E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Histologically Confirmed 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] - Cancer [C04] |
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 trial are: - To determine the incidence of high-grade (CTCAE v4.0 Grade 3 or higher), treatment related, select adverse events in patients with histologically confirmed stage III (unresectable) or stage IV melanoma and progression after prior treatment containing an anti-CTLA-4 monoclonal antibody. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives: - To determine the incidence and to characterize the outcome of all high-grade (CTCAE v4.0 Grade 3 or higher), select adverse events in patients with histologically confirmed stage III (unresectable) or stage IV melanoma and progression after prior treatment containing an anti-CTLA-4 antibody, treated with nivolumab monotherapy. - To estimate OS in all treated patients - To estimate Investigator-assessed objective response rate (ORR) Exploratory objectives: Refer to study protocol
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed Written Informed Consent a) Patients must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal patient care. b) Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study. 2. Target Population a) Patients with progression after prior treatment containing an anti-CTLA-4 monoclonal antibody (Cohorts 1 and 2): i) Patients with histologically confirmed malignant melanoma ii) Eastern Cooperative Oncology Group (ECOG) PS: (1) PS 0 to 1 (Cohort 1) (2) PS 2 (Cohort 2; a minimum of 50 patients and a maximum of 185; clinical risk benefit ratio of Cohort 2 will be monitored by the Scientific Steering Committee) iii) Previously treated unresectable stage III or stage IV melanoma as per the American Joint Committee on Cancer 2010 Guidelines36 regardless of BRAF mutation status iv) Patients must have experienced disease progression or recurrence after prior treatment containing an anti-CTLA-4 monoclonal antibody v) Prior treatment with chemotherapy, interferon (adjuvant setting), IL-2, BRAF/MEK inhibitors for patients with known BRAF mutations, MEK inhibitors for NRAS mutations, and cKIT inhibitor patients with known cKIT mutations are allowed vi) Patients with CNS metastases: (1) Patients are eligible if CNS metastases are treated and patients are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to enrollment. In addition, patients must be either off corticosteroids or on a stable or decreasing dose 10 mg daily prednisone (or equivalent) OR (2) Patients are eligible if they have previously untreated CNS metastases and are neurologically asymptomatic. In addition, patients must be either off corticosteroids or on a stable or decreasing dose of 10 mg daily prednisone (or equivalent) OR (3) Patients with additional leptomeningeal metastases are eligible if they are treated and neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to enrollment and have a life expectancy of at least 3 months. In addition, patients must be either off corticosteroids or on a stable or decrease dose 10 mg daily prednisone (or equivalent) vii)Prior chemotherapy or immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer) must have been completed at least 4 weeks before study drug administration, and all adverse events have either returned to baseline or have been stabilized viii) Prior palliative radiotherapy must have been completed at least 2 weeks prior to study drug administration ix) Prior targeted therapy must have been completed at least 2 weeks prior to study drug administration x) Prior anti-CTLA-4 therapy must have been completed at least 4 weeks before study drug administration xi) Prior radiotherapy or radiosurgery must have be completed at least 2 weeks prior to the first dose of study drug xii)Primary uveal (minimum of 30 patients) and mucosal melanoma are allowed xiii) Screening laboratory values must meet the following criteria prior to commencement of treatment: (1) WBCs ≥ 2000/μL (2) Neutrophils ≥1500/μL (3) Platelets ≥ 100 x 10³/μL (4) Hemoglobin ≥ 9.0 g/dL (5) Serum creatinine of ≤ 1.5 X ULN or creatinine clearance > 40 mL/minute (using Cockcroft/Gault formula) (a) Female CrCl= [(140- age in years) x weight in kg x 0.85) ÷(72 x serum creatinine in mg/ dL)] (b) Male CrCl= [(140- age in years) x weight in kg x 1.00) ÷(72 x serum creatinine in mg/ dL)] (6) AST ≤ 3 X ULN (7) ALT ≤ 3 X ULN (8) Total bilirubin ≤ 1.5x ULN (except patients with Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL) xiv) Patients with a known history of Grades 3-4 adverse reactions during anti-CTLA-4 therapy will be allowed to participate if all toxicities have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of nivolumab (minimum of 40 patients) xv) Patients must have evaluable disease by CT or MRI per RECIST 1.1 criteria (radiographic tumor assessment performed within 6 weeks of first dose of study drug) or clinically apparent disease that the investigator can follow for response. xvi) Patient Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (ie, subject has not been treated). If re-enrolled, the subject must be re-consented. For Other Inclusion Criteria please refer to Protocol |
