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

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii61-ii62
Author(s):  
Justyna Przystal ◽  
Sridevi Yadavilli ◽  
Christina Coleman Abadi ◽  
Viveka Nand Yadav ◽  
Sandra Laternser ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Trial Design ◽  
Meta Analysis ◽  
Clinical Trial Design ◽  
Predictive Biomarkers ◽  
Pharmacokinetic Analysis ◽  
Molecular Testing ◽  
Zebrafish Model

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.

scholarly journals DIPG-64. INTERNATIONAL PRECLINICAL DRUG DISCOVERY AND BIOMARKER PROGRAM INFORMING AN ADOPTIVE COMBINATORIAL TRIAL FOR DIFFUSE MIDLINE GLIOMAS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii300-iii300
Author(s):  
Justyna M Przystal* ◽  
Sridevi Yadavilli* ◽  
Christina Colman Abadi* ◽  
Viveka Nand Yadav ◽  
Sandra Laternser ◽  
...  
Keyword(s):  
Clinical Trial Design ◽  
Predictive Biomarkers ◽  
Drug Efficacy ◽  
Pharmacokinetic Analysis ◽  
Molecular Testing ◽  
Combination Drug ◽  
Combination Treatments ◽  
Drug Assays

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 eight collaborating institutions. The goals of the team are to: i) rapidly identify and validate promising drugs for clinical use, and ii) predict biomarkers for promising drugs. METHODS In vitro (n=15) and in vivo (n=8) models of DMGs across seven institutions were used to assess single and combination treatments with ONC201, ONC206, marizomib, panobinostat, Val-083, and TAK228. In vivo pharmacokinetic assays using clinically relevant dosing of ONC201, ONC206, and panobinostat were performed. Predictive biomarkers for ONC201 and ONC206 were identified using extensive molecular assays including CRISPR, RNAseq, ELISA, FACS, and IHC. RESULTS Inhibitory concentrations (IC50) were established and validated across participating sites. In vivo validation of single and combination drug assays confirmed drug efficacy as 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 stress and ATF4 as the main targets induced by ONC201/6. CONCLUSION Thorough preclinical testing in a multi-site laboratory setting is feasible and identified ONC201 in combination with ONC206 as promising therapeutics for DMGs. Preclinical and correlative-clinical studies are ongoing.

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

2018 ◽  
Vol 52 ◽  
pp. 158-165 ◽  
Author(s):  
M. Morfouace ◽  
S.M. Hewitt ◽  
R. Salgado ◽  
K. Hartmann ◽  
S. Litiere ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Predictive Biomarkers

scholarly journals Status and Recommendations for Incorporating Biomarkers for Cutaneous Neurofibromas into Clinical Research

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012426
Author(s):  
Deeann Wallis ◽  
Anat Stemmer-Rachamimov ◽  
Sarah Adsit ◽  
Bruce Korf ◽  
Dominique Pichard ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Working Group ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Predictive Biomarkers ◽  
Neurofibromatosis Type ◽  
Proteomic Data ◽  
Group A ◽  
Existing Data

Objective:To summarize existing biomarker data for cutaneous neurofibroma (cNF) and inform the incorporation of biomarkers into clinical trial design for cNFs.Methods:The cNF working group, a subgroup of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) consortium, was formed to review and inform clinical trial design for cNFs. Between June 2018 and February 2020, the cNF working group performed a review of existing data on genetic biomarkers for cNFs in the setting of Neurofibromatosis Type 1 (NF1). We also reviewed criteria for successful biomarker application in the clinic. The group then met during a series of meetings to develop a consensus report.Results:Our systematic literature review of existing data revealed a lack of validated biomarkers for cNFs. In our report, we summarize the existing signaling, genomic, transcriptomic, histopathologic and proteomic data relevant to cNF. Finally, we make recommendations for incorporating exploratory aims for predictive biomarkers in clinical trials through biobanking samples.Conclusion:These recommendations are intended to provide both researchers and clinicians with best practices for clinical trial design to aid in the identification of clinically validated biomarkers for cNF.

Integrating radiomics into clinical trial design

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Jessica J. Waninger ◽  
Michael D. Green ◽  
Catherine Cheze Le Rest ◽  
Benjamin Rosen ◽  
Issam El Naqa
Keyword(s):  
Clinical Trial ◽  
Trial Design ◽  
Clinical Trial Design

Avenues to Precision Oncology

2020 ◽  
pp. 36-45
Author(s):  
Alexander Meisel
Keyword(s):  
Precision Medicine ◽  
Trial Design ◽  
Ad Hoc ◽  
Molecular Targets ◽  
Clinical Trial Design ◽  
Predictive Biomarkers ◽  
Precision Oncology ◽  
Companion Diagnostics ◽  
Bona Fide ◽  
The One

Until recently, the clinical management of cancer heavily relied on anatomical and histopathological criteria, with ad hoc guidelines directing the therapeutic choices in specific indications. In the last years, the development and therapeutic implementation of novel anticancer therapies significantly improved the clinical outcome of cancer patients. Nonetheless, such cutting-edge approaches revealed the limitation of the one-size-fits-all paradigm. The newly discovered molecular targets can be exploited either as bona fide targets for subsequent drug development, or as tools to precision medicine, in the form of prognostic and/or predictive biomarkers. This article provides an overview of some of the most recent advances in precision medicine in oncology, with a focus on novel tissue-agnostic anticancer therapies. The definition and implementation of biomarkers and companion diagnostics in clinical trials and clinical practice are also discussed, as well as the changing landscape in clinical trial design.

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