Innovative Clinical Trial Designs Research Articles

Innovative trial designs and analyses for vaccine clinical development

In the past decades, the world has experienced several major virus outbreaks, e.g. West African Ebola outbreak, Zika virus in South America and most recently global coronavirus (COVID-19) pandemic. Many vaccines have been developed to prevent a variety of infectious diseases successfully. However, several infections have not been preventable so far, like COVID-19, which induces an immediate urgent need for effective vaccines. These emerging infectious diseases often pose unprecedent challenges for the global heath community as well as the conventional vaccine development paradigm. With a long and costly traditional vaccine development process, there are extensive needs in innovative vaccine trial designs and analyses, which aim to design more efficient vaccines trials. Featured with reduced development timeline, less resource consuming or improved estimate for the endpoints of interests, these more efficient trials bring effective medicine to target population in a faster and less costly way. In this paper, we will review a few vaccine trials equipped with adaptive design features, Bayesian designs that accommodate historical data borrowing, the master protocol strategy emerging during COVID-19 vaccine development, Real-World-Data (RWD) embedded trials and the correlate of protection framework and relevant research works. We will also discuss some statistical methodologies that improve the vaccine efficacy, safety and immunogenicity analyses. Innovative clinical trial designs and analyses, together with advanced research technologies and deeper understanding of the human immune system, are paving the way for the efficient development of new vaccines in the future.

DDRE-03. INTERNATIONAL PRECLINICAL DRUG DISCOVERY AND BIOMARKER PROGRAM INFORMING AN ADOPTIVE COMBINATORIAL TRIAL FOR DIFFUSE MIDLINE GLIOMAS

Abstract INTRODUCTION DMG-ACT (DMG- multi-arm Adaptive and Combinatorial Trial) aims to implement a highly innovative clinical trial design of combinatorial arms for patients with diffuse midline gliomas (DMGs) at all disease stages that is adaptive to pre-clinical data generated in ten collaborating institutions. Novel drug and drug combination were tested, predictive biomarkers were identified and incorporated in clinical trial design. METHODS In vitro (n=15) and in vivo (n=8) models of DMGs across ten institutions were used to assess single and combination treatments with ONC201, ONC206, marizomib, panobinostat, 5-Azacytidine, Val-083, GDC0084 and TAK228. In vivo drug toxicity screenings were conducted using larval zebrafish model and murine PDX models. Predictive biomarkers for ONC201 and ONC206 were identified using meta-analysis, and extensive molecular assays including CRISPR, RNAseq, FACS, and IHC. RESULTS Inhibitory concentrations (IC50) were established and validated multiple preclinical models. ONC201 and ONC206, ONC201 and TAK228, ONC201 and GDC0084 showed synergism. In vivo survival assays showed increased survival for: ONC201 (p=0.01), ONC206 (p=0.01), ONC201+ONC206 (p=0.02), and ONC201+panobinostat (p=0.01). Marizomib showed toxicity in murine/zebrafish PDXs models. Murine pharmacokinetic analysis showed peak brain levels of ONC201 and ONC206 above pre-clinical IC50. Molecular testing and analyses of existing drug screen across 537 cancer cell lines validated mitochondrial protease ClpP and ATF4 as ONC201/6 targets. Predictive biomarkers of response to drug were identified. CONCLUSION Thorough preclinical testing in a multi-site laboratory setting is feasible and identified ONC201 in combination with ONC206, TAK228 and GDC0084 as promising therapeutics for DMGs.

The current state of Bayesian methods in nonclinical pharmaceutical statistics: Survey results and recommendations from the DIA/ASA-BIOP Nonclinical Bayesian Working Group.

The use of Bayesian methods to support pharmaceutical product development has grown in recent years. In clinical statistics, the drive to provide faster access for patients to medical treatments has led to a heightened focus by industry and regulatory authorities on innovative clinical trial designs, including those that apply Bayesian methods. In nonclinical statistics, Bayesian applications have also made advances. However, they have been embraced far more slowly in the nonclinical area than in the clinical counterpart. In this article, we explore some of the reasons for this slower rate of adoption. We also present the results of a survey conducted for the purpose of understanding the current state of Bayesian application in nonclinical areas and for identifying areas of priority for the DIA/ASA-BIOP Nonclinical Bayesian Working Group. The survey explored current usage, hurdles, perceptions, and training needs for Bayesian methods among nonclinical statisticians. Based on the survey results, a set of recommendations is provided to help guide the future advancement of Bayesian applications in nonclinical pharmaceutical statistics.

Treatment approaches in relapsed or refractory peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of rare and aggressive non-Hodgkin’s lymphomas. Clinical staging, prognostic scoring, and initial treatment strategies have historically been based on paradigms developed in B-cell lymphomas. Despite primary treatment protocols that are typically anthracycline-based and frequently involve consolidative autologous stem cell transplantation in first remission, many patients develop disease progression. There remains a high unmet medical need for improved treatment strategies in the relapsed or refractory setting. Salvage chemotherapy and stem cell transplantation in those who are suitable has traditionally been the accepted approach, but this remains a minority of the total patient population. As increasing knowledge is gleaned regarding the biological heterogeneity within the various PTCL subtypes, newer targeted agents have been developed, studied, and approved in this small, heterogeneous population of relapsed or refractory disease. Given its success and tolerability in this pretreated population, brentuximab vedotin, an anti-CD30 antibody drug conjugate, was brought earlier in the disease course and is a model for advances in the targeted treatment of PTCL. As others undergo further development in the relapsed setting and successes are brought earlier in the disease course, the outcome for PTCL patients is likely to improve. However, innovative clinical trial designs are crucial for the assessment of targeted agents in this highly heterogeneous population. This review explores the current treatment environment for patients with relapsed and refractory PTCL, including newer strategies such as targeted agents and immunotherapy.

Transforming clinical trials in rheumatology: towards patient-centric precision medicine.

Despite the success of targeted therapies in the treatment of inflammatory arthritides, the lack of predictive biomarkers drives a 'trial and error' approach to treatment allocation, leading to variable and/or unsatisfactory responses. In-depth characterization of the synovial tissue in rheumatoid arthritis, as well as psoriatic arthritis and spondyloarthritis, is bringing new insights into the diverse cellular and molecular features of these diseases and their potential links with different clinical and treatment-response phenotypes. Such progress raises the tantalizing prospect of improving response rates by matching the use of specific agents to the cognate target pathways that might drive particular disease subtypes in specific patient groups. Innovative patient-centric, molecular pathology-driven clinical trial approaches are needed to achieve this goal. Whilst progress is clearly being made, it is important to emphasize that this field is still in its infancy and there are a number of potential barriers to realizing the premise of patient-centric clinical trials.

Moving Immune Therapy Forward Targeting TME.

The host immune system shapes the fate of tumor progression. Hence, manipulating patients' immune system to activate host immune responses against cancer pathogenesis is a promising strategy to develop effective therapeutic interventions for metastatic and drug-resistant cancers. Understanding the dynamic mechanisms within the tumor microenvironment (TME) that contribute to heterogeneity and metabolic plasticity is essential to enhance the patients' responsiveness to immune targeted therapies. Riera-Domingo et al. (Riera-Domingo C, Audige A, Granja S, Cheng WC, Ho PC, Baltazar F, Stockmann C, Mazzone, M. Physiol Rev 100: 1-102, 2020) describe the immune landscape within the TME and highlight the significance of metabolic and hypoxic signatures that impact immune function and response to immunotherapy strategies. Current literature in this field confirms that targeting tumor metabolism and the acidic microenvironment commonly associated with tumors may present viable strategies to modulate the host immune system in favor of response to immune targeted therapies. However, development of better tools to understand tumor-immune interactions and identify mechanisms driving nonresponders, more innovative clinical trial design, and new therapies will need to be identified to move the field forward. Personalized immune therapies incorporating metabolic and microbiome-based gene signatures to influence the therapeutic response and novel methods to generate immunologically "hot" tumors are at the forefront of immunotherapy currently. The combination of these approaches with clinically approved immunotherapies will be valuable moving forward.

