Using PET Imaging and Radiolabeling in Phase 0 Oncology Trials

Introduction

Phase 0 oncology trials aim to generate early human data to guide therapeutic development. One of the most powerful tools in these trials is Positron Emission Tomography (PET) imaging, especially when paired with radiolabeled compounds. PET enables researchers to visualize how a drug behaves in tumors, confirming whether it reaches the target, engages it, and stays long enough to exert an effect—all at microdose levels.

What is PET Imaging in Clinical Research?

PET (Positron Emission Tomography) is a non-invasive imaging modality that uses radioisotopes to track the distribution of molecules in the body. In oncology, PET is commonly used to monitor tumor activity, response to treatment, and—within Phase 0 studies—drug-target interaction and biodistribution.

Why Use PET in Phase 0 Oncology Studies?

• Determine whether a drug reaches the tumor site
• Measure receptor binding and target occupancy
• Visualize off-target accumulation or undesirable biodistribution
• Support go/no-go decisions for full clinical development

Unlike blood PK data alone, PET provides spatial information critical for targeted cancer therapies.

Radiolabeling Basics

To visualize drugs using PET, the compound must be radiolabeled with a positron-emitting isotope. The most common include:

• Carbon-11 (¹¹C): Half-life ~20 minutes, ideal for small molecules
• Fluorine-18 (¹⁸F): Half-life ~110 minutes, suitable for antibodies or peptides
• Gallium-68 (⁶⁸Ga): Used in radiopharmaceutical diagnostics

Radiolabeling must preserve the drug’s structure and pharmacologic activity to provide meaningful data.

Workflow for PET-Based Phase 0 Trials

1. Selection of Candidate Molecule

• Must have defined molecular target (e.g., kinase, receptor)
• Should exhibit predictable biodistribution in preclinical models

2. Radiochemistry Development

• Label the compound with ¹¹C or ¹⁸F using validated synthesis protocols
• Confirm radiochemical purity and specific activity

3. Preclinical PET Studies

• Conduct rodent or non-human primate imaging to assess tumor uptake
• Evaluate specificity using blocking studies with unlabeled drug

4. Ethics and Regulatory Approval

• Obtain approval for human exposure to radioactive agents
• Follow country-specific radiation safety and nuclear medicine guidelines

5. Human PET Imaging

• Administer radiolabeled microdose (≤100 µg)
• Perform whole-body and region-specific PET scans at defined time points
• Quantify uptake using Standard Uptake Values (SUVs)

Endpoints in PET-Based Phase 0 Trials

• Tumor-to-background ratio: Measures selectivity of drug accumulation
• Time–activity curves: Estimate residence time and clearance
• Receptor occupancy: Compare uptake with and without blocking doses

These endpoints help validate target engagement and justify continued development or modification.

Case Example: EGFR Inhibitor in NSCLC

A novel EGFR inhibitor was radiolabeled with ¹¹C and administered to NSCLC patients in a Phase 0 trial. PET scans revealed selective uptake in EGFR-mutant tumors but not in wild-type tissues. This imaging biomarker helped stratify patients for subsequent trials and supported the compound’s further development.

Challenges and Considerations

• Short half-life isotopes require on-site cyclotron or rapid logistics
• High costs and technical expertise needed for synthesis and validation
• Radiation exposure must be justified under ICRP guidelines

Despite these challenges, the information gained often outweighs the investment—especially for oncology assets where target engagement is make-or-break.

Best Practices

• Engage radiochemistry and nuclear medicine teams early in protocol design
• Conduct preclinical PET feasibility before clinical imaging
• Ensure radiolabeling does not alter pharmacokinetics or binding affinity
• Interpret results in the context of other PK and PD data

Conclusion

PET imaging and radiolabeling techniques are revolutionizing Phase 0 oncology trials. These tools deliver visual proof of mechanism—showing exactly where and how a drug acts in the body. By leveraging PET early in development, sponsors can eliminate weak candidates, strengthen promising ones, and de-risk oncology pipelines using data that speaks louder than blood levels ever could.