Central Nervous System Clinical Trials Research Articles

Disparities in Neuro-Oncology.

Health disparities are preventable differences in the diagnosis, treatment, and outcomes of many diseases, including central nervous system (CNS) tumors. This review will summarize and compile the existing literature on health disparities in neuro-oncology and provide directions for future research and interventions. Patients from historically marginalized groups are more likely to receive inadequate treatment, develop complications, and experience a shorter life expectancy. Financial toxicity can be particularly severe for patients with CNS tumors due to the high costs of treatment. Additionally, CNS clinical trials and research lack diverse representation.

Translational considerations for immunotherapy clinical trials in pediatric neuro-oncology

While immunotherapy for pediatric cancer has made great strides in recent decades, including the FDA approval of agents such as dinutuximab and tisgenlecleucel, these successes have rarely impacted children with pediatric central nervous system (CNS) tumors. As our understanding of the biological underpinnings of these tumors evolves, new immunotherapeutics are undergoing rapid clinical translation specifically designed for children with CNS tumors. Most recently, there have been notable clinical successes with oncolytic viruses, vaccines, adoptive cellular therapy, and immune checkpoint inhibition. In this article, the immunotherapy working group of the Pacific Pediatric Neuro-Oncology Consortium (PNOC) reviews the current and future state of immunotherapeutic CNS clinical trials with a focus on clinical trial development. Based on recent therapeutic trials, we discuss unique immunotherapy clinical trial challenges, including toxicity considerations, disease assessment, and correlative studies. Combinatorial strategies and future directions will be addressed. Through internationally collaborative efforts and consortia, we aim to direct this promising field of immuno-oncology to the next frontier of successful application against pediatric CNS tumors.

Current drug development and trial designs in neuro-oncology: report from the first American Society of Clinical Oncology and Society for Neuro-Oncology Clinical Trials Conference.

Successful drug development for people with cancers of the CNS has been challenging. There are multiple barriers to successful drug development including biological factors, rarity of the disease, and ineffective use of clinical trials. Based upon a series of presentations at the First Central Nervous System Clinical Trials Conference hosted by the American Society of Clinical Oncology and the Society for Neuro-Oncology, we provide an overview on drug development and novel trial designs in neuro-oncology. This Review discusses the challenges of therapeutic development in neuro-oncology and proposes strategies to improve the drug discovery process by enriching the pipeline of promising therapies, optimising trial design, incorporating biomarkers, using external data, and maximising efficacy and reproducibility of clinical trials.

AAV vectors applied to the treatment of CNS disorders: Clinical status and challenges.

In recent years, adeno-associated virus (AAV) has become the most important vector for central nervous system (CNS) gene therapy. AAV has already shown promising results in the clinic, for several CNS diseases that cannot be treated with drugs, including neurodegenerative diseases, neuromuscular diseases, and lysosomal storage disorders. Currently, three of the four commercially available AAV-based drugs focus on neurological disorders, including Upstaza for aromatic l-amino acid decarboxylase deficiency, Luxturna for hereditary retinal dystrophy, and Zolgensma for spinal muscular atrophy. All these studies have provided paradigms for AAV-based therapeutic intervention platforms. AAV gene therapy, with its dual promise of targeting disease etiology and enabling 'long-term correction' of disease processes, has the advantages of immune privilege, high delivery efficiency, tissue specificity, and cell tropism in the CNS. Although AAV-based gene therapy has been shown to be effective in most CNS clinical trials, limitations have been observed in its clinical applications, which are often associated with side effects. In this review, we summarized the therapeutic progress, challenges, limitations, and solutions for AAV-based gene therapy in 14 types of CNS diseases. We focused on viral vector technologies, delivery routes, immunosuppression, and other relevant clinical factors. We also attempted to integrate several hurdles faced in clinical and preclinical studies with their solutions, to seek the best path forward for the application of AAV-based gene therapy in the context of CNS diseases. We hope that these thoughtful recommendations will contribute to the efficient translation of preclinical studies and wide application of clinical trials.

GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways.