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E.4 | Principal exclusion criteria |
1. Target Disease Exceptions a) As of Amendment 02, this criterion is no longer applicable. b) Patients with untreated, symptomatic CNS metastases are excluded
2. Medical History and Concurrent Diseases a) As of Amendment 03, this criterion is not applicable. b) Patients 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. c) Patients with previous malignancies (except non-melanoma skin cancers, in situ bladder cancer, gastric or colon cancers, cervical cancers/dysplasia or breast carcinoma in situ) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period d) Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the patient to receive protocol therapy e) Any treatment in a BMS-sponsored, interventional nivolumab trial or ipilimumab trial f) Known drug or alcohol abuse
3. Physical and Laboratory Test Findings a) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection b) Positive test for HIV
4. Allergies and Adverse Drug Reaction a) History of severe hypersensitivity reactions to other monoclonal antibodies b) History of allergy or intolerance (unacceptable adverse event) to study drug components or Polysorbate-80-containing infusions. c) As of Amendment 02, this criterion is no longer applicable.
5. Sex and Reproductive Status a) WOCBP who are pregnant or breastfeeding b) Women with a positive pregnancy test at enrollment or prior to administration of study medication c) Women treated with ORAL hormone replacement therapy (HRT) are to be excluded unless the oral replacement therapy was stopped by investigator’s discretion at least 4 weeks prior to screening and was changed to other contraception method.
6. As of Amendment 02, this criterion is no longer applicable
7. Other Exclusion Criteria a) Prisoners or subjects who are involuntarily incarcerated b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the incidence for high-grade (CTCAE v4.0 Grade 3 or higher), treatment-related, select adverse events.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The analysis of primary, secondary (excluding ORR), and exploratory endpoints will be reported for the full safety analysis set and by cohorts based on ECOG PS. ORR will be reported for the response evaluable analysis set and by PS. OS and ORR will be further presented by initial investigator-assessed objective response under treatment with an anti-CTLA-4 monoclonal antibody.
Additional details regarding statistical analysis performed in the study are provided in the Statistical Analysis Plan (SAP), which will be finalized before before data base lock.
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E.5.2 | Secondary end point(s) |
The secondary endpoints include: - Incidence of all high-grade (Grades 3 and higher), select adverse events - Median time to onset and median time to resolution (Grades 3-4) of select adverse events - OS - Investigator-assessed ORR The exploratory endpoints include: - Safety and tolerability will be measured by the incidence of all adverse events, serious adverse events, deaths, and laboratory abnormalities. Adverse event assessments and laboratory tests will be performed at baseline and continuously throughout the study at the beginning of each subsequent cycle. - Investigator-assessed ORR - OS - Quality of Life as mean and change from baseline in domain scores and health status index based on EORTC QLQ-C30 and EQ-5D-3L of the full safety analysis set |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The analysis of primary, secondary (excluding ORR), and exploratory endpoints will be reported for the full safety analysis set and by cohorts based on ECOG PS. ORR will be reported for the response evaluable analysis set and by PS. OS and ORR will be further presented by initial investigator-assessed objective response under treatment with an anti-CTLA-4 monoclonal antibody. |
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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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 210 |
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 |
Austria |
Belgium |
Czech Republic |
Denmark |
Finland |
Germany |
Greece |
Hungary |
Ireland |
Italy |
Netherlands |
Norway |
Poland |
Portugal |
Romania |
Russian Federation |
Spain |
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 | 4 |
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 | 4 |
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 |