E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Melanoma (patients with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma or patients with Stage IIIC cutaneous 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 | 15.0 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025669 |
E.1.2 | Term | Malignant melanoma stage II |
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 |
To evaluate the efficacy of vemurafenib adjuvant treatment administered
over a 52-week period in patients with completely resected BRAFV600
mutation–positive, cutaneous melanoma, as measured by DFS |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of vemurafenib adjuvant treatment administered over a 52-week period, as measured by OS
• To evaluate the efficacy of vemurafenib adjuvant treatment administered over a 52-week period, as measured by DMFS
• To evaluate the safety and tolerability of vemurafenib in the adjuvant setting
• To assess quality of life as measured by EORTC QLQ-C30
• To describe the pharmacokinetics of vemurafenib in the adjuvant setting, assess between-patient variability of PK parameters, and explore and quantify potential covariates that may contribute to between-patient differences in PK parameters, using a population PK approach |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Roche Clinical Repository (RCR optional sub-study)
Samples for exploratory biomarker analyses from patients who give specific consent to participate in this optional research will be stored in the RCR. These specimens will be used to achieve the following objectives:
• To study the association of biomarkers with efficacy, adverse events, or other effects associated with medicinal products
• To increase knowledge and understanding of disease biology
• To study drug response, including drug effects and the processes of drug absorption and disposition
• To develop biomarker or diagnostic assays and establish the performance characteristics for these assays
Protocol version : the protocol is part of the main protocol (see section A) |
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E.3 | Principal inclusion criteria |
•Male or female patients age ≥ 18 years
•Patients with completely resected, histologically confirmed, Stage IIC or Stage III, cutaneous melanoma where the BRAFV600 mutation status of the current primary tumor or involved lymph node is determined to be positive using the cobas® BRAF V600 Mutation Test. Patients with Stage IIIA disease must have at least one lymph node metastasis measuring > 1 mm in diameter
•ECOG performance status of 0 or 1
•Life expectancy of at least 5 years
•Adequate hematologic, liver, and renal function |
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E.4 | Principal exclusion criteria |
•History of any systemic therapy (i.e., chemotherapy, biologic or targeted therapy, or hormonal therapy) or limb perfusion therapy for the treatment or prevention of melanoma, including interferon-alpha-2b and pegylated interferon-alpha-2b
•History of radiotherapy for the treatment of melanoma
•Invasive malignancy other than melanoma at the time of enrollment or within 3 years prior to first study drug administration except for adequately treated (with curative intent) basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, limited stage bladder cancer, or other cancers from which the patient has been disease-free for at least 3 years
•History of or current clinical, radiographic, or pathologic evidence of in-transit metastases, satellite lesions or recurrent lymph node involvement after resection of a primary melanoma with previous lymph node involvement
•History or current radiographic or pathologic evidence of distant metastases
•History of clinically significant cardiac dysfunction including serious arrhythmias requiring treatment (except for atrial fibrillation and paroxysmal supraventricular tachycardia), history of myocardial infarction within 6 months prior to randomization, and history of congenital long QT syndrome or QTc interval > 450 ms at baseline
•Current, recent (within 28 days prior to randomization) or planned use of any investigational product outside of this study |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint, Disease Free Survival (DFS), is defined as the time from randomization until the date of the first local, regional, or distant melanoma recurrence; occurrence of new primary melanoma; or death from any cause. DFS will be assessed by the investigator. For patients without a DFS event, data will be censored at the last date the patient was known to be recurrence free, as documented by radiographic imaging. Details on censoring in the analysis of this endpoint are described in the Statistical Analysis Plan (SAP). For patients whose recurrence has been proven histologically, the date of melanoma recurrence will be defined as the date of the scan or clinical examination that prompted the biopsy. For patients whose suspicious lesions were deemed not amenable to biopsy or for patients who refuse a biopsy, the date of melanoma recurrence will be defined as the date of the scan or clinical examination that would have prompted a biopsy. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final analysis of the primary endpoint of DFS for Cohort 1 will take place when approximately 190 DFS events have occurred and for Cohort 2 when approximately 146 DFS events have occurred. |
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E.5.2 | Secondary end point(s) |
- Overall Survival: Overall Survival (OS) is defined as the time from randomization until the date of death from any cause. For patients still alive at the time of analysis, the data will be censored at the date the patient was last known to be alive.
- DMFS: Distant metastasis-free survival (DMFS) is defined as the time from randomization until the date of diagnosis of distant (i.e., non-locoregional) metastasis or death from any cause. Details on censoring in the analysis of this endpoint are described in the SAP. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- The first OS interim analysis in each cohort will be performed at the time of the final DFS analysis for the cohort (projected to occur for each cohort approximately 37 months after the first patient is randomized). The second OS interim analysis will be performed for Cohorts 1 and 2 after the occurrence of 178 and 136 deaths, respectively (projected to occur at approximately Month 59). The final OS analysis for Cohorts 1 and 2 will be performed after the occurrence of approximately 251 and 177 deaths, respectively (projected to occur at approximately Month 88 in each cohort) or at Month 88, whichever occurs first.
- final DFS analysis in each cohort – i.e. when approximately 190 DFS events have occurred for Cohort 1 and when approximately 146 DFS events have occurred for Cohort 2. |
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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 | Yes |
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, quality of life |
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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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | 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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 76 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
Croatia |
Czech Republic |
France |
Germany |
Israel |
Italy |
Netherlands |
New Zealand |
Poland |
Russian Federation |
Serbia |
South Africa |
Spain |
Sweden |
Switzerland |
Turkey |
Ukraine |
United Kingdom |
United States |
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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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All patients will be followed for melanoma recurrence for up to 5 years and OS for up to 7 years after Cycle 1, Day 1 of study treatment. Patients who exhibit recurrence of melanoma prior to completion of Year 5 of the study will be followed for OS. No study-related observations (including survival status) are planned after the completion of Year 7 of follow-up. |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |