Ignite Creation Date:
2024-07-17 @ 11:36 AM
Last Modification Date:
2024-10-26 @ 3:34 PM
Study NCT ID:
NCT06488482
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-07-05
First Post:
2024-06-10
Brief Title:
Assessment of Short Immunotherapy After Radical Surgery of High-risk Malignant Melanoma
Sponsor:
Uppsala University
Organization:
Uppsala University
Study Overview
Official Title:
A Prospective Randomized International Multicenter Study to Compare Short Versus Long Adjuvant Immunotherapy After Radical Surgery of Stage IIb-c III and IV Cutaneous Malignant Melanoma Grand SLAM
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
1 Rational Every year around 5000 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 andor 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 Aimobjective 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 23 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
2 Aimobjective 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 23 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
Detailed Description:
A prospective randomized international multicenter study to compare Short versus Long Adjuvant immunotherapy after radical surgery of stage IIb-c III and IV cutaneous malignant Melanoma Acronym Grand SLAM Study Long Adjuvant Melanoma Purpose and aims Between 2013 and 2023 the incidence of cutaneous malignant melanoma CMM increased from 3400 to 5800 casesyear in Sweden Swedish Melanoma Registry SweMR and the number of cases is expected to multiply during the next decades wwwcancerfondense
Since 2017 post-operative treatment with programmed death 1 PD-1 inhibitors for 12 months is routine in the Western world for stage III melanoma patients However a rational for having chosen a 12-month treatment period in the registration studies is lacking
As in other malignancies adjuvant treatment for CMM is most often given in vain as many patients would not relapse even without adjuvant treatment and a large group of patients relapse despite having received adjuvant treatment Noteworthy no randomized study has investigated whether a shorter adjuvant treatment is as effective as 12 months and there is no ongoing study on this subject wwwclinicaltrialsgov
One major disadvantage with a long adjuvant treatment is the increased risk for severe toxicity In the adjuvant studies the observed grade 3-4 toxicity is 10-15 1 2 Another drawback with adjuvant treatment is the resources required including costs The cost for checkpoint inhibitors has been estimated to raise from astonishing 24 billion USD in 2021 to 46 billion USD in 2026 httpswwwresearchandmarketscomreportcheckpoint-inhibitors A large unknown part of this sum could be referred to adjuvant treatments
In conclusion since adjuvant studies on malignant melanoma patients usually have been conducted with pharmaceutical companies as sponsors the important question whether a shorter adjuvant treatment period is as effective as the current one-year schedule has so far not been addressed A shorter treatment period would clearly be advantageous for patients and lead to a substantial reduction in drug costs and health care resources
The aim is to conduct a prospective randomized international multicenter non-inferiority study with systemic immunotherapy comparing treatment for 6 months experimental arm versus treatment for 12 months standard arm in patients having undergone radical surgery for stage IIb-c III and IV CMM The main research question is whether 6 months of immunotherapy in this patient group with high risk of relapse is as effective as the current 12-month scheme The primary clinically relevant outcome variables are distant metastatic free survival DMFS and relapse free survival RFS Substudies investigating the risk with food supplements Melanoma Kost MelKo and biomarkers are also planned
Survey of the field The introduction of adjuvant immunotherapy was based on two phase III studies one for nivolumab Opdivo and the other for pembrolizumab Keytruda Two years ago results were presented from another randomized phase III study assessing immunotherapy in patients operated for thick CMM without lymph node involvement stage IIb-c Treatment with PD-1 inhibitor significantly prolonged RFS compared to placebo In addition results from a randomized phase II study in patients with macroscopic stage III and operable stage IV CMM were published last year showing that the event-free survival was significantly better for patients receiving neoadjuvant PD-1 inhibitor compared to standard adjuvant treatment The ongoing phase III NADINA study aims to confirm the increased benefit of neoadjuvant over adjuvant immunotherapy NCT04949113