Medical research during the COVID-19 pandemic.

The current pandemic of coronavirus disease 2019 (COVID-19) which was first detected in Wuhan, China in December 2019 is caused by the novel coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The virus has quickly spread to a large number of countries leading to a great number of deaths. Unfortunately, till today there is no specific treatment or vaccination for SARS-CoV-2. Most of the suggested treatment medications are based on in vitro laboratory investigations, experimental animal models, or previous clinical experience in treating similar viruses such as SARS-CoV-1 or other retroviral infections. The running of any clinical trial during a pandemic is affected at multiple levels. Reasons for this include patient hesitancy or inability to continue investigative treatments due to self-isolation/quarantine, or limited access to public places (including hospitals). Additional barriers relate to health care professionals being committed to other critical tasks or quarantining themselves due to contact with COVID-19 positive patients. The best research approaches are those that adapt to such external unplanned obstacles. Ongoing clinical trials before COVID-19 pandemic have the potential for identifying important therapies in the long-term if they can be completed as planned. However, these clinical trials may require modifications due a pandemic such as this one to ensure the rights, safety, and wellbeing of participants as well as medical staff involved in the conduction of clinical trials. Clinical trials initiated during the pandemic must be time-efficient and flexible due to high contagiousness of severe acute respiratory syndrome coronavirus 2, the significant number of reported deaths, and time constraints needed to perform high quality clinical trials, enrolling adequate sample sizes. Collaboration between different countries as well as implementation of innovative clinical trial designs are essential to successfully complete such initiatives during the current pandemic. Studies looking at the long term sequalae of COVID-19 are also of importance as recent publications describe multi-organ involvement. Long term follow-up of COVID-19 survivors is thus also important to identify possible physical and mental health sequellae.

Management of glioblastoma: State of the art and future directions.

Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor-treating fields, delivering low-intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood-brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.

Pathology, diagnostics, and classification of medulloblastoma.

Medulloblastoma (MB) is the most common CNS embryonal tumor. While the overall cure rate is around 70%, patients with high‐risk disease continue to have poor outcome and experience long‐term morbidity. MB is among the tumors for which diagnosis, risk stratification, and clinical management has shown the most rapid advancement. These advances are largely due to technological improvements in diagnosis and risk stratification which now integrate histomorphologic classification and molecular classification. MB stands as a prototype for other solid tumors in how to effectively integrate morphology and genomic data to stratify clinicopathologic risk and aid design of innovative clinical trials for precision medicine. This review explores the current diagnostic and classification of MB in modern neuropathology laboratories.

Evolving use of liquid biopsy in non-small-cell-lung cancer patients.

Liquid biopsy is routinely used to detect epidermal growth factor receptor mutations in advanced or metastatic lung cancer, due to some limitations of tissue genotyping, especially at relapse. However, the existence of a non-marginal proportion of oncogene-addicted lung cancers that can benefit from target therapy is rapidly expanding clinical relevance of plasma genotyping. Apart from static assessment of mutations in circulating free DNA, the fact that liquid biopsy is minimally invasive and can be repeated several times makes it a suitable assay for the dynamic monitoring of cancer response to treatment. It is likely that quantitative mutation assessment by liquid biopsy will be increasingly included in the design of innovative clinical trials for patient stratification purposes.

Molecularly Targeted Agents in the Therapy of Pediatric Brain Tumors.

Pediatric brain tumors are the leading cause of cancer-related death in children. Recent advances in sequencing techniques, and collaborative efforts to encode the mutational landscape of various tumor subtypes, have resulted in the identification of recurrent mutations that may present as actionable targets in these tumors. A number of molecularly targeted agents are approved or in development for the treatment of various tumor types in adult patients. Similarly, these agents are increasingly being incorporated into pediatric clinical trials, allowing for a targeted approach to treatment. However, due to the genetic heterogeneity of these tumors, focused clinical trials in pediatric patients are challenging and regulatory hurdles may delay access to therapeutic compounds that are in regular use in adult patients. The tumor site-agnostic clinical development of TRK inhibitors for pediatric solid tumors is a current example of how the combination of genetic testing and innovative clinical trial design can accelerate the clinical development of targeted agents for pediatric patients.

Clinical Development of Molecular Targeted Therapy in Head and Neck Squamous Cell Carcinoma.

A better understanding of cancer biology has led to the development of molecular targeted therapy, which has dramatically improved the outcome of some cancer patients, especially when a biomarker of efficacy has been used for patients’ selection. In head and neck oncology, cetuximab that targets epidermal growth factor receptor is the only targeted therapy that demonstrated a survival benefit, both in the recurrent and in the locally advanced settings, yet without prior patients’ selection. We herein review the clinical development of targeted therapy in head and neck squamous cell carcinoma in light of the molecular landscape and give insights in on how innovative clinical trial designs may speed up biomarker discovery and deployment of new molecular targeted therapies. Given the recent approval of immune checkpoint inhibitors targeting programmed cell death-1 in head and neck squamous cell carcinoma, it remains to be determined how targeted therapy will be incorporated into a global drug development strategy that will inevitably incorporate immunotherapy.

Clinical Trial Design Considerations in the Era of Targeted Therapy

Abstract In the era of targeted therapy use of complex innovative clinical trial designs may be necessary to deliver the treatment to the population that benefits most. This presentation will include some of the examples highlighting the clinical trial considerations and their complexities in the regulatory setting involved in oncology clinical trials.

Advancing Drug Development in Gynecologic Malignancies.

Gynecologic malignancies continue to be a major cause of morbidity and mortality in the United States despite recent advances in oncologic therapies. To realize the promise of immunotherapy and biomarker-driven approaches to improve clinical outcomes for patients, better communication among stakeholders in the drug development and approval pathways is needed. To this end, the FDA-AACR-SGO Drug Development in Gynecologic Malignancies Workshop brought together clinicians, patient advocates, researchers, industry representatives, and regulators in June 2018, to review the state of the science in gynecologic cancers and explore how scientific advances impact approval processes. Topics of discussion and key takeaways are summarized in this Perspectives in Regulatory Science and Policy article. Single-agent immunotherapies have demonstrated variable and often modest response rates among gynecologic cancers. Combination therapies and other novel approaches, such as cell-based therapies, may show improved efficacy compared with single-agent immunotherapies; however, utilizing innovative clinical trial designs will be necessary to progress further. Companion and complementary diagnostics inform physicians of potential benefits of specific therapeutics for patients; however, they serve different functions that have important regulatory implications, thus trialists should understand the distinctions between diagnostic types. PARP inhibitors hold great promise for treating ovarian cancers, both as monotherapies and in combination with chemotherapeutics, other targeted agents, and immunotherapies. Rare gynecologic cancers often exhibit unique molecular characteristics that can serve as effective targets to which novel therapeutics can be developed. This workshop highlighted the importance of future open discussions on scientific and regulatory challenges in drug development for gynecologic malignancies.

Accelerating Pediatric Cancer Drug Development: Challenges and Opportunities for Pediatric Master Protocols.

Although outcomes for children with cancer have significantly improved over the past 40 years, there has been little progress in the treatment of some pediatric cancers, particularly when advanced. Additionally, clinical trial options and availability are often insufficient. Improved genomic and immunologic understanding of pediatric cancers, combined with innovative clinical trial designs, may provide an enhanced opportunity to study childhood cancers. Master protocols, which incorporate the use of precision medicine approaches, coupled with the ability to quickly assess the safety and effectiveness of new therapies, have the potential to accelerate early-phase clinical testing of novel therapeutics and which may result in more rapid approval of new drugs for children with cancer. Designing and conducting master protocols for children requires addressing similar principles and requirements as traditional adult oncology trials, but there are also unique considerations for master protocols conducted in children with cancer. The purpose of this paper is to define the key challenges and opportunities associated with this approach in order to ensure that master protocols can be adapted to benefit children and adolescents and ensure that adequate data are captured to advance, in parallel, the clinical development of investigational agents for children with cancer.

A transatlantic perspective on the integration of immuno-oncology prognostic and predictive biomarkers in innovative clinical trial design.

Immuno-therapeutics aim to activate the body's own immune system against cancer and are one of the most promising cancer treatment strategies, but currently limited by a variable response rate. Biomarkers may help to distinguish those patients most likely to respond to therapy; they may also help guide clinical decision making for combination therapies, dosing schedules, and determining progression versus relapse. However, there is a need to confirm such biomarkers in preferably prospective clinical trials before they can be used in practice. Accordingly, it is essential that clinical trials for immuno-therapeutics incorporate biomarkers. Here, focusing on the specific setting of immune therapies, we discuss both the scientific and logistical hurdles to identifying potential biomarkers and testing them in clinical trials.

Pharmacoproteomic characterisation of human colon and rectal cancer

Most molecular cancer therapies act on protein targets but data on the proteome status of patients and cellular models for proteome‐guided pre‐clinical drug sensitivity studies are only beginning to emerge. Here, we profiled the proteomes of 65 colorectal cancer (CRC) cell lines to a depth of > 10,000 proteins using mass spectrometry. Integration with proteomes of 90 CRC patients and matched transcriptomics data defined integrated CRC subtypes, highlighting cell lines representative of each tumour subtype. Modelling the responses of 52 CRC cell lines to 577 drugs as a function of proteome profiles enabled predicting drug sensitivity for cell lines and patients. Among many novel associations, MERTK was identified as a predictive marker for resistance towards MEK1/2 inhibitors and immunohistochemistry of 1,074 CRC tumours confirmed MERTK as a prognostic survival marker. We provide the proteomic and pharmacological data as a resource to the community to, for example, facilitate the design of innovative prospective clinical trials.

ALL in Older Adults

ALL in Older Adults

Inclusion of pregnant and breastfeeding women in research - efforts and initiatives.

Pregnant and breastfeeding women have been rendered therapeutic orphans as they have been historically excluded from clinical trials. Labelling for most approved drugs does not provide information about safety and efficacy during pregnancy. This lack of data is mainly due to ethico-legal challenges that have remained entrenched in the post-diethylstilbestrol and thalidomide era, and that have led to pregnancy being viewed in the clinical trial setting primarily through a pharmacovigilance lens. Policy considerations that encourage and/or require the inclusion of pregnant or lactating women in clinical trials may address the current lack of available information. However, there are additional pragmatic strategies, such the employment of pharmacometric tools and the introduction of innovative clinical trial designs, which could improve knowledge about the safety and efficacy of medication use during pregnancy and lactation. This paper provides a broad overview of the pharmacoepidemiology of drugs used during pregnancy and lactation, and offers recommendations for regulators and researchers in academia and industry to increase the available pharmacokinetic and -dynamic understanding of medication use in pregnancy.

Innovative Clinical Trial Designs for Precision Medicine in Heart Failure with Preserved Ejection Fraction.

A major challenge in the care of patients with heart failure and preserved ejection fraction (HFpEF) is the lack of proven therapies due to disappointing results from randomized controlled trials (RCTs). The heterogeneity of the HFpEF syndrome and the use of conventional RCT designs are possible reasons underlying the failure of these trials. There are several factors-including the widespread adoption of electronic health records, decreasing costs of obtaining high-dimensional data, and the availability of a wide variety of potential therapeutics-that have evolved to enable more innovative clinical trial designs in HFpEF. Here, we review the current landscape of HFpEF RCTs and present several innovative RCT designs that could be implemented in HFpEF, including enrichment trials, adaptive trials, umbrella trials, basket trials, and machine learning-based trials (including examples for each). Our hope is that the description of the aforementioned innovative trial designs will stimulate new approaches to clinical trials in HFpEF.