Title of the Study

Minitub: Prospective registry of Sentinel Node (SN)   positive melanoma patients with minimal SN tumor burden who undergo   Completion Lymph Node Dissection (CLND) or Nodal Observation

Objective(s)

With this prospective registry we aim to evaluate   the outcome of patients with a T2-T3 primary melanoma and minimal SN tumor   burden, treated by CLND or nodal observation:

♦   The main objective is to determine if T2-T3 melanoma patients with minimal SN   tumor burden and managed by nodal observation have a 5-year DMFI comparable   to similar patients (T2-T3 melanoma patients with minimal SN tumor burden)   treated by CLND based on historical data from the literature. We will compare   this with SN-negative patients, based on historical data as well.

♦   We will also determine the actual proportion of patients and their   characteristics, who opt to undergo a CLND compared to those, who opt to   undergo nodal observation.

Methodology

This is a prospective registry of all melanoma   patients with minimal SN tumor burden attending the participating sites,   aiming to evaluate whether management of these patients with serial nodal   observation only provides an equal outcome than immediate CLND.

Since the focus of this study is represented by   patients with minimal SN burden and melanoma of intermediate Breslow   thickness, the primary aim population will be composed of T2-T3 (Breslow   thickness 1.01-4 mm)   patients with minimal SN tumor burden. However, T1 and T4 patients with   minimal SN tumor burden will be allowed to enter the registry for descriptive   analyses.

This is not a randomized trial. At each site   melanoma patients with minimal SN tumor burden will be managed with CLND or   serial nodal observation only according to patient decision, and will   be offered the possibility to be included in the registry. Participating   patients will be registered after signing the informed consent form and after   eligibility criteria have been assessed. Data and blood samples for TR will   be collected.

Accrual will last approximately 5 years. Patients   will be followed up for 10 years.

Number of patients

Number planed
  (Statistical design)

Number analyzed

The determination of the sample size was   based on results from a more recent evaluation, where patients with melanoma   of intermediate Breslow thickness, namely T2-T3 (Breslow thickness 1.01 – 4 mm) (N=110), and minimal   SN burden had a 5- and 10-year Melanoma Specific Survival rate of 87% and   80%. As generally, the majority of patients who have distant metastasis die   within 1-2 years, one may estimate that the 5-year Distant Metastasis Free   Interval (DMFI) rate of this group of patients is probably close to 87%. So, for   a comparable group of patients, who would not undertake a CLND, an observed   loss in the 5-year DMFI rate of approximately 3% would be considered as   acceptable; a higher observed loss of the DMFI rate, compatible with a true   5-yr DMFI rate of 80 % or lower would be considered to be inacceptable.

It is expected that 243 patients with an   T2-T3 primary tumor and minimal SN tumor burden choosing a serial nodal   observation will be registered in 5 years. If out of these 243 patients, in   38 (15.7%) patients or less a Distant Metastasis is reported within 5 years   from their study enrollment, so 205 (84.3%) patients or more are DM-Free at   5-years, then one may reject the null hypothesis (the loss in 5-year DMFI   rate is >= 7 %, i.e. 5-year DMFI rate is <= 80%) in favor of the   alternative (5-year DMFI rate is 87%) with a statistical power of 90%   (1-sided alpha=0.05 and beta=0.10, A'Hern design).

As a drop-out of 7% is expected, the   total number of T2-T3 patients to be registered will be increased to 260   patients.

T1 and T4 patients will be excluded from   the primary aim population, but allowed to enter the registry for descriptive   analyses.

Diagnosis and main criteria for   inclusion

♦ Histological evidence of primary cutaneous melanoma  

♦ Metastases solely confined within the SN:

♦ in the sub-capsular space (with no parenchymal   infiltration) and with a maximum diameter of the largest metastasis not   greater than 0.4 mm  

or

♦ regardless of the site, any sub-micrometastasis   with a maximum diameter not greater than 0.1 mm

If there is more than 1 metastatic SN,   the patient will be still eligible provided that all involved SN have minimal   tumor burden, regardless of the amount of positive SNs and the basin of   interest

♦ Absence of clinically apparent metastatic disease   at the time of or before undergoing a SN procedure

♦ No previous SN procedure for locally recurrent   melanoma or uncertain malignant disease, such as atypical Spitz tumor/naevi

♦ Age ≥18 years

♦ No history of a previous melanoma (preceding the   melanoma which prompted the SN biopsy)

♦   No history of any other malignancy within the past 5 years, except for non-melanoma   skin cancer (Basal Cell Carcinomas or Squamous Cell Carcinomas) and in situ   cervical cancer

♦   Absence of any psychological, familial, sociological or geographical   condition potentially hampering compliance with the study protocol and   follow-up schedule; those conditions should be discussed with the patient   before registration in the trial

♦   Before patient registration, written informed consent must be given according   to ICH/GCP, and national/local regulations

Test product, dose and mode of administration

NA

Duration of treatment

NA

Reference therapy, dose and mode of administration

NA

  Criteria for evaluation

Efficacy

♦   Primary endpoint

♦   Distant Metastasis Free Interval (DMFI), defined as the time from SN positive   biopsy until distant metastasis or death due to melanoma, whichever comes   first.

♦   Secondary endpoints

♦   Regional Control Rate (secondary endpoint):

♦   Regional Metastasis Free Interval (RMFI): time from SN positive biopsy (date   of surgical procedure) until regional relapse, on the same basin as the SN   was previously removed.

♦   Regional Control Rate (RCR): rate of lymph node relapse (date of delayed   CLND) in the same basin as the SN was previously removed.

 Regional relapse does not include any local or   in-transit recurrences.

♦   Relapse Free Interval (RFI), defined as the time from SN positive biopsy   until first relapse – regional or distant metastasis – or death due to   melanoma.

♦   Melanoma Specific Survival (MSS), defined as the time from SN positive biopsy   until death due to melanoma.

♦   Overall Survival (OS), defined as the time from SN positive biopsy until death due to any cause.

Safety

Morbidity: rates of wound infections, lymphedema and neurological   damage, based on the clinical judgment of the local physician.

All the main analyses of the efficacy endpoints will be performed on   the intent-to-treat (ITT) population using the ITT principle

The Kaplan-Meier technique will be used to obtain estimates of the   survival-type distributions and the standard error of the estimates will be   computed using the Greenwood   formula.

Medians - if reached - will be presented with a 2-sided (1-alpha)%   confidence interval based on the non-parametric method

All the analyses of the morbidities of interest will be performed on   the safety population. Morbidities (frequency and percentage, unless   otherwise noted) will be reported by arm.

Translational research

To prospectively collect biological material (whole blood, plasma,   serum and tissue) for optional translational research projects to gain   insight into tumor biology, especially in this study, which targets a   specific population of melanoma patients with minimal SN tumor burden.

The objective of the optional translational research studies   associated with this prospective registry is to answer the following   questions:

Are micro-metastases within the minimal tumor burden positive SN   capable of proliferation and migration?

Are any markers of disease dissemination detectable in peripheral   blood?

Are there any markers, which can predict disease recurrence or disease   outcome?

In order to explore these questions, this protocol includes a   prospective collection of biological material (whole blood, plasma, serum and   tissue) from patients who have consented to take part in this research.

Quality of Life

NA

PK – PD

NA