Local immunotherapy by the synergism of monobenzone and imiquimod cream (MI) for cutaneous metastases in stage III-IV melanoma patients.

Melanoma is an aggressive life-threatening type of cancer that still lacks
effective treatment options for metastatic disease. Some patients also develop
cutaneous metastases which are preferably surgically excised. In patients with
large numbers of cutaneous metastases cold steel surgery no longer is an option
and radiotherapy, isolated limb perfusion (ILP) carbon dioxide laser ablation,
topical immune modifiers and intralesional therapy are used, often in an
experimental, palliative setting. Clinical results vary; most therapies yield
only temporary responses and fail to control disease.
Due to its immunogenicity, melanoma a good candidate for immunotherapy, during
which vitiligo development has been associated with a favourable clinical
outcome. Recently, we developed a new therapy, based on the potent depigmenting
agent monobenzone cream combined with imiquimod (MI). MI treatment induced
effective melanoma-reactive immunity against established melanoma in mice. The
topical immunostimulating compound imiquimod has been used as local therapy for
cutaneous melanoma metastases in several experimental trials, showing an
efficient anti-tumor response and sustained tumor regression after local
application.
In this pilot study we aim at inducing immunity against melanocytes by
skin-bleaching using monobenzone, combined with immunostimulation, using
imiquimod, as means of local immunotherapy for cutaneous melanoma. The
monobenzone/imiquimod (MI) regimen is a low-cost, simple therapy consisting of
two creams. It is a non-invasive therapy and besides local skin irritation and
depigmentation, no systemic side effects are expected to occur. It is
applicable in broad range of patients as it requires no selection of HLA
haplotypes. Based on our preclinical data, we expect MI therapy to be a good
alternative or adjuvant for current local therapies used. The MI compounds have
been registered and used for human skin application in the international
dermatology practise, making the therapy easy applicable in the clinic.
Melanoma patients with stable stage III-IV disease with unresectable cutaneous
metastases will be asked to participate in this study. Treatment will consist
of daily application of monobenzone 20% cream and 5x/week imiquimod cream
(Aldara 5%) to cutaneous melanoma metastases during 12 weeks.

Primary Objective:
• To study the clinical efficacy of local treatment with monobenzone and
imiquimod cream on cutaneous metastases in stage III-IV melanoma patients

Secondary Objective
• To study the induction of local tumor-specific immunity by MI treatment as
measured by the accumulation of melanoma/melanocyte specific T-cells at the
treatment site. In addition, potential systemic immunity will be measured in
the peripheral blood.

Phase 2 open label clinical study.

Daily monobenzone cream and 5x/week imiquimod cream application on cutaneous
metastases during a period of 12 weeks.

Eligible patients will daily apply monobenzone cream and 5x/week imiquimod
cream on cutaneous melanoma metastases. Patients will be seen at the outpatient
clinic biweekly for clinical evaluation of therapy. Before, during and after
treatment (t=0,6,12), a more elaborate clinical examination will be performed
by a senior dermatologist (L. Nieuweboer-Krobotova) to assess general disease
progression. At t =0, 6, 12 also standard haematology and clinical chemistry
analysis will be performed. In addition, extra blood will be drawn for
immunomonitoring purposes in order to perform cellular and serum assays
(t=0,t=6, t=12 ). In order to study the immune response in skin, at baseline a
4 mm punch biopsy from healthy skin next to a lesion to be treated and a 6 mm
biopsy of a melanoma lesion to be treated will be taken. At t =6 and 12 this
will be repeated. Thus, in total 6 biopsies will be taken for immunomonitoring
purposes. If depigmentation (vitiligo) is induced in skin not treated with MI,
an additional 4 mm skin biopsy will be taken from the vitiligo lesion.
Skin bleaching is a common treatment in dermatology for patients with severe
vitiligo universalis. Monobenzone 20% cream has been approved in the US by FDA
in the past for this purpose and is listed as an official depigmentation agent
by the American Academy for Dermatology. In The Netherlands however,
monobenzone cream is not officially registered. Nevertheless, it is listed as
an obsolete compound in the formularium dermatologica. Patients have been
treated with monobenzone 20% cream for depigmentation purposes at the
Netherlands Institute for Pigment Disorders (SNIP), which is affiliated to the
Department of Dermatology of the Academic Medical Center in Amsterdam.
Currently, in the dermatology Department (N. van Geel) in UZ Gent patients are
treated with monobenzone 20% for depigmentation purposes. Monobenzone 20%
cream is known to cause a burning sensation and irritated skin leading to
effective depigmentation. However, most patients treated at the SNIP continued
daily therapy for >6 months without severe skin toxicity. Preclinical data in
mice showed that MI therapy yielded erythematous skin sometimes slightly
exfoliative especially the first 2 weeks post treatment. Other side effects
have not been described.
Aldara 5% imiquimod cream is officially registered for actinic keratosis,
genital warts and superficial basal cell carcinoma. Side effects are
inflammation of the skin and burning sensations, which is of temporary nature.
We will use the treatment regimen for superficial basal cell carcinoma which is
application of Aldara cream 5 times a week. In other experimental studies, no
limiting skin toxicity was seen when imiquimod was applied once or twice daily
on melanoma cutaneous metastases for up to 7 days a week continued for a long
treatment period (>3 months).
As described above, both creams (monobenzone and Aldara) have been used in
experimental clinical studies as well as in daily clinical practice. However,
the combination has not been applied yet. We start treatment in this study with
a treatment scheme based on known dosages being well tolerated in earlier
studies. (See also Investigator Brochure)
Considering the seriousness of the condition and the limited treatment options
available for patients with cutaneous melanoma metastases to control
locoregional disease, we consider this locally applied immunotherapy with known
agents as a relative easy and probably well-tolerable therapy for this category
of patients.