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How to design your first-in-human study: patient and tracer selection

Prof. Go van Dam, MD, PhD

Patient selection for your first-in-human trial should be based on the disease you want to treat with your compound. In turn, the patient population influences which tracer and imaging modality serves your purpose best. In general, there are a few guidelines that will help you select the best option for your study.

Which patients should I select for my first in-human study?

In first in-human studies, the compound should be evaluated in patients who have the disease your therapeutic compound intends to treat. For example, a novel antibody for cancer treatment should preferably be tested in patient with the cancer type of interest. Testing a targeted compound in healthy volunteers is not recommended for the initial study. Namely, as there is no cancer present, the on and off-target effect of your compound cannot be determined. Therefore, a reliable estimate of potential therapeutic and off-site side-effects cannot be made in following Phase 1 and 2 clinical studies.

What imaging modality and tracer should I use in my study?

Depending on the selected target population and disease you decided on a suitable imaging modality: nuclear, fluorescent, or bimodal imaging. Respectively, these require radioactive, fluorescent, or both tracers.

When do you use nuclear imaging and radioactive tracers?

Nuclear imaging with radioactive tracers comes with the inherent risk of ionizing radiation. Therefore, medical ethical committees weigh the use of radionuclide with a short and long half-life against the possible benefit for the individual or the population at large. This means that in the case using a radioactive ligand, the disease entity with its accompanying morbidity, and even mortality or prognosis, is weighed against the impact of obtaining your scientific data by using ionizing radiation.

Patients with malignant diseases are considered more eligible for the use of radioactive ligands than patients with benign diseases. Nevertheless, sometimes benign diseases impact daily life to such an extent that radioactive ligands are also used. For example, when it severely impacts morbidity and/or even reduces prognosis.

The advantage of using a radioactive tracer is true quantification regarding whole-body pharmacokinetics (PK) and biodistribution (BD) data. For example, a tracer suited for whole-body PET/CT imaging reveals complete on- and off-target data of the labelled therapeutic compound in the target population of interest.

When do you use fluorescent imaging and fluorescent tracers?

Non-radioactive fluorescent tracers are mainly used in patients with benign disease with a normal prognosis. This way the impact of radioactivity on an otherwise ‘healthy’ patient is avoided. Another advantage of fluorescent imaging is that you can see the binding (tissue biodistribution) of the fluorescent labeled compound on a microscopic level.

As fluorescence imaging is characterized by limited penetration depth, it is best used for superficial diseases. For example, skin diseases. lung or gastrointestinal diseases that can be reached with an endoscope.

When do you use bimodal imaging?

In some cases, you would like to combine whole-body PET/CT for PK/BD data with more in-depth biodistribution at the disease-site. For example, in patients with a solid tumor it is of interest not only to evaluate the targeting of the labeled therapeutic in a whole-body imaging setup for PK and BD data, but also in-depth at the primary tumor at the tissue (microscopic) level.

Is this your goal? Then you should include patients in your first in-human study who will undergo surgery or a biopsy. The whole-body PET/CT imaging data can be obtained the day prior to surgery or biopsy procedure. Next, after excision of the primary tumor or taking the biopsy, the specimen can be examined at the back-table by autoradiography and cross-correlated with histopathology.

The disadvantage is that autoradiography has a limited resolution. Therefore, a fluorescent labeled compound has more advantages compared to a radiolabeled compound in terms of resolution and microscopic cross-correlation with known biomarkers. This raises the choice of either unimodal or bimodal labelling and imaging of a therapeutic compound. Again, this is dependent on the target population (i.e. benign, malignant, prognosis, (co-)morbidity) and the research question to be answered (i.e. PK, BD, microscopic biodistribution).

Generally speaking, it is best to initiate a nuclear labelling and imaging technique followed by a unimodal (or bimodal) fluorescent imaging study to evaluate the distribution of the labelled compound at the microscopic level of the excised specimen or biopsy. In benign diseases, such as chronic inflammatory diseases, you would mostly use a unimodal fluorescent labelling technique. This is due to restrictions in the use of radioactivity in patients with a favorable prognosis.

However, for example in lung cancer, a bimodal labeling technique (radioactive and fluorescent) would be a better fit. Namely, besides whole-body PK/BD data this also provides the opportunity to evaluate by fluorescence molecular endoscopic / bronchoscopic imaging the primary tumor. This can take place through either biopsies or even after resection/surgery.

Key takeaways

  1. Always initiate targeted molecular imaging studies in your target population of interest, delivering true quantitative PK and BD data
  2. Depending on the disease entity, morbidity and prognosis involved, start with a nuclear, fluorescent, or bimodal imaging study
  3. In disease-entities with a favorable prognosis (benign) and ‘easy-to-reach’ diseases such as skin, lung and bowel diseases, a fluorescent labelling strategy is more appropriate
  4. In benign disease with a more limited prognosis, a bimodal labelling strategy seems to be advisable, delivering whole body PK/BD and biodistribution data at the microscopic level in one procedure.
  5. The time-point of imaging are dependent of the half-life of the therapeutic compound, which also determines in case of a radiolabeling strategy the type of radioactive tracer. In case of a fluorescent labelling strategy, the fluorescent dye is not determining the endpoints for imaging, but the therapeutic compound itself. For example, by using a fluorescent labelled antibody, the optimal time of imaging and sampling is 3-5 days after systemic injection of the fluorescent labelled antibody.

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