Official Title
Pre-Treatment of Highly Suspicious Pigmented Skin Lesions With Interleukin-2
Summary:
This study is meant to assess the use of intralesional IL-2 to modulate the immunological
response to suspected melanoma, or melanoma in situ, in an effort to increase lymphocyte
infiltration and decrease disease metastasis.
Patients that are clinically diagnosed with suspected Melanoma or Melanoma in situ will be
assigned to either a treatment or control arm. The treatment group will be subjected to two
intralesional IL-2 injections, whereas the control group will be subjected to two
intralesional injections of saline.
The proteomic and metabolomic profiles of both groups will be analyzed using urine and blood
samples in an effort to assess the systemic immunological response, if any, to the treatment.
Also, upon disease confirmation and staging by a qualified pathologist, lesions will be
assessed for lymphocyte infiltration using immunohistochemical methods.
This study will determine whether pre-treatment of IL-2 on lesions (clinically diagnosed as
melanoma or melanoma in situ) is effective in generating an adaptive immune response, and
whether that immune response may play a role in preventing disease metastasis.
Trial Description
Primary Outcome:
- Assessment of Number of Patients Needed to Obtain Significance
- Assessment of Metastasis
Secondary Outcome:
- Assessment of RNA genetic profile
- Assessment of Systemic Immune Response: Proteomic Analysis
- Assessment of Systemic Immune Response: Metabolomic Analysis
This study is primarily designed to determine if tumour specific immunity can be generated in
patients with highly suspicious pigmented lesions in response to intralesional IL-2, and
whether that immunity can confer resistance to melanoma metastasis. Patients will be
identified by qualified dermatologists and interviews will be held at the surgery clinic (4th
floor Dickson Centre) QEII HSC, NSHA.
The standard wait time from consultation to surgical biopsy is up to 4 weeks. Investigators
will ensure that patients are seen immediately upon notification from participating
dermatologist and all research components of the study are completed within the normally
anticipated wait time. Through utilization of this standard wait time, intralesional IL-2 can
potentially affect an immune response, that otherwise could not be achieved after the biopsy
is completed. Given that the study is conducted within the normal wait time, it doesn't
deviate from the normal standard of care. Following the study protocol, patients will receive
intralesional injections on Day 1(Week 1 Visit) and Day 8 (Week 2 Visit), and excisional
biopsies will be performed on Day 15 (Week 3 Visit), well within the accepted wait time from
consultation to biopsy. The intralesional injections and collection of biospecimens beyond
the biopsy deviate from but does not delay the normal standard of care. Two additional visits
are required in addition to the initial consultation.
This study is a randomized, controlled, double-blind study. Patients with highly suspicious
pigmented lesions will be randomly assigned by an algorithm to one of two groups: 1)
treatment group patients will be treated intralesionally with IL-2 (Proleukin (Aldesleukin),
Novartis Pharmaceuticals Canada Inc.) at a dose of 500,000 International Units (IU) in 0.1ml
of sterilized saline (0.9%, m/v) for 2 treatment cycles 1 week apart (Day 1 and Day 7); 2)
control group patients will be treated intralesionally with sterilized saline (0.9%, m/v) of
the same volume (0.1ml). Randomization will be generated by a Random Block algorithm for each
patient, and instruction preparation for each patient will be sent to pharmacy. IL-2
(Proleukin) will be obtained from Novartis by the pharmacy, paid for by Dr. Carman
Giacomantonio's research services account. The pharmacy will be given instruction to prepare
either IL-2 treatment or injectable control (saline). The pharmacy will assign a codified ID
which will be provided along with the syringe with the patient name labeled as
"Interleukin-2/Placebo" (thus blinding study to clinician and patient). As a pilot study, the
principle of the design is to test the feasibility of proceeding to a larger and more
expensive trial following the methodology and protocol proposed. As such there will be a
minimum of 20 (10 treatment, 10 placebo) participants (up to a maximum of 60). It is
estimated that statistical significance will be reached with 20 patients, however if it is
not reached after 20 patients, an additional 10 (5 treatment, 5 control) patients will be
enrolled. If significance is still not reached after 30 patients, an additional 10 patients
will be enrolled and so on up to a maximum of 60 patients. If after 60 patients, significance
is not achieved then further recruitment under the current protocol would not be logical and
therefore the methodology would need to be revised or study discontinued.
On Day 1 (first treatment) and 15 (excisional biopsy), all patients will have blood (4 vials)
and urine (25-50 ml) samples taken. Local reactions to injections will be monitored for non-
specific signs such as bleeding, arythema, infection, or irritation. Investigators do not
anticipate specific changes in the pigmented lesion related to the injection in this short
time period, however all changes will be noted.
On Day 15, following the second intralesional injection an excisional biopsy will be
performed following standard surgical techniques, as follows: ellipse of skin encompassing
the pigmented lesion extending into the subcutaneous fat will be performed to achieve a
grossly clear but narrow margin of excision. This small defect will be closed primarily with
interrupted sutures. The biopsied specimen will be subsequently evaluated using standard
histological techniques to confirm diagnoses, assess margin status (clear or involved) and
depth of lesion invasion. The depth of lesion invasion will dictate the extent of subsequent
surgical excisions and margin selection according to standard National Comprehensive Cancer
Network (NCCN) guidelines. Pre-biopsy intralesional injections of 0.1ml into the lesion will
not alter dimensions or architecture of the lesion or impact the extent the subsequent biopsy
required. Lesions that are felt to be too large for closure without tissue manipulation or
creation of flaps, will be biopsied using a punch biopsy sampling technique whereby 4mm
diameter discs of tissue from representative areas of the lesion will be taken to confirm the
diagnosis and the depth of invasion. The depth of invasion will dictate the extent and
complexity of subsequent surgery required to remove the lesion and achieve clear margins
according to NCCN guidelines. The biopsied specimen will be processed as follows: using a 22G
needle a fine needle aspiration biopsy will be performed (the needle will be passed through
the centre of the lesion two times) for RNA analysis. The remainder of the tissue will be
sent to pathology for standard histological assessment. The pathologist will also report the
extent of observed tumour infiltrating lymphocytes (TILs) associated with treatment compared
to control injections. Blood and urine will be assessed using metabalomic and proteomic
methods to assess systemic immune response to treatment.
All blood, urine, and lesion biopsy samples will be labeled with a codified number (will not
contain any patient identifying information) and will be immediately transported to Dr.
Carman Giacomantonio laboratory (Sir Charles Tupper Medical Building, 11F11) at Dalhousie
University for storage. Fine needle aspiration of excised samples will be assessed for tumour
genetic and epigeneitic profile. Blood and urine will be assessed for proteomic and
metabolomic profiles, respectively.
A database containing patient IDs and codified numbers will be restricted to the office of
Dr. Giancomantonio (11th floor, VG). This is a locked office, and the data will only be
accessible to the investigators named on this application. This database for will contain
patient IDs, and info on disease status, treatment/control, follow up visits, and sample
analysis
- only info pertinent to the outcome measures. All sample data will be assessed
using codified descriptors and will contain no patient ID info. Once the RNA, proteomic,
metabolomic and pathology data has been analyzed, unmasking treatment and control groups will
be conducted at the VG office of Dr. Giacomantonio, by the named investigators. If the data
reaches statistically significance, the study will not accept any more patients, if not, a
further 10 patients will be incorporated
- to a maximum of 60 patients. Any publications of
study results will be completed devoid of any information that could be used to identify
patients included in the study.
All study participants will receive assessments every 4 months for 2 years and biannual
assessments for years 3 to 5 after the initial intervention to assess disease progression, or
the development of new melanoma, to compare between both treatment and control groups. There
is no standardize test or measurable biomarker to assess established or lasting immunity.
This aspect of the study is identical to the patient assessment conducted as per standard of
care for melanoma patients. Again, any publications of study results will be completed devoid
of any information that could be used to identify patients included in the study.
View this trial on ClinicalTrials.gov
