Imaging Agent Development and Early Phase Clinical Trials

 PET scans of  lymph nodes with lymphoma in the groin and armpit (red areas).

PET scans of lymph nodes with lymphoma in the groin and armpit (red areas). Credit: Jorge Carrasquillo, NIH

NCI’s Cancer Imaging Program (CIP) is responsible for oversight and funding of oncology imaging research, such as the application of MRI (magnetic resonance imaging) and PET (positron emission tomography) in clinical trials. However, the larger goal of CIP is the development of new imaging techniques and their application to the development of new therapies for the cancer patient.

“Imaging is an interdisciplinary science consisting of technology, imaging drugs, data extraction methods, and analytical techniques that are designed to monitor living systems—from cells to humans—and to improve our understanding of cancer from discovery to clinical care,” said James Tatum, M.D., associate director, CIP, Division of Cancer Treatment and Diagnosis, NCI.

“One of the most exciting challenges today is the explosion in cancer biology data, including genomic and proteomic data that must be integrated into the complex systems that define cancer. Imaging is unique in its ability to extract real-time data from a living system without destruction or significant perturbation of that system. Realizing this capability is the key to understanding and treating the aberrant systems that constitute cancer,” said Tatum.

Specifically, imaging provides the ability to non-invasively extract spatially defined data continuously, and from multiple areas, simultaneously. For example, with kinetic PET imaging, researchers can study the uptake, retention, and elimination of a new drug in multiple organs and tumors in the same subject. In addition, imaging can be used to study the action of a drug on a target. In some respects this data is complementary to traditional pharmokinetic and pharmodynamic studies which examine how a drug acts in the body, but in others the data is unique—even beyond the advantage of not requiring invasive bio-sampling.

Imaging and Phase 0 Clinical Trials

Although imaging agents that are classified as drugs by the FDA are usually given in very small quantities, there is significant preclinical development and testing that is required before they can be utilized in human studies. This includes such things as scale-up synthesis of clinical grade imaging drugs, appropriate safety testing, and required regulatory filing.

The earliest in-man studies of new drugs—including imaging agents—are phase 0 trials, sometimes referred to as early phase I trials, and are a fairly new concept in clinical trial design. Phase 0 trials currently play an important role in CIP’s activities.

In phase 0 trials (for imaging agents) the goal is the development of assays that are verified in preclinical models that can be applied to first in-human studies to evaluate relevant biomarkers related to the target of interest. These studies, as would be expected, precede the established phase I through III trials that are required to establish safety and efficacy. These first in human studies are performed on a very small number of eligible trial participants. One of the underlying rationales for  phase 0 studies of imaging agents is the intrinsic shortcomings of some animal models, specifically, the transferability of animal model data to humans.

The information from phase 0 trials can be pivotal to making early decisions about the feasibility and strategy for further development of a drug or imaging agent. The identification of poor candidates at this stage not only saves limited resources but also prevents further testing in humans. On the other hand, in the case of promising candidates, the identification and optimization of biomarkers is critical to successful development.

NCI’s Infrastructure and Expertise to Perform Phase 0 Trials

NCI is fortunate to have access to a wide range of infrastructure and expertise to perform the required preclinical work, including animal model imaging, regulatory filing, protocol development, and review prior to the start of a clinical trial. NCI also has the ability to subsequently perform phase 0 trials in the NCI Molecular Imaging Clinic, which is a unique facility custom designed to handle phase 0 trials that include imaging.

CIP is currently managing five imaging projects in support of phase o trials. Each is in various stages of development and each provides different challenges with different degrees of complexity. Examining a sample project gives a good idea of the necessary interactions and parallel processes that would be difficult to manage without the access and coordination possible at NCI.

A Breast Cancer Drug Used in Phase 0 Imaging Research

Lapatinib is a small molecule drug that is approved by the FDA for use in patients with advanced breast cancer. This drug is a dual tyrosine kinase inhibitor. Tumor sensitivity to lapatinib as reported in preclinical work directly relates to HER2 expression.

HER2 is a cell membrane enzyme that is normally involved in pathways leading to cell growth. It is encoded within the genome by HER2/neu, a protein that is involved in normal cell growth.

While the drug has shown good activity clinically in HER2 positive tumors—cancer tumors that overexpress the HER2/neu protein and show an increased risk for recurrence—treatment failure and resistance does occur and the mechanism for resistance is not fully understood.

A phase 0 trial using imaging to study lapatinib offers an opportunity to understand the factors that contribute to drug response in humans by evaluating the pharmokinetics of the drug by administration of radiolabeled drug and monitoring of target changes with an imaging assay.

The first challenge for researchers was to develop a radiolabeled version of lapatinib by substituting the positron emitting element 18F (which can be detected by a PET scanner) for the stable fluorine in the molecule. This difficult task was accomplished by the NIH Imaging Probe Development Center. The precursor and technology platform was then transferred to the NCI/CIP radiochemistry facility at Frederick, Maryland for radio-synthesis and characterization.

Concurrent with the technology platform transfer to Frederick, an animal study protocol was developed at the NCI Small Animal Imaging Facility to perform imaging in various xenographs (tissue derived from one species and grafted into another) with a range of lapatinib sensitivities. As part of the animal study protocol, an imaging assay for HER2 expression is to be verified in the same animal model.

Initial results from the animal imaging study provided data to make a ‘go decision’ leading to further studies to estimate human radiation exposure from the imaging agent and production of clinical grade labeled agent, both of which are required to file an Exploratory Investigational New Drug (EIND) application with the FDA. Assuming FDA acceptance and protocol approval, this phase 0 concept will become an actual clinical trial that will be performed in the NCI Molecular Imaging Clinic.

Print This Post Print This Post

Comments are closed.