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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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 | 20.0 |
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 |
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, endocrine, infusion-related, or hypersensitivity) 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 receivedprior systemic treatment for their advanced disease.
NOTE: Prior adjuvant or neoadjuvant melanoma therapy (including 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 the therapy was used in the adjuvant or neoadjuvant setting but not in the metastatic setting. These drugs must be discontinued 6 months prior to study entry. All AEs related to prior adjuvant or neoadjuvant therapy must have either returned to baseline, and eligible patients
must not have experienced severe or life-threatening irAEs except those that are unlikely to reoccur with standard countermeasures (eg, hormone replacement after adrenal crisis).
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 prior to first dose of study drug administration. (If MRI is contraindicated, CT scan is acceptable). 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.
i)Subjects are eligible if they have previously untreated brain metastases and are neurologically asymptomatic (This criterion is restricted to the investigators who have treated at least 3 patients with nivolumab plus ipilimumab combination regimen):
(1)No clinical requirement for local intervention (surgery, radiosurgery, corticosteroid therapy) or other systemic therapy.
(2)Subjects must be free of neurologic signs and symptoms related to metastatic brain lesions and must not have received systemic corticosteroid therapy in the 14 days prior to beginning protocol therapy.
ii)If patients had been previously treated and then developed asymptomatic progression (This criterion with details below is restricted to the investigators who have treated at least 3 patients with nivolumab plus ipilimumab combination regimen)
(1)Prior stereotactic radiotherapy (SRT) and prior excision of up to 3 melanoma brain metastases is permitted if there has been complete recovery, with no neurologic sequelae.
(2)Growth or change in a lesion previously irradiated will not be considered measurable. Regrowth in cavity of previously excised lesion will not be considered measurable.
(3)Any prior surgery or radiotherapy must have occurred at least 6 weeks before the start of dosing for this study.
d)ECOG PS 0-1
e)ECOG PS of 2 (This criterion is restricted to investigators who have treated at least 3 patients with nivolumab plus ipilimumab combination regimen)
f)Tissue tumor (archival or recent acquisition) must be available (block or a minimum of 10 unstained slides of FFPE tissue) for correlative studies |
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E.4 | Principal exclusion criteria |
a)Leptomenigeal metastases
b)As of Amendment 04, this criterion is no longer applicable
c)Subjects previously treated with SRT > 3 lesions in the brain
d)Brain lesion > 3 cm
e)History of carcinomatous meningitis (lumbar puncture is not required)
f)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.
g)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.
h)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, endocrine, infusion-related, or hypersensitivity). |
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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, 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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 104 |
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 |
Belgium |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
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 |