Protein kinases (PKs) have been recognized as central nervous system (CNS)-disease-relevant targets due to their master regulatory role in different signal transduction cascades in the neuroscience space. Among them, GSK-3β, FYN, and DYRK1A play a crucial role in the neurodegeneration context, and the deregulation of all three PKs has been linked to different CNS disorders with unmet medical needs, including Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD), and several neuromuscular disorders. The multifactorial nature of these diseases, along with the failure of many advanced CNS clinical trials, and the lengthy approval process of a novel CNS drug have strongly limited the CNS drug discovery. However, in the near-decade from 2010 to 2020, several computer-assisted drug design strategies have been combined with synthetic efforts to develop potent and selective GSK-3β, FYN, and DYRK1A inhibitors as disease-modifying agents. In this review, we described both structural and functional aspects of GSK-3β, FYN, and DYRK1A and their involvement and crosstalk in different CNS pathological signaling pathways. Moreover, we outlined attractive medicinal chemistry approaches including multi-target drug design strategies applied to overcome some limitations of known PKs inhibitors and discover improved modulators with suitable blood–brain barrier (BBB) permeability and drug-like properties.

Salvaging CNS Clinical Trials Halted Due to COVID-19.

The COVID-19 pandemic has halted many ongoing CNS clinical trials, especially in Alzheimer's disease. These long-duration trials involve many stakeholders, especially the patients and their family members, who have demonstrated their commitment to developing new therapeutic interventions for this devastating disease. We certainly do not want to lose all the knowledge we have gained from these ongoing trials because of the pandemic. While some of these trials will need to restart, others can re-start at different points along the trial protocol with substantial protocol amendments. However, there is an urgent need to combine useful information from the completers with those subjects undergoing complex protocols deviations and amendments after re-start. We propose the concept of mechanistic modeling-based virtual twin patients as a possible solution to harmonize the readouts from these complex and fragmented clinical datasets in a biologically relevant way.

A modeling informed quantitative approach to salvage clinical trials interrupted due to COVID-19.

Many ongoing Alzheimer's disease central nervous system clinical trials are being disrupted and halted due to the COVID‐19 pandemic. They are often of a long duration’ are very complex; and involve many stakeholders, not only the scientists and regulators but also the patients and their family members. It is mandatory for us as a community to explore all possibilities to avoid losing all the knowledge we have gained from these ongoing trials. Some of these trials will need to completely restart, but a substantial number can restart after a hiatus with the proper protocol amendments. To salvage the information gathered so far, we need out‐of‐the‐box thinking for addressing these missingness problems and to combine information from the completers with those subjects undergoing complex protocols deviations and amendments after restart in a rational, scientific way. Physiology‐based pharmacokinetic (PBPK) modeling has been a cornerstone of model‐informed drug development with regard to drug exposure at the site of action, taking into account individual patient characteristics. Quantitative systems pharmacology (QSP), based on biology‐informed and mechanistic modeling of the interaction between a drug and neuronal circuits, is an emerging technology to simulate the pharmacodynamic effects of a drug in combination with patient‐specific comedications, genotypes, and disease states on functional clinical scales. We propose to combine these two approaches into the concept of computer modeling‐based virtual twin patients as a possible solution to harmonize the readouts from these complex clinical datasets in a biologically and therapeutically relevant way.

Risk-Based Data Monitoring: Quality Control in Central Nervous System (CNS) Clinical Trials.

Monitoring the quality of clinical trial efficacy outcome data has received increased attention in the past decade, with regulatory guidance encouraging it to be conducted proactively, and remotely. However, the methods utilized to develop and implement risk-based data monitoring (RBDM) programs vary, and there is a dearth of published material to guide these processes in the context of central nervous system (CNS) trials. We reviewed regulatory guidance published within the past 6 years, generic white papers, and studies applying RBDM to data from CNS clinical trials. Methodologic considerations and system requirements necessary to establish an effective, real-time risk-based monitoring platform in CNS trials are presented. Key RBDM terms are defined in the context of CNS trial data, such as "critical data," "risk indicators," "noninformative data," and "mitigation of risk." Additionally, potential benefits of, and challenges associated with implementation of data quality monitoring are highlighted. Application of methodological and system requirement considerations to real-time monitoring of clinical ratings in CNS trials has the potential to minimize risk and enhance the quality of clinical trial data.

Statistical challenges in a regulatory review of cardiovascular and CNS clinical trials

There are several challenging statistical problems identified in the regulatory review of large cardiovascular (CV) clinical outcome trials and central nervous system (CNS) trials. The problems can be common or distinct due to disease characteristics and the differences in trial design elements such as endpoints, trial duration, and trial size. In schizophrenia trials, heavy missing data is a big problem. In Alzheimer trials, the endpoints for assessing symptoms and the endpoints for assessing disease progression are essentially the same; it is difficult to construct a good trial design to evaluate a test drug for its ability to slow the disease progression. In CV trials, reliance on a composite endpoint with low event rate makes the trial size so large that it is infeasible to study multiple doses necessary to find the right dose for study patients. These are just a few typical problems. In the past decade, adaptive designs were increasingly used in these disease areas and some challenges occur with respect to that use. Based on our review experiences, group sequential designs (GSDs) have borne many successful stories in CV trials and are also increasingly used for developing treatments targeting CNS diseases. There is also a growing trend of using more advanced unblinded adaptive designs for producing efficacy evidence. Many statistical challenges with these kinds of adaptive designs have been identified through our experiences with the review of regulatory applications and are shared in this article.

