E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Resected Stage IIIA/B/C/D or Stage IV melanoma in an adjuvant setting |
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E.1.1.1 | Medical condition in easily understood language |
Melanoma Stage III or Stage IV |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025671 |
E.1.2 | Term | Malignant melanoma stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025670 |
E.1.2 | Term | Malignant melanoma stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Part 1: - To demonstrate PK (pharmacokinetics) non-inferiority of nivolumab SC coformulated with rHuPH20 (recombinant human hyaluronidase PH20 enzyme) versus nivolumab IV (intravenous administration).
Part 2: - To characterize the PK of nivolumab SC coformulated with rHuPH20. |
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E.2.2 | Secondary objectives of the trial |
Part 1, Key secondary: - To assess the safety and tolerability of nivolumab SC coformulated with rHuPH20 and nivolumab IV. - To assess the efficacy of nivolumab SC coformulated with rHuPH20 and nivolumab IV.
Part 1, Other Secondary: - To characterize additional PK parameters following nivolumab SC coformulated with rHuPH20 and nivolumab IV. - To evaluate the immunogenicity of nivolumab SC coformulated with rHuPH20 and nivolumab IV and the impact of anti-nivolumab antibodies on safety. - To assess satisfaction with route of treatment administration.
Part 2: - To characterize additional PK parameters following nivolumab SC coformulated with rHuPH20. - To assess the safety and tolerability profile of nivolumab SC injection with rHuPH20. - To assess the immunogenicity of nivolumab SC and the impact of anti-nivolumab antibodies on safety. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• All participants must have been diagnosed with either Stage IIIA (> 1mm tumor in lymph node)/B/C/D or Stage IV melanoma by AJCC 8th edition and have histologically confirmed melanoma (as documented in the pathology report) that is completely surgically resected (free of disease) with negative margins in order to be eligible. All melanomas, except uveal and mucosal melanoma, regardless of primary site of disease, will be allowed. • Complete resection must be performed within 12 weeks prior to randomization (Part 1) or treatment assignment (Part 2). Management of residual lymph nodes after positive sentinel lymph node biopsy (ie, completion lymph node dissection) will be as per local standards and recommendations for the individual participant. • Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
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E.4 | Principal exclusion criteria |
• History of uveal or mucosal melanoma. • Untreated/unresected CNS metastases or leptomeningeal metastases. • Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. • Participants with serious or uncontrolled medical disorders within 4 weeks prior to screening. - Additionally, in the case of prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, acute symptoms must have resolved and based on investigator assessment in consultation with the Medical Monitor, there are no sequelae that would place the participant at a higher risk of receiving investigational treatment. • Concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to randomization (Part 1) or treatment assignment (Part 2) (ie, participants with a history of prior malignancy are eligible if treatment was completed at least 2 years before randomization/treatment assignment and the patient has no evidence of disease). Participants with history of prior early stage basal/squamous cell skin cancer or noninvasive or in situ cancers that have undergone definitive treatment at any time are also eligible. • Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) within 14 days or other immunosuppressive medications within 30 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. • Any condition that according to investigator criteria makes a participant ineligible from participation in the study, including but not limited to medical conditions (including psychological, psychiatric), or social conditions; or conditions that can impact ability to comply with protocol requirements (eg, conditions that preclude the use of IV or subcutaneous [SC] route of study drug administration) or that can put the participant at risk. Participants with history of self-harm including suicidal attempts will be excluded from the study. • Prior immunotherapy treatments for any prior malignancies are not permitted (such as, but not limited to anti-programmed death-1, anti-programmed death-ligand 1, anti-programmed death-ligand 2, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways). • Participants treated with anti-cancer therapy directed against the resected melanoma (for example, but not limited to, systemic, local, radiation, and radiopharmaceuticals) except: - Surgery for the melanoma lesion(s) - Adjuvant radiation therapy after neurosurgical resection for CNS lesions - Prior adjuvant interferon completed ≥ 6 months prior to randomization (Part 1) or treatment assignment (Part 2). • Treatment with any live attenuated vaccine within 30 days of first study treatment (Vaccines that are not live attenuated are allowed, including COVID-19 vaccines). • History of allergy or hypersensitivity to study drug components or device components. • Known human immunodeficiency virus (HIV) positive with an AIDS defining opportunistic infection within the last year, or a current CD4 count < 350 cells/uL. Participants with HIV are eligible if: i) they have received antiretroviral therapy (ART) for at least 4 weeks prior to randomization (Part 1) or treatment assignment (Part 2) as clinically indicated while enrolled on study. ii) they continue on ART as clinically indicated while enrolled on study. iii) CD4 counts and viral load are monitored per standard of care by a local healthcare provider. NOTE: Testing for HIV must be performed at sites where mandated locally. HIV positive participants must be excluded where mandated locally. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1 -Cavgd28 (Time averaged nivolumab serum concentration over the first 28 days) - Cminss (Minimum nivolumab serum concentration at steady-state)
Part 2 -Cavgd28 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1 -Cavgd28 : First 28 days of treatment -Cminss : 17 weeks after the start of treatment
Part 2 -Cavgd28 : First 28 days of treatment
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E.5.2 | Secondary end point(s) |
Part 1, Key secondary: a) Incidence of all AEs/SAEs, treatment-related AEs, including IMAEs, SAEs, AEs (including device-related adverse reactions, injection/infusion-related AEs) leading to discontinuation or death, and laboratory abnormalities for each treatment group. b) RFS (recurrence-free survival) per investigator - rates at 12, 18, 24, and 36 months follow-up. c) OS (overall survival) rates at 12, 18, 24, and 36 months follow-up.
Part 1, other secondary: d) Cmind28 (minimum nivolumab serum concentration on Day 28), Cmax1 (maximum nivolumab serum concentration after the first dose), Tmax (time to maximum nivolumab serum concentration after the first dose.) e) Cmaxss (maximum nivolumab serum concentration at steady-state), and Cavgss (time-averaged nivolumab serum concentration at steady-state). f) Percentage of participants who develop anti-nivolumab antibodies and neutralizing antibodies, if applicable, and the impact of anti-nivolumab antibodies on AEs, administration-related reactions, and events within MedDRA SMQ Anaphylactic reactions g) Mean CTSQ (Cancer Treatment Satisfaction Questionnaire) Satisfaction domain scores and score change from baseline at each assessment time point.
Part 2 h) Cmind28, Cmax1, Tmax i) Cmaxss, Cavgss, and Cminss. j) Incidence of AEs/SAEs, treatment-related AEs, including IMAEs, SAEs, AEs (including device-related adverse reactions, injection/infusion-related AEs) leading to discontinuation or death, and laboratory abnormalities. k) Percentage of participants who develop anti-nivolumab antibodies and neutralizing antibodies, if applicable, and the impact of anti-nivolumab antibodies on AEs, administration-related reactions, and events within MedDRA SMQ Anaphylactic reactions. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
a) Up to 100 days after the last treatment of study intervention or up to discontinuation of study treatment b) Until recurrence event, up to minimum follow-up of 12 months from last participant randomized in the study or death whichever is earlier c) Until death, up to 36 months d) First 28 days of treatment e) 17 weeks after the start of treatment f) Up to 100 days after the last study treatment or up to discontinuation of study treatment g) At each assessment time Point h) First 28 days of treatment i) 17 weeks after the start of treatment j) Up to 100 days after the last treatment of study intervention or up to discontinuation of study treatment k) Up to 100 days after the last study treatment or up to discontinuation of study treatment |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability, Immunogenicity |
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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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
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 |
Australia |
Canada |
United States |
Belgium |
France |
Germany |
Italy |
Poland |
United Kingdom |
Spain |
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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
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End of trial is defined as the last participant last visit or completion of Follow-up Visit 2. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |