E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Stage III (Unresectable) or Stage IV Melanoma |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
MedDRA Classification |
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 |
The primary objective of this study is to determine the incidence of high-grade (CTCAE v4.0 Grades 3-5), treatment-related, select adverse events of potentially immune-mediated etiology (pulmonary, gastrointestinal, skin, renal, hepatic, pancreatic, neurologic, endocrine) of nivolumab plus ipilimumab combination regimen as firstline
therapy for unresectable or metastatic melanoma.
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
*To determine the incidence and to characterize the outcome (duration of serious adverse events [SAE] treatment, dose of immune-modulating agents [ie, steroids] used, time to event onset, and event resolution, and worst grade of event) of high-grade (CTCAE v4.0 Grade 3 or higher), select adverse events of potentially immune-mediated etiology in subjects with unresectable or metastatic melanoma treated with nivolumab and ipilimumab combination regimen
*To estimate overall survival (OS) in all treated subjects
*To assess safety, tolerability, investigator-assessed objective response rate (ORR), progression-free survival (PFS), and OS in all subjects and in a subset of with Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1, ECOG PS 2, ocular and mucosal melanoma, and brain metastasis |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
a) Subjects with histologically-confirmed unresectable stage III or stage IV melanoma as per AJCC 2010 staging system, including mucosal and ocular melanoma, regardless of BRAF mutation status
b) Subjects are included if they are newly diagnosed with advanced/metastatic disease and have not received prior systemic treatment for their advanced disease.
Note: Prior adjuvant or neoadjuvant melanoma therapy (except anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2, or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways, such as anti-CD-137) is permitted if it was completed at least 6 weeks prior to study entry, and all related AEs have either returned to baseline or stabilized.
c) Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 2 weeks after treatment is complete and within 6 weeks of first dose of study drug administration. There must also be no requirement for high doses of systemic corticosteroids that could result in immunosuppression (> 10 mg/day prednisone equivalents) for at least
2 weeks prior to study drug administration. |
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E.4 | Principal exclusion criteria |
a) Active (symptomatic) and not treated brain metastases or leptomeningeal metastases.
b) Subjects who received prior therapy with an anti-CTLA-4, anti-PD-1, anti PD-L1 or anti-PD-L2, anti-CD-137 agents (or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways) for adjuvant, neo-adjuvant, or advanced melanoma treatment or as part of clinical trial (including those who have been randomized to blinded control)
c) Subjects with active, known, or suspected autoimmune disease. Subjects 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.
d) Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
e) All toxicities attributed to prior anti-cancer therapy other than alopecia, fatigue, or peripheral neuropathy must have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of study drug |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the incidence of high-grade (CTCAE v4.0 Grade 3-5), treatment related, select adverse events of potentially immune-mediated etiology (pulmonary, gastrointestinal, skin, renal, hepatic, pancreatic, neurologic, endocrine). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The initial tumour assessment is completed at week 12 (+/- 5 days) after the first treatment dose |
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E.5.2 | Secondary end point(s) |
* Incidence of all high-grade (Grades 3-5), select adverse events
* Median time to onset and median time to resolution (Grades 3-4) of select adverse events
* Resolution of an AE is a subject experiencing complete resolution or improvement to the baseline grade for the AE
* OS is defined as the time from first dosing date to the date of death. A subject who has not died will be censored at last known date alive.
* Safety and tolerability will be measured by the incidence of all AEs, treatment-related AEs, serious AEs, deaths, laboratory abnormalities, and select AEs such as pulmonary, gastrointestinal, skin, renal, hepatic, pancreatic, neurologic, endocrine, infusion-related, or hypersensitivity.
* The ORR is defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of all treated subjects. BOR is defined as the best response designation, recorded between the date of first dose and the date of the initial objectively documented tumor progression by the investigator per RECIST v1.1 or the date of subsequent therapy, whichever occurs first.
For subjects without documented progression or subsequent therapy, all available response designations will contribute to the BOR determination.
* Investigator-assessed PFS is defined as radiological evidence of progression, significant clinical symptomatic progression, or the need to introduce a non-study drug therapy. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Nivolumab plus Ipilimumab: Adverse Event assessments are done during office visits and by weekly calls to subject during weeks the subject is not in the office for a clinic visit.
Nivolumab monotherapy: Every 2 weeks (+/- 3 days) |
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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 | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
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 | No |
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 | No |
E.8.1.1 | Randomised | No |
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 | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 18 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 99 |
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 |
Austria |
Finland |
France |
Germany |
Ireland |
Italy |
Norway |
Sweden |
Switzerland |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
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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The study is scheduled to run for a maximum of 24 months. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |