Adverse Reaction to Diagnostic Agents and Kits Nos Clinical Trial
Official title:
A Phase I Study Evaluating the Feasibility of Using Fluorine-19 Cell Sense to Image Human Peripheral Blood Mononuclear Cells In Vivo
Cell-based therapies in the form of stem cell-based or immune cell-based therapies are becoming important treatment options that are either approved for clinical use or are showing promise in clinical trials. One of the issues regarding cell-based therapies is that, once the cells are injected into a subject, there is no easy way to track where they go, assess whether adequate numbers of cells arrive at the intended therapeutic target and for how long they persist at a given location. To address this issue non-invasive imaging methods have been developed using magnetic resonance imaging (MRI). When used with an appropriate cell labelling contrast agent, Cellular MRI can track cells non-invasively in vivo. Detection of cells is accomplished with an inert imaging agent containing the MRI sensitive fluorine-19 (19F) nuclei. The objective of this study is to demonstrate that 19F-MRI is safe to use in humans so that it can subsequently be used to track cell-based immunotherapies in future clinical trials. The long term goal is to be able to quantify immune cell migration to secondary lymphoid tissues and potentially to tumors and correlate to therapeutic outcomes.
Background: None of the currently available Good Manufacturing Practices (GMP)-grade MRI cell
labelling agents are approved for use in Canada. There is one iron oxide nanoparticle GMP
grade preparation that is commercially available but it is not suitable for labelling the
immune cell populations the investigators are interested in tracking in vivo. The
investigators have, instead, chosen to develop the commercially available, GMP-grade
19F-based perfluorocarbon, known as Cell Sense, for the purpose of tracking immune cell-based
vaccine therapies in vivo. This agent has been successful used in a phase I clinical trial in
United States and is approved for a second trial current recruiting, under the oversight of
the FDA.
The cell tracing agent Cell Sense (CS-1000) is an inert, non-metabolizable tracer. As CS-1000
is taken-up and incorporated into the cell traditional pharmacodynamic and pharmacokinetic
analyses in animals and humans are not appropriate, as adsorption and biodistribution will
vary with cell type, and therefore have not been done. In vitro studies of toxicity towards
various cell types did not yield evidence of adverse effects on various cell functions. Cell
Sense also was shown to be non-mutagenic using the Ames and Forward thymidine kinase (TK)
assays. Some limited skin irritation was observed when >2,500 fold more Cell Sense than
expected to be maximally injected into humans was injected intradermally into rats.
Examples of MRI cell tracking labels include superparamagnetic iron oxide nanoparticles and
19F-containing compounds such as perfluorocarbons. The advantage of using cellular MRI to
track cells is that a non-radioactive tracer is used that is suitable for longitudinal
studies. MRI offers 3D imaging with exquisite soft tissue contrast. The additional advantage
of using 19F over iron-based agents is that 19F is a positive, easily quantifiable contrast
cell labelling agent. Furthermore, there is no 19F-background MRI signal in humans whereas
MRI involving iron can be confounded by different imaging artifacts and it is a negative
contrast agent that is difficult to accurately quantify. The investigators are particularly
interested in whether immune cells arrive in secondary lymphoid organs such as lymph nodes.
Study Design:
Open label, dose escalating, single centre, phase I study that will accrue (a) 6 healthy
adults and (b) 6 prostate cancer patients.
Three healthy adults and three prostate cancer patients will be enrolled into the first
cohort. Whole blood (150 ml) will be obtained by venipuncture. After processing of the blood
to obtain peripheral blood mononuclear cells (PBMC), half of the PBMC will be treated with
Cell Sense for 8-24 hours. Given the robustness of our data using 5 donors during dry runs,
the investigators do not propose to compare labeled vs unlabeled cells as release criteria.
However, the investigators will be collecting this data for information and research
purposes. Three million (3 x 106) Cell Sense labeled autologous PBMC will be administered
intradermally to the cohort 1 subjects. The three healthy adults and the 3 prostate cancer
subjects will be tested concurrently.
If no grade 2 or higher adverse events are observed with the 1st cohort, concurrent enrolment
will proceed to recruit a second set of 3 healthy adult subjects and the second set of 3
prostate cancer patients. The second cohort of subjects will be subjected to the same design
but with an escalation of the dose to 2-3 x 107 Cell Sense-labeled autologous PBMC
administered intradermally.
Endpoints:
Primary Endpoints:
Determine the feasibility of using Cell Sense to detect and monitor the migration of PBMC in
humans
Secondary Endpoints:
- Confirm and further optimize the 19F Cell Sense detection and Hydrogen- 1 (1H)
anatomical imaging parameters for imaging using the 19F/1H dual coil.
- Determine if Cell Sense-labeled PBMC migration to the draining lymph node can be
detected.
- Determine if the lymph nodes in the area of interest imaged change in size on the
injected side compared to the contralateral side.
- Quantify the number of Cell Sense-labeled PBMC detected.
- Evaluate safety parameters (toxicity) as defined by:
- adverse events.
- serious adverse events.
- changes in laboratory determination and vital sign parameters as assessed by medical
history, physical examination and clinical laboratory tests.
The following categories will be used to grade any adverse events:
- Grade 1: does not interfere with daily activity,
- Grade 2: interferes with daily activity, no treatment required, except paracetamol,
- Grade 3: prevents daily activity or requires treatment.
- Grade 4: Life-threatening
NIH and FDA (or CTCAE v 4.0) guidelines will be used to determine the severity of adverse
events
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