E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Completely resected Stage IIb/c melanoma subjects. |
|
E.1.1.1 | Medical condition in easily understood language |
Subjects with completely resected cutaneous melanoma |
|
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 | LLT |
E.1.2 | Classification code | 10053571 |
E.1.2 | Term | Melanoma |
E.1.2 | System Organ Class | 100000004864 |
|
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 |
To compare the efficacy, as measured by recurrencefree survival (RFS), provided by nivolumab monotherapy versus placebo in participants with completely resected stage IIB/C melanoma with no evidence of disease |
|
E.2.2 | Secondary objectives of the trial |
- To compare the overall survival (OS) provided by nivolumab monotherapy versus placebo in participants with completely resected stage IIB/C melanoma with no evidence of disease, who are at high risk for recurrence.
- To assess safety and toxicity of nivolumab monotherapy in participants with completely resected stage IIB/C melanoma with no evidence of disease.
- To evaluate distant metastases-free survival (DMFS)
- To evaluate investigator-assessed outcomes on nextline therapies. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
a) Participants must have been diagnosed with stage IIB/C cutaneous melanoma (AJCC Cancer Staging, 8th edition) and have histologically confirmed melanoma that is completely surgically resected with documented negative margins (per local standard) for disease on resected specimens. All melanomas, except ocular and mucosal melanoma,
regardless of primary site of disease will be allowed.
b) Complete resection must be performed within 12 weeks prior to randomization.
Participants must have had a negative sentinel lymph node biopsy. Patients in whom a sentinel lymph node biopsy procedure could not be done or a sentinel lymph node was not detected are not eligible.
c) Participants must have disease-free status documented by a complete physical examination (within 14 days) and imaging studies within 4 weeks (28 days) prior to randomization.
Imaging studies must include CT scans of the chest/abdomen/pelvis or CT scan of the chest and MRI scans of the abdomen and pelvis, and all known sites of resected disease (lymph nodes ≥ 15 mm in short axis). Participants with signs and symptoms consistent with brain metastases should have imaging studies done to rule out the presence of brain metastases.
d) Has not been previously treated for melanoma beyond complete surgical resection of the
melanoma lesion.
e) Has recovered adequately from toxicity and/or complications from surgery prior to study
start.
f) ECOG performance status of 0 or 1 at the time of enrollment
g) Tumor tissue (minimum of 15 unstained slides or 1 FFPE block) from the resected site of disease must be provided to the central lab prior to randomization. |
|
E.4 | Principal exclusion criteria |
a) History of ocular and mucosal melanoma.
b) Participants with 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.
c) Prior malignancy active 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.
d) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
e) Women who are pregnant or breastfeeding
f) Participants with serious or uncontrolled medical disorders. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Censoring rules for the primary analysis of RFS are presented in Table 10.3.1.1-1 |
|
E.5.2 | Secondary end point(s) |
- OS
- AE, clinical laboratory values, vital signs, ECGs, or other safety biomarkers
- DMFS
- Objective response rates (if applicable)
- Duration of treatment on next-line therapies
- PFS2 defined as time from randomization to second recurrence/objective disease progression, or death from any cause, whichever occurs first.
- End-of-next-line-treatment: To be used for situations where PFS2 cannot be reliably determined. Event defined as end or discontinuation of next-line treatment, second objective disease progression, or death from any cause, whichever occurs first. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
- For participants without documentation of death, OS will be censored on the last date the participant was known
to be alive. OS will be followed continuously while participants are on the study drug and every 12 weeks after participants discontinue the study drug.
- Censoring rules for the analysis of DMFS are presented in Table 10.3.1.2-1.
- The Investigator-Assessed Outcomes on Next-Line Therapies endpoints will be analyzed using a two-sided log-rank test at the overall significance level of 5% (two-sided) in all randomized participants.
- Safety and tolerability of nivolumab and placebo will be measured by the incidence of adverse events, serious adverse events, deaths, and laboratory abnormalities. |
|
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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity Assessments; Biomarkers |
|
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 |
OL period with Nivo is possible- open label phase in case of reccurence |
|
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 66 |
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 |
Austria |
Belgium |
Czechia |
Denmark |
Finland |
France |
Germany |
Greece |
Italy |
Norway |
Poland |
Sweden |
United Kingdom |
Netherlands |
Romania |
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
|
End of trial is defined as the completion of the the last visit or scheduled procedure shown in the Schedule of Activities for the last participant, or the final date on which data for the primary endpoint was or is expected to be
collected, if this is not the same. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 27 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 2 |