in ADA (+) samples • Titres in ADA (+) samples

Investigational products

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

Test 1

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Mabxience Research S.L.

Sponsor organisation

Mabxience Research S.L.

Address

Calle De Manuel Pombo Angulo 28

City

Madrid

Postcode

28050

Country

Spain

Scientific contact point

Organisation

Mabxience Research S.L.

Contact name

Calle Manuel Pombo Angulo, Madrid, Spain

Public contact point

Organisation

Mabxience Research S.L.

Contact name

Calle Manuel Pombo Angulo, Madrid, Spain

Third parties 10

Locations

7 EU/EEA countries · 22 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 55 files

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

Application history

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