There are ongoing studies assessing new drugs in the adjuvant setting for high risk CMM patients Two phase III studies investigate the potential benefit of adding a LAG 3 inhibitor to anti PD-1 treatment In RELATIVITY-098 relatlimab is given together with nivolumab Opdualag NCT05002569 while fianlimab is tested together with cemiplimab Libtayo in the other study NCT05608291 Furthermore whether pembrolizumab in combination with the TIGIT-inhibitor vibostolimab is more effective than pembrolizumab alone is addressed in another large study NCT05665595 Yet another potential registration study is KEYNOTE-942 where patients who have undergone surgery for different stages of high risk CMM receive pembrolizumab combined with injections with a neoantigen mRNA-based vaccine which has shown promising results in a phase 2 study NCT03897881
Study design Research questions PICO High risk CMMTreatment at standard doses with checkpoint inhibitor for 6 monthsStandard treatment with checkpoint inhibitor for 12 monthsDMFS and RFS
Variables and measures DMFS and RFS at 2 years measured in months from start of treatment
The patient must be randomized and start systemic treatment within 12 weeks after final surgery ie excision sentinel node biopsy lymph-node dissection or metastasectomy
Study procedures Randomization procedure Randomization is performed after stratification according to tumor stage Study treatment Adjuvant treatment with current immunotherapy standard drugs at present nivolumab or pembrolizumab will be given in both study groups The standard drugs might change during the study based on upcoming results from ongoing adjuvant studies see above Patients who have undergone neoadjuvant immunotherapy are also eligible for the study providing that a complete pathological response has not been achieved which usually is the case in 20 of the cases 4 Since the neoadjuvant treatment duration is two months these patients will in the standard arm receive 10 months post-operative treatment and in the experimental arm four months only Follow-up visits blood tests and management of side effects will follow current practice based on national guidelines
Study Follow-up Scheme in brief A baseline visit 1-11 weeks after the final surgery is scheduled for study information inclusion and randomization The national routine schedule for follow-up visits will be applied for all patients in the study according to standard practice which normally includes doctor appointments with physical examinations after each scan These visits are important for ethical reasons the results of the scans should always be delivered to the patient in person
The imaging scheme follows national guidelines but computor tomography CT thorax abdomen and brain or iv contrast enhanced whole body FluoroDeoxyGlucose-Position Emission Tomography FDG-PET-CT including brain at baseline and at 6 and 36 months is mandatory see flow-chart below The scan at 36 months is not included in Swedish practice but the minimum scheme is clearly less extensive than currently used in most other countries and in previous adjuvant studies 1 2
Extra diagnostic evaluation imaging and laboratory tests will be allowed for all subjects presenting signs andor symptoms Patients in both groups are instructed to contact their study center if they experience any symptoms suspicious of recurrence
Estimated sample size and power The study design is a non-inferiority trial investigating whether short-term adjuvant immunotherapy is non-inferior to long-term adjuvant immunotherapy standard of care with a non-inferiority margin of 40 being clinically appropriate in this study population
Assumptions for the sample size calculation
DMFS at 2 years was 881 for stage IIb-c patients Keynote 716 study 1
DMFS at 2 years was 70 for stage III-IV patients Checkmate 238 trial 2
DMFS for the sample size will be based on these two measurements with a conservative estimate of 750 at 2 years
Power 80 Alpha level 5 Non-inferiority Margin 4
Accrual time 48 months Follow up time 60 months A sample size of 1792 patients 896 in each study arm will have 80 power with one-sided 95 confidence to declare non-inferiority with a margin of 40 based on a 11 randomization with a corresponding HR of 119 If emerging data demonstrate a higher 3-year DMFS proportion than 75 the sample size may be either re-estimated or the non-inferiority boundary adjusted or if the number of patients lost to follow-up is of concern
Statistical methods Anders Berglund PhD is responsible statistician and the efficacy analyses will include all randomized patients Kaplan-Meier techniques will be used to plot both outcomes Comparison of outcomes between the study arms will be based on a Cox regression model The hazard ratio HR associated with the study arms will be derived along with the associated 95 confidence interval CI The p value for testing the null hypothesis that the HR between the interventions will be greater than or equal to 119 will be derived from this model by comparing the log-likelihood of the fitted model with the log-likelihood of a model where the HR between the groups is set to 119 by use of a likelihood ratio test
Co-primary endpoints