A structured interview guide for global impressions: increasing reliability and scoring accuracy for CNS trials

BackgroundThe clinical global impression of severity (CGI-S) scale is a frequently used rating instrument for the assessment of global severity of illness in Central Nervous System (CNS) trials. Although scoring guidelines have been proposed to anchor these scores, the collection of sufficient documentation to support the derived score is not part of any standardized interview procedure. It is self evident that the absence of a standardized, documentary format can affect inter-rater reliability and may adversely affect the accuracy of the resulting data.MethodWe developed a structured interview guide for global impressions (SIGGI) and evaluated the instrument in a 2-visit study of ambulatory patients with Major Depressive Disorder (MDD) or schizophrenia. Blinded, site-independent raters listened to audio recorded SIGGI interviews administered by site-based CGI raters. We compared SIGGI-derived CGI-S scores between the two separate site-based raters and the site-independent raters.ResultsWe found significant intraclass correlations (p = 0.001) on all SIGGI-derived CGI-S scores between two separate site-based CGI raters with each other (r = 0.768) and with a blinded, site-independent rater (r = 0.748 and r = 0.706 respectively) and significant Pearson’s correlations between CGI-S scores with all MADRS validity comparisons for MDD and PANSS comparisons for schizophrenia (p- 0.001 in all cases). Compared to site-based raters, the site-independent raters gave identical “dual” CGI-S scores to 67.6% and 68.2% of subjects at visit 1 and 77.1% at visit 2.ConclusionWe suggest that the SIGGI may improve the inter-rater reliability and scoring precision of the CGI-S and have broad applicability in CNS clinical trials.

Double-Blind, Efficacy Evaluation of Gadobenate Dimeglumine, a Gadolinium Chelate With Enhanced Relaxivity, in Malignant Lesions of the Brain

The diagnostic efficacy of gadobenate dimeglumine (Gd BOPTA) was compared with that of gadodiamide (Gd DTPA-BMA) in patients with primary malignant tumors or metastases of the brain. A subset of patients was evaluated from the 410 enrolled in the United States in phase III central nervous system clinical trials with gadobenate dimeglumine. From these trials, there were 82 patients with intraaxial malignant neoplasms of the brain, the focus of the current study. Patients were randomized to one of three incremental dosing regimens. Imaging with gadodiamide at doses of 0.1 and 0.3 mmol/kg was compared with gadobenate dimeglumine at doses of 0.05 and 0.15 mmol/kg and at doses of 0.1 and 0.2 mmol/kg. The on-site physician, patient, and all off-site reviewers were blinded to the agent injected and the administered dose. Scans were obtained before contrast administration and within 5 minutes after administration of each dose. The two contrast injections in any one patient were separated by 15 minutes. An independent laboratory performed signal intensity measurements. The magnetic resonance (MR) films were evaluated for level of diagnostic information, number of lesions detected, and confidence in MR imaging diagnosis by two independent board-certified neuroradiologists unaffiliated with any study site. The lesion-to-brain signal intensity ratio after a dose of 0.1 mmol/kg gadobenate dimeglumine was higher than that after a dose of 0.1 mmol/kg gadodiamide, with this result statistically significant (P = 0.02). After the second dose of contrast, results were comparable in all three groups. The level of diagnostic information contained on the MR films increased significantly for all three groups from pre- to postcontrast for both the first and second administered doses. In between-group comparisons, the level of diagnostic information was similar after the first contrast dose for all three dosing regimens. This was also true after the second contrast dose. For all three groups, the number of lesions detected increased significantly postdose (whether first or second). Confidence in MR diagnosis increased from predose to postdose for all three groups, with no statistically significant difference between groups. Gadobenate dimeglumine, used at slightly lower doses, is comparable to gadodiamide in terms of efficacy in imaging of malignant intraaxial brain lesions. As with other gadolinium chelates, higher doses (0.15 and 0.2 mmol/kg) of gadobenate dimeglumine offer greater diagnostic information.