Choosing the Assessment Criteria

The presentation of disease at baseline and over time can vary significantly depending on the type of brain tumor. Despite glioblastomas being solitary tumors, they often have different morphologies and may contain multiple regions in different stages of malignant degeneration. Hence, it is critical to select and diligently implement the right criteria for disease assessment in glioblastoma clinical trials (i.e. RANO-HGG vs. RANO-LGG vs. modified RANO (mRANO) vs. immunotherapy RANO (iRANO)).

RANO 2.0 criteria authors intend to unite all the earlier RANO versions into one, for all grades of IDH-mutated gliomas, and other glial tumors, regardless of the specific therapies being evaluated. However, this unification still holds some additional considerations due to the complexities of brain tumors and their potential treatments.

For example, for HGG the enhancing disease as captured in contrast-enhanced T1w imaging would represent the disease, and bi-dimensional measurement on the most representative slice would be sufficient to capture the cross-sectional area, i.e., the state of the disease and its change over time. For LGG, the entirety of the tumor (i.e. including non-enhancing) as captured in T2w/FLAIR may be needed and due to the characteristics of the typical LGG over time, volumetric characterization at each time point may still be needed

Highlights from RANO 2.0

• Use post-radiotherapy scan as baseline:Especially for newly diagnosed glioblastoma, the post-radiotherapy MRI (~4 weeks post from the end of radiotherapy) as opposed to post-surgery MRI, will be utilized as baseline to evaluate the disease progression and/or treatment response. This approach assumes that clinical trial randomization will take place after radiotherapy. For patients not undergoing radiotherapy, the post-surgery MRI will be used as the baseline. The duration between the baseline scans and the initiation of therapy should not exceed 2 weeks.

• Confirmation of PD scan 3 months post-radiotherapy: Additional confirmatory scans (at 4- or 8-week intervals) are required for treatment decisions due to high incidence of pseudoprogression within 12 weeks after radiotherapy. In addition, for treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended to prevent pre-mature progression determination.

• Two-dimensional measurements remain the accepted approach for quantification of disease cross-sectional area for capturing the enhancing lesions for HGG as well as non-contrast enhancing lesions for LGG. The more advanced approaches, including volumetric assessments, diffusion and/or perfusion imaging or PET imaging, remain valuable options to provide further insight. However, these additional assessments come with challenges regarding the implementation of acquisition and assessments within multi-site clinical trials, resulting in additional cost and study complexity.

• Clinical deterioration as well as corticosteroid information remain crucial components for response assessment. Further guidance on the adaptation of the Neurologic Assessment in Neuor-Oncology (NANO) scale can benefit further standardization of assessments.

Conclusion

The introduction of RANO 2.0 is a positive step for glioblastoma assessments within clinical trials as it will drive consistency for researchers and regulators in the evaluation of product efficacy. However, for optimum efficacy assessment, it remains critical for researchers to consider the specifics of the patient population, study design, as well as the treatment approach, and to adapt the needed nuances in the application of criteria.

Advanced imaging technology is enabling us to answer critical questions as we strive to understand disease pathophysiology and inform the clinical development of new medical treatments. Here, we review how Calyx Medical Imaging is providing valuable insights intended to help researchers further understand the mechanisms in the brain that are associated with addictive behavior.

Calyx is delivering expertise in imaging within a clinical trial framework along with our partner, Ceretype Neuromedicine, Inc. to help researchers further understand the brain’s reward system through functional MRI (fMRI). The study we are currently working on aims to map out how brain mechanisms differ between people with addictive behaviors and those without and how that deviation will change over time with medication.

fMRI enables us to study neuronal activity as well as functional connectivity across the entire brain. This approach demonstrates that when nerve cells are active in certain areas of the brain, there’s an increase in blood flow to those areas, resulting in measurable changes. Moreover, if multiple brain regions are activated simultaneously, they are assumed to have a strong functional connectivity among them. Hence, fMRI allows us to look at activity within and connectivity among those brain regions responsible for mediating the physiological and cognitive processing of reward. Addiction treatments may target these regions associated with the brain’s reward network.

Participants’ brain activity can be captured while at rest or while observing images of items that depict addictions, as well as images of less addictive and/or unrelated items. Further analyses of MR images reveal the differences in brain activity and connectivity of those who are addicted compared to healthy participants. The same approach can be employed to investigate the objective change as a response to addiction treatment.

Historically, due to the complexity of image acquisition and analysis, fMRI has not been successfully used within the clinical trial framework. However, by combining Ceretype’s proven capabilities in acquiring high-quality data with a high signal-to-noise ratio and innovative data analysis pipelines with Calyx’s scientific and operational expertise, it is possible to obtain statistically significant results illustrating possible treatment effects.

Contact us to learn about Calyx Medical Imaging’s expertise and how our advanced solutions and services can help you optimize clinical trial imaging and meet your clinical development objectives.

Recent research highlights the importance of developing and utilizing cost-effective, sensitive, and specific plasma biomarkers using commercially available assays for screening subjects in Alzheimer’s Disease (AD) clinical trials. This approach overcomes limitations associated with the clinical diagnosis of AD, especially in individuals with mild cognitive impairment or dementia who exhibit typical AD symptoms lacking Aβ pathology.

There is evidence that targeting p-tau217 in blood has yielded the best results as a diagnostic and prognostic tool for assessing longitudinal change. Studies showed that the p-tau217 assay outperformed MRI and showed comparable performance with CSF biomarkers in detecting Aβ PET positivity and tau PET positivity.

Utilizing the approach recommended by Alzheimer’s Association guidelines, commercial immunoassay has shown high positive and negative predictive accuracy at screening in clinical studies.

Learn about other advances in Alzheimer’s Disease research, including why the FDA’s recognition of using medical imaging as an objective biomarker is a big step forward for the clinical development of new AD treatments.