DMFS and RFS at 2 years are co-primary endpoints and to preserve the overall type I error rate comparisons will be performed according to hierarchical testing
1 The alternative non-inferiority hypothesis H11 DMFS short-term treatment is not inferior to long-term treatment standard of care for the first co-primary endpoint DMFS If H11 is accepted ie non-inferiority is declared in 1 then the following hypothesis will be tested
2 The alternative non-inferiority hypothesis H12 DMFS short-term treatment is not inferior to long-term treatment standard of care for the second co-primary endpoint RFS
5 level of significance will be applied with comparisons in the sequential testing procedure being conditional on rejection of the null hypothesis of the previous comparison
Interim analysis The interim analysis will be conducted when two-thirds of the total number of planned subjects are enrolled which is the optimal timing when using the OBrien-Fleming Boundary 5
Organisation The PIs in Sweden have been involved in the TRIM study and the PIs in the other countries are also experienced and active researchers at university centers
The statistician has been responsible for the TRIM study The study coordinator has been involved in several clinical studies over the years The monitors from the research unit at Uppsala University Hospital are very experienced
All principal PIs will be GCP trained There is support for agreements at the research unit at Uppsala University Hospital and that unit is highly competent in GDPR
Study subject information will be handled strictly confidentially and only by authorized personnel When data is processed name and personal number will be replaced by a code
Patients will be recruited from centers all over Sweden and university clinics in other European countries Based on data from the SweMR the expected incidence of stage IIIb-d according to AJCC8 classification at the time of diagnosis is 250 patientsyear With a recruitment rate of 60 150 patients are estimated to be enrolledyear in Sweden only
In addition CMM patients diagnosed with stage III at relapse and patients undergoing radical surgery for stage IV CMM are also eligible We estimate that 50 patients from these subgroups will be includedyear yielding a total recruitment of 200 patientsyear
Time plan
2023 Planning fund-raising writing the final protocol
Spring 2024 Setting up the eCRF and randomization procedure gaining ethical and radiation protection committees and the Swedish Medical Products Agency approvals
2023-2024 Recruitment of centers
2024-2028 Inclusion of patients around 200year Sweden 450year in total
Interim analysis in 2027
2033 Last patient followed-up for 5 years Risk mitigation As the study is a non-inferiority study it will require a large number of participants The Swedish Melanoma Study Group the Nordic Melanoma Group and the European Melanoma Group are in favor of the study We will take advantage of the organization for the ongoing TRIM study which has recruited over 1100 patients despite that only Swedish centers participate More university centers will likely join when the study is up and running
Equipment Need for research infrastructure No equipment is needed for this project Not applicable for this study
Since 2017 post-operative treatment with programmed death 1 PD-1 inhibitors for 12 months is routine in the Western world for stage III melanoma patients However a rational for having chosen a 12-month treatment period in the registration studies is lacking
As in other malignancies adjuvant treatment for CMM is most often given in vain as many patients would not relapse even without adjuvant treatment and a large group of patients relapse despite having received adjuvant treatment Noteworthy no randomized study has investigated whether a shorter adjuvant treatment is as effective as 12 months and there is no ongoing study on this subject wwwclinicaltrialsgov
One major disadvantage with a long adjuvant treatment is the increased risk for severe toxicity In the adjuvant studies the observed grade 3-4 toxicity is 10-15 1 2 Another drawback with adjuvant treatment is the resources required including costs The cost for checkpoint inhibitors has been estimated to raise from astonishing 24 billion USD in 2021 to 46 billion USD in 2026 httpswwwresearchandmarketscomreportcheckpoint-inhibitors A large unknown part of this sum could be referred to adjuvant treatments
In conclusion since adjuvant studies on malignant melanoma patients usually have been conducted with pharmaceutical companies as sponsors the important question whether a shorter adjuvant treatment period is as effective as the current one-year schedule has so far not been addressed A shorter treatment period would clearly be advantageous for patients and lead to a substantial reduction in drug costs and health care resources
