Evaluation of the Efficacy and Safety of [18F]-ML-10, as a PET Imaging Radiotracer, in Early Detection of Response of Brain Metastases of Solid Tumors to Radiation Therapy.

Overview

The purpose of this study is to evaluate the potential of \[18F\]-ML-10 to serve as an imaging tool for the early detection of response of brain metastases to radiation therapy. Such early detection may help early identification of responsive and non-responsive lesions. The experimental design of the present study aims to evaluate the potential of PET imaging with \[18F\]-ML-10 to address the currently unmet clinical need for very early (within one day)assessment of response to therapy. Currently, response assessment is available only after several weeks or months after completion of therapy, when tumor shrinkage can be detected by anatomical imaging (by MRI). Early detection of tumor response to treatment is now widely-recognized as a highly-desirable goal in oncology, and is respectively the target of intense research worldwide. In the future, the option to know early upon treatment administration, that the treated tumor is a non-responsive, may improve clinical management of patients with brain metastases of solid tumors.

Early assessment of the efficacy of anti-cancer therapy is highly desirable and an unmet need in clinical oncology. Currently, treatment efficacy is mostly measured by following tumor size by anatomical imaging (CT scan or MRI). However, changes in tumor size may be observed only after several weeks to several months after completion of treatment. Meanwhile, in cases where there is no response, the patient is unnecessarily exposed to treatment's side effects, and precious time may be lost before the initiation of an alternative, potentially more beneficial line of therapy. Therefore, there is an urgent and serious need for better tools for monitoring of tumor response to anti-cancer treatments. To address this need, \[18F\]-ML-10, a novel small molecular-weight probe (MW 205) was developed for clinical detection of apoptosis in vivo by positron emission tomography (PET). \[18F\]-ML-10 is a member of the Aposense family of compounds, a novel class of molecular probes for molecular imaging of cell death. The proposed indication for which \[18F\]-ML-10 is being developed is for early assessment of response of solid tumors to radiation and chemoradiation therapy. Previous preclinical and clinical studies have substantiated the safety of \[18F\]-ML-10, its very high stability in vivo, its favorable biodistribution profile, and its efficacy in clinical detection of cell death. In preclinical studies, the selective retention of \[18F\]-ML-10 in the focus of the neurovascular cell death in cerebral ischemia was demonstrated in respective animal models. \[18F\]-ML-10 has been examined in two clinical trials in Uppsala Imanet, Sweden, and has been found safe in administration to healthy subjects and to elderly subjects with acute ischemic cerebral stroke. In these clinical trials, \[18F\]-ML-10 was also found efficacious in the clinical imaging of apoptosis, being either physiological apoptosis as observed in the testes in young healthy males, and pathological cell death, as observed in the brains of patients with acute ischemic cerebral stroke. Additional Phase 2 study demonstrated the suitability and safety of 18F-ML-10, designed to serve as a PET radiotracer for early detection of cellular apoptosis of brain metastases in response to WBRT. The relationship between the early change in 18F-ML-10 uptake by the tumor, observed during or upon completion of treatment, and subsequent tumor shrinkage as observed by MRI eight weeks after the completion of WBRT, was demonstrated.18F-ML-10 demonstrated a good safety profile with no drug-related AEs or any effect on safety parameters.