This Phase 3, open-label, triple arm study aims to evaluate the overall survival (OS) of fotemustine versus the combination of ipilimumab and fotemustine or the combination of Ipilimumab and nivolumab in patients with metastatic melanoma with brain metastasis.
Name: Fotemustine
Name: Fotemustine and Ipilimumab
Name: Ipilimumab and nivolumab
Description: To compare the efficacy of the combination of ipilimumab and fotemustine or the Combination of ipilimumab and nivolumab versus fotemustine in terms of overall survival (OS) in patients with metastatic melanoma with brain metastasis.Overall Survival (OS) is defined as the time from randomization until the date of death. For those subjects who have not died, OS will be censored at the recorded last date of subject contact, and for subjects with a missing recorded last date of contact, OS will be censored at the last date the subject was known to be alive.
Measure: Overall Survival (OS) Time: 2 yearsDescription: Reporting of safety, extent of exposure, concomitant medications and discontinuation of study therapy will be based on all treated subjects; for on-study laboratory test results, all treated subjects with at least one on-study laboratory measurement available will be included in the analysis. The reporting period for safety data will be from the date of first dose received on this study to 70 days (5 half-lives) after the last dose is received. Serious adverse events are reported from the time of consent forward for all subjects.All subjects who receive at least 1 dose of study treatment will be evaluated for safety parameters
Measure: safety (adverse events) Time: 2 yearsDescription: m-WHO and immune-related is the proportion of treated subjects with a ir-BOR of confirmed irCR, confirmed irPR or irSD in and outside the brain.
Measure: m-WHO and immune-related Disease Control Rate (DCR) in and outside the brain Time: Weeks 24Description: Immune-related progression free survival (irPFS) per irRC will be defined as the time between the date of randomization and the date of progression per irRC or death, whichever occurs first. A subject who dies without reported progression per irRC will be considered to have progressed on the date of death.
Measure: Immune-related Progression-free Survival (irPFS) Time: 2 yearsDescription: Progression-free survival (PFS) per mWHO criteria will be defined as the time between the date of randomization and the date of progression per mWHO criteria or death, whichever occurs first. A subject who dies without reported progression per mWHO criteria will be considered to have progressed on the date of death.
Measure: m-WHO Progression-free Survival (irPFS) Time: 2 yearsDescription: is the proportion of treated subjects with a BOR of confirmed CR or confirmed PR.
Measure: Objective Response Rate (ORR) Time: Weeks 24Description: is the proportion of treated subjects with a irBOR of confirmed irCR or confirmed irPR.
Measure: Immune-related Objective Response Rate (irORR) Time: Weeks 24Description: Time to Response (TTR) is defined as the time from first dosing date until the measurement criteria are first met for overall response of PR or CR (whichever status comes first, and provided it is subsequently confirmed).
Measure: Time to Response (TTR) Time: Weeks 24Description: Immune-related Time to Response (irTTR) is defined as the time from first dosing date until the measurement criteria are first met for overall response of irPR or irCR (whichever status comes first, and provided it is subsequently confirmed).
Measure: Immune-related Time to Response (irTTR) Time: Weeks 24Description: Duration of Response (DoR) is defined as the time between the date the measurement criteria are first met for an CR or PR (whichever status comes first and provided it is subsequently confirmed) and the date of PD or death (whichever comes first). For a subject who undergoes tumor resection following response but prior to disease progression, DOR will be censored at the date of the last evaluable TA on or prior to the date of resection. For subjects who remain alive and have no progressive disease as assessed by the investigator using RC, DOR will be censored on the date of last evaluable tumor assessment.
Measure: Duration of Response (DoR) Time: 2 yearsDescription: Immune-related Duration of Response (irDoR) for the subjects whose irBOR is irCR or irPR will be defined as the time between the date of response of confirmed irCR or confirmed irPR (whichever occurs first) and the date of irPD or death (whichever occurs first). The onset of a confirmed irCR or irPR is determined by the initial assessment of response, not by the confirmatory assessment. Note that if an assessment of irPR occurs before confirmation of irCR, the duration of immune-related response endpoint will not begin at the time that the irBOR of irCR is shown but rather at the earlier time-point showing irPR. For subjects who remain alive and have not progressed following response, irDoR will be censored on the date of last evaluable TA.
Measure: Immune-related Duration of Response (irDoR) Time: 2 yearsDescription: Brain progression-free survival (Brain-PFS) (3 and 6 months rates) is defined as the time from randomization date to the date of progression as per MRI of existing brain lesions, or of occurrence as per MRI of a new lesion located in the brain, or of death, whichever occurs first. For subjects who remain alive and have not progressed as per definition above, Brain-PFS will be censored at the day of last evaluable brain imaging assessment.
Measure: Brain progression-free survival (Brain-PFS) Time: 6 monthsAllocation: Randomized
Parallel Assignment
There is one SNP
- Subjects must have known BRAF V600E mutation status or consent to BRAF V600E mutation testing per local institutional standard. --- V600E ---
- Subjects must have known BRAF V600E mutation status or consent to BRAF V600E mutation testing per local institutional standard. --- V600E --- --- V600E ---