The aim is to conduct a prospective randomized international multicenter non-inferiority study with systemic immunotherapy comparing treatment for 6 months experimental arm versus treatment for 12 months standard arm in patients having undergone radical surgery for stage IIb-c III and IV CMM The main research question is whether 6 months of immunotherapy in this patient group with high risk of relapse is as effective as the current 12-month scheme The primary clinically relevant outcome variables are distant metastatic free survival DMFS and relapse free survival RFS Substudies investigating the risk with food supplements Melanoma Kost MelKo and biomarkers are also planned
Survey of the field The introduction of adjuvant immunotherapy was based on two phase III studies one for nivolumab Opdivo and the other for pembrolizumab Keytruda Two years ago results were presented from another randomized phase III study assessing immunotherapy in patients operated for thick CMM without lymph node involvement stage IIb-c Treatment with PD-1 inhibitor significantly prolonged RFS compared to placebo In addition results from a randomized phase II study in patients with macroscopic stage III and operable stage IV CMM were published last year showing that the event-free survival was significantly better for patients receiving neoadjuvant PD-1 inhibitor compared to standard adjuvant treatment The ongoing phase III NADINA study aims to confirm the increased benefit of neoadjuvant over adjuvant immunotherapy NCT04949113
There are ongoing studies assessing new drugs in the adjuvant setting for high risk CMM patients Two phase III studies investigate the potential benefit of adding a LAG 3 inhibitor to anti PD-1 treatment In RELATIVITY-098 relatlimab is given together with nivolumab Opdualag NCT05002569 while fianlimab is tested together with cemiplimab Libtayo in the other study NCT05608291 Furthermore whether pembrolizumab in combination with the TIGIT-inhibitor vibostolimab is more effective than pembrolizumab alone is addressed in another large study NCT05665595 Yet another potential registration study is KEYNOTE-942 where patients who have undergone surgery for different stages of high risk CMM receive pembrolizumab combined with injections with a neoantigen mRNA-based vaccine which has shown promising results in a phase 2 study NCT03897881
Study design Research questions PICO High risk CMMTreatment at standard doses with checkpoint inhibitor for 6 monthsStandard treatment with checkpoint inhibitor for 12 monthsDMFS and RFS
Variables and measures DMFS and RFS at 2 years measured in months from start of treatment
The patient must be randomized and start systemic treatment within 12 weeks after final surgery ie excision sentinel node biopsy lymph-node dissection or metastasectomy
Study procedures Randomization procedure Randomization is performed after stratification according to tumor stage Study treatment Adjuvant treatment with current immunotherapy standard drugs at present nivolumab or pembrolizumab will be given in both study groups The standard drugs might change during the study based on upcoming results from ongoing adjuvant studies see above Patients who have undergone neoadjuvant immunotherapy are also eligible for the study providing that a complete pathological response has not been achieved which usually is the case in 20 of the cases 4 Since the neoadjuvant treatment duration is two months these patients will in the standard arm receive 10 months post-operative treatment and in the experimental arm four months only Follow-up visits blood tests and management of side effects will follow current practice based on national guidelines
Study Follow-up Scheme in brief A baseline visit 1-11 weeks after the final surgery is scheduled for study information inclusion and randomization The national routine schedule for follow-up visits will be applied for all patients in the study according to standard practice which normally includes doctor appointments with physical examinations after each scan These visits are important for ethical reasons the results of the scans should always be delivered to the patient in person
The imaging scheme follows national guidelines but computor tomography CT thorax abdomen and brain or iv contrast enhanced whole body FluoroDeoxyGlucose-Position Emission Tomography FDG-PET-CT including brain at baseline and at 6 and 36 months is mandatory see flow-chart below The scan at 36 months is not included in Swedish practice but the minimum scheme is clearly less extensive than currently used in most other countries and in previous adjuvant studies 1 2
Extra diagnostic evaluation imaging and laboratory tests will be allowed for all subjects presenting signs andor symptoms Patients in both groups are instructed to contact their study center if they experience any symptoms suspicious of recurrence
Estimated sample size and power The study design is a non-inferiority trial investigating whether short-term adjuvant immunotherapy is non-inferior to long-term adjuvant immunotherapy standard of care with a non-inferiority margin of 40 being clinically appropriate in this study population
