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) |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 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) |
|
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 | 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) |
|
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 |
|
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 |
|
E.2.3 | Trial contains a sub-study | No |
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 |
|
E.4 | Principal exclusion criteria |
•History of any systemic or local therapy (e.g., chemotherapy, biologic or targeted therapy, hormonal therapy or photodynamic 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 5 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, or limited stage bladder cancer. This requires that the patient pathology evaluation of the screening Papanicolaou (Pap) smear, and of any polyps resected at the screening coloscopy, is negative for invasive malignancy.
•Known personal history of more than three (>3) adenomatous colorectal polyps or a personal history of adenomatous colorectal polyp(s) > 2 cm in size. This also applies to the screening colonoscopy for select patients.
•History of or current clinical, radiographic, or pathologic evidence of in-transit metastases, satellite, or microsatellite lesions or recurrent lymph node involvement after resection of a primary melanoma with lymph node involvement at any time in the past
•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 |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint, 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.
The DFS component of melanoma recurrence will be assessed by the investigator. The DFS component of an occurrence of a new primary melanoma will be based upon the diagnosis made by a Roche-designated central pathology laboratory.
For patients without a DFS event, data will be censored at the date of the last disease assessment.
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 earliest 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 earliest date of the scan or clinical examination that would have prompted a biopsy. For patients with an occurence of a new primary melanoma, the date of the new primary melanoma will be defined as the earliest date of the clinical examination or scan that prompted the biopsy. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final analysis of the primary endpoint of DFS will take place when approximately 120 DFS events have occurred for Cohort 1 and approximately 105 DFS events have occurred for Cohort 2 (see Section 6.1).
The final DFS analyses for both cohorts will be conducted at the same time by using the dataset from the same data cutoff date for both cohorts.
|
|
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. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
-The OS interim analysis in each cohort will be performed at the time of the final DFS analysis for both cohorts
The final OS analysis for Cohorts 1 & 2 will be performed after the occurrence of approximately 107 and 118 deaths,respectively (projected to occur at approximately Month 72 in each cohort) or at Month 72, whichever occurs first.
-DMFS will be analyzed at the time of the final DFS analysis in each cohort–viz.,when approximately 190 DFS events have occurred for Cohort 1 and when approximately 146 DFS events have occurred for Cohort 2. |
|
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 |
|
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.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 88 |
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 |
Estonia |
France |
Germany |
Ireland |
Israel |
Italy |
Mexico |
Netherlands |
New Zealand |
Norway |
Poland |
Portugal |
Russian Federation |
Serbia |
South Africa |
Spain |
Sweden |
Switzerland |
Turkey |
Ukraine |
United Kingdom |
United States |
|
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
|
All patients will be followed for melanoma recurrence or occurrence of new primary melanoma and overall survival for at least 2 years after Cycle 1, Day 1 of study treatment. Patients may be followed for melanoma recurrence or occurrence of new primary melanoma for up to 5 years and OS for up to 6 years after Cycle 1, Day 1 of study treatment. Patients who exhibit recurrence of melanoma or a new primary melanoma during the study will be followed for OS. (details in protocol section 3.2)
|
|
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 |