Trial Title:
Assessment of Short Immunotherapy After Radical Surgery of High-risk Malignant Melanoma
NCT ID:
NCT06488482
Condition:
High-risk Melanoma
Conditions: Official terms:
Melanoma
Pembrolizumab
Nivolumab
Study type:
Interventional
Study phase:
Phase 3
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
1:1 randomization
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
nivolumab or pembrolizumab
Description:
See above
Arm group label:
12 months of immunotherapy
Arm group label:
6 months of immunotherapy
Other name:
Opdivo and Keytruda
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.
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 cases/year in Sweden (Swedish Melanoma Registry, SweMR) and the number of
cases is expected to multiply during the next decades (www.cancerfonden.se).
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 (www.clinicaltrials.gov).
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
(https://www.researchandmarkets.com/report/checkpoint-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 CMM/Treatment at standard doses with
checkpoint inhibitor for 6 months/Standard treatment with checkpoint inhibitor for 12
months/DMFS 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, i.e. 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 i.v. 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 and/or 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 4.0% being clinically
appropriate in this study population.
Assumptions for the sample size calculation:
- DMFS at 2 years was 88.1% 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 75.0% 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 4.0% based on a 1:1
randomization with a corresponding HR of 1.19. 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 1.19
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 1.19 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., i.e., 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
O'Brien-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 patients/year. With a
recruitment rate of 60%, 150 patients are estimated to be enrolled/year 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 included/year, yielding a total recruitment of 200 patients/year.
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 200/year (Sweden), 450/year 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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Provision of written informed consent for participation.
2. ≥ 18 years of age.
3. Performance status ECOG/WHO 0-1.
4. Adequate organ functions as per standards for immunotherapy.
5. Radical surgery for CMM (including acral) stage IIb-c, III (including in transit)
and IV. Stage III CMM patients with unknown primary and stage IIb-c CMM patients who
have not undergone sentinel node procedure are eligible.
6. A complete physical examination within 28 days prior to randomization
7. Previous adjuvant treatment with BRAF + MEK inhibitors is allowed.
8. Neoadjuvant treatment with immunotherapy for two months (currently pembrolizumab
every third weeks three times or nivolumab every fourth week two times) is allowed
providing that a complete or near complete pathological response was not achieved
and patients with clear progressive disease according to the pathology report are
not eligible.
9. All participants who have not received neo-adjuvant treatment must have disease-free
status documented by radiological assessment within 28 days prior to randomization
while 6 weeks is sufficient for neo-adjuvant treated patients.
10. Participants must be off immunosuppressive doses of systemic steroids (>10 mg/day
prednisone or equivalent) for a minimum of 14 days prior to study drug
administration.
11. Sufficient renal function for radiological assessments with i.v. contrast.
12. Peri-operative radiation therapy is allowed.
13. Patients who experience a locoregional lymph node relapse, i.e. stage III disease or
operable stage IV at a time-point later than primary diagnosis are welcome to
participate.
Exclusion Criteria:
1. The patient is, in the opinion of the investigator, assessed as unfit to receive
systemic adjuvant treatment.
2. Serious and/or uncontrolled medical disorder that in the opinion of the investigator
is contraindicated.
3. An active, known, or suspected autoimmune disease. Participants with type I diabetes
mellitus, hypothyroidism requiring hormone replacement only and skin disorders (such
as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are eligible.
4. Life-expectancy less than 2 years due to concurrent disease (e.g., cardiac disease
and liver cirrhosis).
5. Inability to provide informed consent or refusal to do so.
6. Inability to comply with the study protocol.
7. Participation in other clinical trials interfering with the current study protocol.
8. Existing or previous malignancies within the past 5 years (except for in situ breast
and in situ cervical cancer, melanoma in situ, malignant melanoma, non-melanoma skin
cancer and low risk prostate cancer).
9. Pregnancy or planned pregnancy.
10. Ocular and mucosal melanoma.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
September 2024
Completion date:
September 2033
Lead sponsor:
Agency:
Uppsala University
Agency class:
Other
Collaborator:
Agency:
Karolinska University Hospital
Agency class:
Other
Collaborator:
Agency:
Skane University Hospital
Agency class:
Other
Collaborator:
Agency:
Sahlgrenska University Hospital, Sweden
Agency class:
Other
Collaborator:
Agency:
Norrlands University Hospital
Agency class:
Other
Collaborator:
Agency:
Region Örebro County
Agency class:
Other
Collaborator:
Agency:
University Hospital, Linkoeping
Agency class:
Other
Collaborator:
Agency:
Karlstad Central Hospital
Agency class:
Other
Collaborator:
Agency:
Västmanland County Council, Sweden
Agency class:
Other
Collaborator:
Agency:
Gävle Hospital
Agency class:
Other
Collaborator:
Agency:
Falu Hospital
Agency class:
Other
Source:
Uppsala University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06488482