Assumptions for the sample size calculation
DMFS at 2 years was 881 for stage IIb-c patients Keynote 716 study 1
DMFS at 2 years was 70 for stage III-IV patients Checkmate 238 trial 2
DMFS for the sample size will be based on these two measurements with a conservative estimate of 750 at 2 years
Power 80 Alpha level 5 Non-inferiority Margin 4
Accrual time 48 months Follow up time 60 months A sample size of 1792 patients 896 in each study arm will have 80 power with one-sided 95 confidence to declare non-inferiority with a margin of 40 based on a 11 randomization with a corresponding HR of 119 If emerging data demonstrate a higher 3-year DMFS proportion than 75 the sample size may be either re-estimated or the non-inferiority boundary adjusted or if the number of patients lost to follow-up is of concern
Statistical methods Anders Berglund PhD is responsible statistician and the efficacy analyses will include all randomized patients Kaplan-Meier techniques will be used to plot both outcomes Comparison of outcomes between the study arms will be based on a Cox regression model The hazard ratio HR associated with the study arms will be derived along with the associated 95 confidence interval CI The p value for testing the null hypothesis that the HR between the interventions will be greater than or equal to 119 will be derived from this model by comparing the log-likelihood of the fitted model with the log-likelihood of a model where the HR between the groups is set to 119 by use of a likelihood ratio test
Co-primary endpoints
DMFS and RFS at 2 years are co-primary endpoints and to preserve the overall type I error rate comparisons will be performed according to hierarchical testing
1 The alternative non-inferiority hypothesis H11 DMFS short-term treatment is not inferior to long-term treatment standard of care for the first co-primary endpoint DMFS If H11 is accepted ie non-inferiority is declared in 1 then the following hypothesis will be tested
2 The alternative non-inferiority hypothesis H12 DMFS short-term treatment is not inferior to long-term treatment standard of care for the second co-primary endpoint RFS
5 level of significance will be applied with comparisons in the sequential testing procedure being conditional on rejection of the null hypothesis of the previous comparison
Interim analysis The interim analysis will be conducted when two-thirds of the total number of planned subjects are enrolled which is the optimal timing when using the OBrien-Fleming Boundary 5
Organisation The PIs in Sweden have been involved in the TRIM study and the PIs in the other countries are also experienced and active researchers at university centers
The statistician has been responsible for the TRIM study The study coordinator has been involved in several clinical studies over the years The monitors from the research unit at Uppsala University Hospital are very experienced
All principal PIs will be GCP trained There is support for agreements at the research unit at Uppsala University Hospital and that unit is highly competent in GDPR
Study subject information will be handled strictly confidentially and only by authorized personnel When data is processed name and personal number will be replaced by a code
Patients will be recruited from centers all over Sweden and university clinics in other European countries Based on data from the SweMR the expected incidence of stage IIIb-d according to AJCC8 classification at the time of diagnosis is 250 patientsyear With a recruitment rate of 60 150 patients are estimated to be enrolledyear in Sweden only
In addition CMM patients diagnosed with stage III at relapse and patients undergoing radical surgery for stage IV CMM are also eligible We estimate that 50 patients from these subgroups will be includedyear yielding a total recruitment of 200 patientsyear
Time plan
2023 Planning fund-raising writing the final protocol
Spring 2024 Setting up the eCRF and randomization procedure gaining ethical and radiation protection committees and the Swedish Medical Products Agency approvals
2023-2024 Recruitment of centers
2024-2028 Inclusion of patients around 200year Sweden 450year in total
Interim analysis in 2027
2033 Last patient followed-up for 5 years Risk mitigation As the study is a non-inferiority study it will require a large number of participants The Swedish Melanoma Study Group the Nordic Melanoma Group and the European Melanoma Group are in favor of the study We will take advantage of the organization for the ongoing TRIM study which has recruited over 1100 patients despite that only Swedish centers participate More university centers will likely join when the study is up and running
Equipment Need for research infrastructure No equipment is needed for this project Not applicable for this study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None