Melanoma Patients Immunized With Natural DenDritic Cells

Study Overview
=================
Brief Summary
-----------------
The aim of this study is to determine whether adjuvant treatment with nDC vaccination, after complete radical lymph node dissection or sentinel node procedure in stage IIIB and IIIC melanoma patients, improves recurrence-free survival (RFS) as compared to treatment with matching placebo.

Detailed Description
-----------------
This is a phase 3, randomized, double-blind, interventional study of nDC vaccination versus placebo. Dendritic cell-based immunotherapy consists of antigen-loaded autologous DC that are administered to patients with the intention of inducing antigen-specific T and B cell responses and proved safe with minimal side effects. Natural DC (nDC) consist of plasmacytoid DC and myeloid DC. Subjects will be randomized 2:1 and stratified by stage of disease, adjuvant radiotherapy, BRAF mutation status, HLA-type and nDC production centre. The treatment will be continued for a maximum of 1.5 years or until recurrence of disease, unacceptable toxicity or withdrawal from the study.

Official Title
-----------------
A Randomized, Double--Blind, Placebo-Controlled Phase III Study to Evaluate Active Immunization in Adjuvant Therapy of Patients With Stage IIIB and IIIC Melanoma With Natural Dendritic Cells Pulsed With Synthetic Peptides.

Conditions
-----------------
Melanoma (Skin)

Intervention / Treatment
-----------------
* Biological: nDC vaccination
* Biological: placebo injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Eligibility Criteria: at least 18 years of age. Histologically confirmed stage III cutaneous melanoma, classified as IIIB or IIIC disease (AJCC 2009). Patients with completely resected in-transit and/or satellite metastases and patients with unknown primary melanoma are allowed in this trial. Radical lymph node dissection involved site with complete resection or sentinel node procedure (in case of patients without RLND because of limited sentinel-node positive disease) of melanoma as documented on the operating report and pathology report with at least the minimal levels excised as stated in national guidelines. Radical lymph node dissection involved site with complete resection or sentinel node procedure (in case of patients without RLND because of limited sentinel-node positive disease) must be performed within 12 weeks prior to start of study. Recovered from definitive surgery (e.g. no uncontrolled wound infections or indwelling drains). Absence of distant metastases must be documented by a CT scan of the chest and abdomen (including pelvis) or a Positron Emission Tomography (PET) scan, the scan should have been performed within 6 weeks before surgery or after surgery prior to inclusion. In addition, a physical exam after surgery must be performed also excluding distant metastases. No clinical evidence for brain metastasis. If brain metastases are clinically suspected, a CT or Magnetic Resonance Imaging (MRI) scan of the brain must exclude brain metastases. World Health Organization (WHO) performance status of 0 or 1 at time of randomization. Adequate hematologic, renal and liver function as defined by laboratory values performed within 4 weeks of randomization. No second malignancy in the previous 5 years, with the exception of adequately treated carcinoma in-situ and basal or squamous cell carcinoma of the skin. No concomitant use of immunosuppressive drugs orally or intravenously. Topical and intranasal steroids are permitted. No uncontrolled infectious disease, i.e. negative testing for HIV, HBV, HCV and syphilis. No autoimmune disease such as, but not limited to, inflammatory bowel disease, multiple sclerosis, and lupus. Patients with type 1 diabetes mellitus, hypothyroidism after autoimmune thyroiditis and skin disorders are not excluded. No serious (bleeding and clotting) condition that may interfere with safe leukapheresis. No pregnant or lactating women. No Women Of Child-Bearing Potential (WOCBP) who are unwilling or unable to use an acceptable method to avoid pregnancy for up to 8 weeks after the last administration of the treatment. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea > 12 consecutive months]. Patients must have absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions must be discussed with the patient before registration in the trial. Expected adequacy of follow-up. Written informed consent.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nDC vaccination arm<br>Patients in the nDC vaccination arm will receive a maximum of 3 cycles each consisting of 3 nDC injections intranodally (3-8x10^6 nDC). | Biological: nDC vaccination<br> <br> |
| Placebo Comparator: placebo arm<br>Patients will receive a maximum of 3 cycles each consisting of 3 placebo injections intranodally. | Biological: placebo injection<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival rate | The primary objective of this study is to determine whether adjuvant nDC vaccination, after complete radical lymph node dissection or sentinel node procedure in stage IIIB and IIIC melanoma patients, improves 2-year RFS rate as compared to treatment with matching placebo. Defined as the percentage of patients who are alive and without recurrence of melanoma 2 years after randomization. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival | Median RFS duration will be assessed by physical examination and CT of the chest and abdomen every 3-12 months, or on clinical indication, during 5 years. | 2 years and 5 years | 
| Overall survival |  | 2-years and median | 
| Tumor specific T-cell response |  | week 1, week 9, week 10, week 31, week 39, week 57, week 65, week 78, month 24, month 60 | 
| Quality of Life Questionnaires |  | baseline, week 14, week 26, month 12, month 24, month 36, month 60 | 
| Costs (direct and indirect) of treatment |  | 2 years | 
| QALY | A cost-effectiveness acceptability curve will be derived that is able to evaluate efficiency by using different tresholds (willingness to pay) for a QALY. | 2 years | 
| Adverse Events related to treatment |  | 1,5 year |