Title: DANTE - A randomised phase III trial to evaluate the duration of anti-PD1 monoclonal antibody treatment in patients with metastatic melanoma
Funder: Department of Health and Social Care

Abstract: Design A multicentre, randomised, controlled, multi-stage, non-inferiority trial comparing 12 months (m) of anti-PD1 therapy with standard duration until progression. The recruitment period is 5 years (y); each patient will be followed up for 4y. To ensure that both feasibility of the intervention & any lack of efficacy are identified early in the trial, we have incorporated 3 intermediate stages in the trial design with stop/go rules depending on randomisation & recruitment rate (stage 1 & 2) & an intermediate assessment of efficacy (stage 3). Providing these conditions are met, the trial will continue seamlessly enabling the stage 4 primary & secondary objectives to be attained in a timely manner. The stage 4 primary analysis will occur when all patients have completed 12 months of follow-up after randomisation. A long-term analysis (stage 5) will be conducted when all patients have completed 4y of follow-up. Randomisation (1:1) will be by minimisation with a random element incorporating BRAF status, prior BRAF/MEK inhibitor therapy for advanced disease, prior adjuvant immunotherapy, disease stage, presence of brain metastases, performance status, centre, treatment (pembrolizumab or nivolumab) & response after 1st 12m therapy (complete/partial response or stable disease). Patients will be followed for response & progression with standard 12 weekly imaging for 12m post-randomisation then 6-monthly until 4y post-randomisation (2 & 5y after start of anti-PD1 therapy). Setting 45 NHS cancer centres with expertise in treatment of advanced melanoma Target population Patients (18y or older) with advanced (unresectable or metastatic) melanoma who have commenced first line anti-PD1 therapy who are progression-free after 12m of treatment HTA technologies being assessed Anti-PD1 therapy for the standard duration of until progression will be compared against shorter duration of 12m Outcomes Primary PFS Secondary QoL (by 3-monthly EORTC QLQ-C30, QLQ-MEL38 & EQ5D until 18m post-randomisation) Response (by RECIST) OS Drug-induced toxicity Cost effectiveness (within trial & longer term modelling) Sample size Estimating the 2-year PFS rate in the control arm to be 51% for patients alive and progression-free at 12m & defining non-inferiority as a reduction in 2-year PFS of no more than 7.9% (a hazard ratio of 1.25), with 80% power and a one-sided significance level of 5%, 1,014 patients are required to test for this degree of non-inferiority using a one-sided log-rank test, assuming patients are followed for a fixed length of time (i.e. 12 months following randomisation) and that the hazard ratio is constant. To account for a 5% drop-out rate, 1,068 patients (534 per arm) will be required in total. SAMPLE SIZE REVISION AUGUST 2017 (Due to emergence of updated, longer-term follow-up data from the CheckMate-067 trial, which was used to inform the underlying assumptions of the DANTE sample size calculation) The PFS rate at 12 months post-randomisation (i.e. 2 years after the start of anti-PD1 therapy – ‘2-year PFS’) for patients in the control arm has been re-assessed; this is now estimated to be 86% rather than 51%. In addition the non-inferiority margin has been re-assessed. This was previously defined as a reduction in 2-year PFS of no more than 7.9%; this has now been reduced to 6%. As a result of these changes, the sample size is now 1208 randomised patients in total. Project timetables 1-12 months Project set-up 13-72 months Recruitment 73-120 months Follow-up, including primary analysis and write-up 121-124 months Long-term follow-up analysis & write-up Expertise in team Medical Oncology co-investigators who have conducted many clinical trials in patients with melanoma & have expertise in immunology & QoL. Clinical Trials Unit co-investigators for trial management, health economics, qualitative research & statistical expertise with extensive experience in cancer clinical trials.

Lay abstract: Metastatic melanoma has a poor prognosis if untreated. In the past five years, two types of drugs activating the immune system have been shown to extend patient survival. The most active appear to be those targeting a molecule known as PD1 to switch on the immune system. Two anti-PD1 drugs, pembrolizumab and nivolumab, are licensed to treat metastatic melanoma and are rapidly becoming the initial treatment of choice, in the UK and worldwide, for many patients with inoperable disease. Pembrolizumab and nivolumab are given to patients as intravenous infusions 2- or 3-weekly for as long as there is benefit. Patients are required to attend clinic prior to each treatment for safety checks. Clinical trials suggest that up to 40% of patients remain on treatment after 1-2 years of starting, so the burden to patients, their carers and the NHS is significant. What we don’t know is whether treatment can be given for a shorter duration, as with another immunotherapy drug, ipilimumab, which is given only for a total of 12 weeks. Anti-PD1 drugs are given continuously because that is how they were given in clinical trials. Continuing treatment exposes patients to potentially severe immune-related side-effects such as inflammation of the lungs or the bowel, resulting in admission to hospital, intensive care or surgery. In clinical trials of nivolumab and pembrolizumab, some patients stopping treatment due to side-effects have continued to respond. Anti-PD1 drugs seem to make most difference to patients within the first year of treatment. There is no evidence that continuing treatment beyond 1 year brings a better outcome than stopping at 1 year and it is possible that shorter durations may be equally effective, with fewer side-effects. Anti-PD1 drugs are being assessed in other tumour types too. This study will assess whether treatment with anti-PD1 drugs can be stopped after 1 year. Consenting patients who have been on anti-PD1 therapy for less than 12 months will be registered and, after 12 months of treatment, randomly allocated to stop treatment, or to continue for as long as there is benefit (the current standard). All patients will be closely monitored for response to treatment and to assess and manage side-effects. Tumour measurements will occur every 12 weeks to 2 years and then 6-monthly to 5 years, as is standard. Patients who are allocated to stop treatment at 12 months will be offered standard care if their disease regrows. This may involve a different immunotherapy, a BRAF inhibitor or another treatment recommended by a specialist. The main goal of this study is to compare how long patients in the two groups live without melanoma re-growing. Patients who decline or accept to be randomised will be invited to take part in an interview to provide insights into the study. There will be no pressure to continue on the study and those who do not will receive standard care. The study was developed by the NCRI Skin Cancer Clinical Studies Group, with patients and doctors contributing. Results will be presented to healthcare professionals and the public at national and international conferences, and published in medical journals. If the trial shows that anti-PD1 drugs can be administered for a shorter time compared with standard recommendations, without compromising their effectiveness and safety, then these findings will change clinical practice worldwide.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS