DANTE: A randomised phase III trial to evaluate the Duration of ANti-PD1 monoclonal antibody Treatment in patients with metastatic mElanoma

INTERVENTION: Product Name: Pembrolizumab Pharmaceutical Form: Powder for concentrate for solution for infusion INN or Proposed INN: Pembrolizumab CAS Number: 1374853‐91‐4 Concentration unit: mg/kg milligram(s)/kilogram Concentration type: equal Concentration number: 2‐ Product Name: Nivolumab Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: Nivolumab CAS Number: 946414‐94‐4 Concentration unit: mg/kg milligram(s)/kilogram Concentration type: equal Concentration number: 3‐ CONDITION: Advanced (unresectable stage III or stage IV (metastatic)) melanoma ; MedDRA version: 20.0 Level: PT Classification code 10025670 Term: Malignant melanoma stage III System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) ; MedDRA version: 20.0 Level: PT Classification code 10025671 Term: Malignant melanoma stage IV System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) ; MedDRA version: 20.0 Level: PT Classification code 10068117 Term: Metastatic ocular melanoma System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Therapeutic area: Diseases [C] ‐ Cancer [C04] SECONDARY OUTCOME: Secondary end point(s): The key secondary outcome measure is Quality of Life (QoL) measured using the EORTC QLQ‐C30 questionnaire and the melanoma‐specific module QLQ‐MEL38, and the EQ‐5D‐5L (EuroQol). The main QoL outcome of interest is the EORTC QLQ‐C30 summary score. This is a superiority outcome measure. ; ; Other secondary endpoints are:; ; • Overall survival (OS), calculated from the date of randomisation to the date of death (from any cause), or the date last known to be alive for patients who are not known to have died. This is a non‐inferiority outcome measure; • Objective response rate, calculated as the proportion of patients achieving either a complete or partial response. This is a non‐inferiority outcome measure; • Best tumour response rate, calculated as the proportion of patients achieving each best response (complete response, partial response, stable disease or progressive disease). This is a non‐inferiority outcome measure; • Duration of response, calculated as the time from first tumour response (after randomisation) until disease progression. This is a non‐inferiority outcome measure; • Safety and anti‐PD1 therapy‐related toxicity. Toxicity will be recorded using CTCAE v4; • Cost‐effectiveness of the two treatment strategies Timepoint(s) of evaluation of this end point: All secondary endpoints will be formally assessed during stage 4 of the trial. In addition, the secondary endpoints of OS and toxicity will be analysed at stage 5. Stage 4 (primary assessment of efficacy) analysis will occur when all participants have completed 12 months of follow‐up after randomisation, which is anticipated to be 6 years from the start of recruitment. Stage 5 (long‐term assessment of efficacy) analysis will take place when all participants have completed 4 years of follow‐up after randomisation. PRIMARY OUTCOME: Main Objective: This trial is for patients with advanced melanoma (skin cancer) who are being treated with ‘anti‐PD1’ drugs. The current standard practice is to treat patients for as long as they continue to benefit, only stopping treatment if the patient’s cancer comes back, or if the side effects are too bad. Often treatment can go on for several years. ; ; This trial will compare the standard treatment duration with a shorter, fixed, treatment duration (1 year). The main aim is to find out if treatment can be stopped after 1 year, by assessing whether treating for 1 year is no worse than treating for longer than 1 year, in terms of the cancer coming back.; ; ; Primary end point(s): The primary outcome measure is progression‐free survival (PFS), calculated from the date of randomisation to the date of documented evidence of first progression or death (from any cause), or the date last known to be alive and progression‐free for patients without a PFS event. This is a non‐inferiority outcome measure. ; ; A sensitivity analysis to the primary endpoint will assess time to progression, where deaths without documented evidence of progression will be considered a competing risk event. Secondary Objective: The key secondary objective is to evaluate how the length of treatment affects patients’ quality of life (QoL), and determine whether shorter duration treatment achieves better QoL outcomes. ; ; Other secondary objectives are:; • to determine whether overall survival (OS) and tumour response are no worse when using shorter duration therapy compared to standard duration; • to compare safety and toxicity of the two treatment strategies; • to evaluate the cost‐effectiveness of the two treatment strategies; ; Timepoint(s) of evaluation of this end point: PFS will be formally assessed during stages 3‐5 of the trial. Stage 3 (interim assessment of efficacy) analysis will occur when at least half the required number of participants have been randomised and have completed 12 months of trial follow‐up, and the study is at least 30 months into recruitment. Stage 4 (primary assessment of efficacy) analysis will occur when all participants have completed 12 months of follow‐up after randomisation, which is anticipated to be 6 years from the start of recruitment. Stage 5 (long‐term assessment of efficacy) analysis will take place when all participants have completed 4 years of follow‐up after randomisation. INCLUSION CRITERIA: Eligibility for REGISTRATION • Histologically or cytologically confirmed unresectable stage III or stage IV (metastatic) melanoma, including cutaneous and non‐cutaneous melanoma • Aged = 18 years • Planned or currently receiving (<12 months) treatment with first‐line pembrolizumab or nivolumab • Written informed consent for registration Inclusion criteria for RANDOMISATION • Registered in DANTE • Progression‐free by RECIST v1.1 criteria at 12 months (+/‐ 4 weeks) from the start of pembrolizumab or nivolumab • 12 months (+/‐ 4 weeks) from start of pembrolizumab or nivolumab • Eastern co‐operative oncology group (ECOG) performance status 0‐2 • Considered fit by the treating clinician to continue to receive ongoing treatment with pembrolizumab or nivolumab • Written informed consent for randomisation Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18‐64 years) ye