The primary objective is to determine whether adjuvant treatment with natural dendritic cell (nDC) vaccination, after complete radical lymph node dissection or sentinel node procedure in stage IIIB and IIIC melanoma patients, improves recurrence-…
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Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this study is to determine whether adjuvant nDC
vaccination improves 2-year RFS rate as compared to placebo in patients with
resected stage IIIB or IIIC melanoma. Based on previous results on adjuvant DC
vaccination in stage IIIB and IIIC melanoma patients, we expect that 70% of the
DC vaccinated patients will remain recurrence free for 2 years. The anticipated
2-year RFS rate of the control arm is 50%.
Secondary outcome
The secondary objectives are to compare the median RFS, 2-year and median
overall survival, adverse events profiles (safety), determine immunological
responses and factors responsible for the variability of immune responses,
quality of life and health economic aspects of nDC vaccination versus placebo.
Background summary
Melanoma is a highly malignant melanocyte-derived tumor. Standard treatment for
patients with stage III disease consists of radical lymph node dissection or
sentinel-node procedure in case of limited positive nodal disease. With this
treatment patients still have a high risk of local recurrence and development
of distant metastases. The life expectancy is therefore limited, with a 5-year
overall survival rate of 67% for stage IIIA, 53% for stage IIIB and 26% for
stage IIIC melanoma. No standard adjuvant therapy is currently available that
results in a clear clinical benefit.
We have explored dendritic cell-based immunotherapy. The therapy consists of
antigen-loaded autologous DC that are administered to patients with the
intention of inducing antigen-specific T and B cell responses. We have now
vaccinated well over 300 melanoma patients with monocyte-derived dendritic cell
(moDC) vaccines and proved that DC therapy is safe with minimal side effects.
Recently we showed that functional anti-melanoma-specific immune responses are
observed in about 30% of the metastatic melanoma patients and in about 70% of
the stage III melanoma patients, a difference probably due to lower tumor
burden in stage III melanoma patients, hence less immunosuppression.
Furthermore, we observed an significantly higher overall survival in stage III
melanoma patients after adjuvant DC vaccination compared to 209 matched
controls, 63.6 months versus 31.0 months (p=0.018; hazard ratio 0.59; 95%CI
0.42-0.84).
However, moDC may not be the optimal source of DC for DC vaccination studies,
due to extensive culture periods and compounds required to differentiate them
into mature moDC. Natural DC (nDC), consisting of plasmacytoid DC and myeloid
DC may be a good alternative since they do not require extensive culture
periods. In our previous clinical trials in metastatic melanoma patients using
the nDC subsets separately both immunological outcomes, as well as clinical
outcomes are promising. Interestingly, the subsets seem to complement each
other functions and act synergistically for optimal immune responses. We
therefore hypothesize that co-administration of both subsets may generate more
potent and longer-lasting anti-tumor immune responses in cancer patients
compared to vaccination with the administration of an individual nDC subset.
After the decades of optimization of DC vaccines it is of importance to
re-explore DC vaccination in a randomized fashion in melanoma. Therefore, the
aim of this study is to show the potential of nDC vaccination on clinical
outcome in high risk melanoma patients.
Study objective
The primary objective is to determine whether adjuvant treatment with natural
dendritic cell (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.
The secondary objectives are to compare the median RFS, 2-year and median
overall survival, adverse events profiles (safety), determine immunological
responses and factors responsible for the variability of immune responses,
quality of life and health economic aspects of nDC vaccination versus placebo.
Study design
This is a phase 3, randomized, double-blind, interventional study of nDC
vaccination versus placebo. Subjects will be randomized 2:1 and stratified by
stage of disease, BRAF mutation status, HLA-A2 status, adjuvant radiotherapy
and nDC production centre.
Intervention
Patients in both arms will undergo a leukapheresis in cycle 1. The patients in
the nDC vaccination arm (arm A) will receive 3 nDC injections intranodally
(8x106 nDC) and 4 DTH challenges with nDC (0.5x106 nDC) intradermally injected
at the back of the patient. Patients in the placebo arm (arm B) will receive 3
placebo injections intranodally and 4 DTH challenges with placebo intradermally
injected at the back of the patient. In both arms punch biopsies will be taken
from each DTH site (6mm) and normal skin (3mm) 48 after the DTH challenges. If
patients remain clinically free of melanoma, this cycle will be repeated twice
with 6 months intervals without a leukapheresis and DTH skin test.
Study burden and risks
Based on the experience with the pDC and myDC vaccination separately, we expect
that the single and combined DC vaccine will be well tolerated. Common and
expected side effects of DC vaccination are usually mild and include flu-like
symptoms and local reaction at injection site, both not greater than common
toxicity criteria grade 1-2, which are expected in approximately 30% of the
patients receiving dendritic cells. Besides a leukapheresis in cycle 1, the 3
intranodal study administrations per cycle (maximum of 3 cycles) and the DTH
tests including skin biopsies in each cycle, upon multiple visits around 100 ml
of blood will be drawn for immunomonitoring and safety purposes.
Geert Grooteplein 26
Nijmegen 6525GA
NL
Geert Grooteplein 26
Nijmegen 6525GA
NL
Listed location countries
Age
Inclusion criteria
- Histologically confirmed, resected stage III cutaneous melanoma, classified as stage IIIB or IIIC disease (AJCC 2009).
- Radical lymph node dissection 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.
- Absence of distant metastases
Exclusion criteria
- No concomitant use of immunosuppressive drugs orally or intravenously. Topical and intranasal steroids are permitted.
- No uncontrolled infectious disease
- No autoimmune disease. Patients with type 1 diabetes mellitus, hypothyroidism after autoimmune thyroiditis and skin disorders are not excluded.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | EUCTR2015-005322-19-NL |
CCMO | NL55823.000.15 |