Assessment of Short Immunotherapy After Radical Surgery of High-risk Malignant Melanoma
NCT Number: NCT06488482
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE3
Conditions: High-risk Melanoma
Interventions: DRUG: nivolumab or pembrolizumab
Sponsor: Uppsala University
Collaborators: Karolinska University Hospital|Skane University Hospital|Sahlgrenska University Hospital, Sweden|Norrlands University Hospital|Region Örebro County|University Hospital, Linkoeping|Karlstad Central Hospital|Västmanland County Council, Sweden|Gävle Hospital|Falu Hospital
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 1792
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-09
Completion Date: 2033-09

Summary:
1. Rational Every year, around 5,000 people in Sweden are diagnosed with malignant skin melanoma. In the early stages of malignant skin melanoma, the chance of cure with surgery is very good. At a later stage, when the melanoma has become thick and/or has spread, the risk of recurrence is greater despite radical surgery. Therefore, in these cases (even in cases of recurrence after radical surgery), additional treatment with immunotherapy is often given, as it has been shown to reduce the risk of recurrence. Immunotherapy is given for one year based on previous research studies, but it has not been investigated whether a shorter treatment period has the same effect. The hypothesis is that six months of treatment is equally effective, which would have several advantages. The main advantage of a shorter treatment period is that the risk of severe side effects is reduced. A shorter treatment period also means fewer hospital visits for patients. In addition, significant drug costs and other healthcare resources could be saved.
2. Aim/objective The aim of the study is to investigate whether 6 months of treatment with immunotherapy, in addition to radical surgery, for malignant skin melanoma at high risk of recurrence, is as effective in preventing recurrence as 12 months of treatment.

   Secondary objectives:

   To investigate overall survival after 6 versus 12 months of treatment with immunotherapy.

   To investigate the health economic effects of a shorter treatment.
3. Primary endpoints The two primary endpoints of the study are relapse-free survival (RFS) and distant metastatic-free survival (DMFS) and they will be analyzed for the first time in the interim analysis conducted after 2/3 of the estimated number of patients have been included in the study.
4. Secondary outcome measures Overall survival will be analyzed for the first time in the interim analysis. Health economic calculations are planned only at the final stage of the study.
5. Study design This is a randomised phase 3 study, with the aim of showing that treatment in the experimental arm (6 months of immunotherapy) is not inferior to the treatment in the standard arm (12 months of immunotherapy). Patients will be followed up to five years. The visits in the study follow clinical routine.
6. Study population Patients aged ≥18 years undergoing radical surgery for stage IIb-c, III or IV cutaneous malignant melanoma, with a WHO general condition score of 0-1 and deemed tolerable to immunotherapy.
7. Study treatment The study treatment consists of immunotherapy according to clinical routine, currently nivolumab or pembrolizumab given intravenously for either 6 months (experimental treatment) or 12 months (standard treatment). For patients receiving neoadjuvant treatment (additional treatment before surgery), the neoadjuvant treatment time is added to the adjuvant treatment time (additional treatment after surgery) to give a total treatment time of 6 or 12 months. Treatment is followed up according to routine, with imaging (CT or PET-CT) at baseline and after 6 months and at an additional time beyond clinical routine, after 36 months, as well as medical examination at baseline, 6, 12, 18, 24 and 36 months. In case of any signs of relapse, additional examinations are performed as needed. If relapse is detected, the patient is discussed at a local multidisciplinary conference to select the best available treatment for each patient. All study patients are followed for survival status for up to five years.
8. Risk-benefit and ethical issues If this study shows that a shorter treatment period is as effective as the current one-year treatment, it would greatly benefit patients by reducing the risk of side effects and reducing the number of hospital visits. It would also save healthcare resources, which could then be used in other areas. The Swedish Melanoma Patient Association (Melanompatientföreningen) has been consulted and is positive about the study, however they expect that patients may be reluctant to participate for fear of receiving inferior treatment.

However, none of the pivotal studies conducted to date have shown that adjuvant systemic treatment of patients with malignant melanoma significantly prolongs overall survival, but its routine use is based on prolonged relapse-free survival. In addition, a recent cohort study indicated no survival benefit after the introduction of immunotherapy.

To ensure that the experimental arm is not clearly inferior to the standard arm, an interim analysis will be conducted in this study (see above). It is worth mentioning that similar studies to Grand SLAM have been conducted in breast and colon cancer where additional treatment after surgery has been introduced as it not only reduces the risk of recurrence but also prolongs overall survival. These studies have shown that shorter treatment is equally effective.

Primary Outcome Measures: DMFS, Distant Metastasis Free Survival, At 2 years|RFS, Relapse Free Survival, At 2 years
Secondary Outcome Measures: DMFS, Distant Metastasis Free Survival, Up to 5 years|RFS, Relapse Free Survival, Up to 5 years|OS, Overall Survival, Up to 5 years