The root causes of pharmacodynamic assay failure

Ferry-Galow, Katherine V.; Makhlouf, Hala R.; Wilsker, Deborah; Lawrence, Scott M.; Pfister, Thomas D.; Marrero, Allison M.; Bigelow, Kristina M.; Yutzy, William H.; Ji, Jiuping J.; Butcher, Donna; Gouker, Brad; Kummar, Shivaani; Chen, Alice; Kinders, Robert J.; Parchment, Ralph E.; Doroshow, James H.

doi:10.1053/j.seminoncol.2016.06.006

Cited by 11 publications

(16 citation statements)

References 21 publications

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“…A retrospective analysis of research biopsy tissues obtained in four early-phase clinical trials at the National Cancer Institute (NCI) Developmental Therapeutics Clinic found that only 83 of 112 18-gauge needle biopsies performed for pharmacodynamic studies using slidebased analyses (74%) met assay quality control criteria; reasons for failure included extensive necrosis or fibrosis, no or insufficient tumor content, and/or inadequate tissue quality for morphologic assessment. 1,2 The most common reason for failure was the absence of tumor ( Fig 1); 44% of the biopsy specimens evaluated contained , 25% viable tumor cells, rates comparable to those reported at other clinical centers. 3 These insufficiency rates are somewhat higher than those previously cited for diagnostic biopsies [3][4][5][6] because of the greater amount of tumor and control of preanalytical variables required for successful pharmacodynamic analyses.…”

Section: Introductionsupporting

confidence: 73%

What Can Be Done to Improve Research Biopsy Quality in Oncology Clinical Trials?

Ferry-Galow

Datta

Makhlouf

et al. 2018

JOP

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Purpose: Research biopsy specimens collected in clinical trials often present requirements beyond those of tumor biopsy specimens collected for diagnostic purposes. Research biopsies underpin hypothesis-driven drug development, pharmacodynamic assessment of molecularly targeted anticancer agents, and, increasingly, genomic assessment for precision medicine; insufficient biopsy specimen quality or quantity therefore compromises the scientific value of a study and the resources devoted to it, as well as each patient’s contribution to and potential benefit from a clinical trial. Methods: To improve research biopsy specimen quality, we consulted with other translational oncology teams and reviewed current best practices. Results: Among the recommendations were improving communication between oncologists and interventional radiologists, providing feedback on specimen sufficiency, increasing academic recognition and financial support for the time investment required by radiologists to collect and preserve research biopsy specimens, and improving real-time assessment of tissue quality. Conclusion: Implementing these recommendations at the National Cancer Institute’s Developmental Therapeutics Clinic has demonstrably improved the quality of biopsy specimens collected; more widespread dissemination of these recommendations beyond large clinical cancer centers is possible and will be of value to the community in improving clinical research and, ultimately, patient care.

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Section: Introductionsupporting

confidence: 73%

What Can Be Done to Improve Research Biopsy Quality in Oncology Clinical Trials?

Ferry-Galow

Datta

Makhlouf

et al. 2018

JOP

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“…Successful pharmacodynamic studies resulting in reportable data require a multitude of elements (2–4). Usually this is in the realm of an early-phase clinical trial, as understanding the mechanism of action and selection of biomarkers—both predictive and prognostic—are critical to successful development of a drug, for example rucaparib and crizotinib (5,6).…”

mentioning

confidence: 99%

“…The clinical trial protocol must include all relevant biomarker assay requirements including appropriate biopsy specimen collection parameters and timepoints as well as a thorough statistical plan including justification for the designated number of patients and biopsy specimens. Without these critical steps, the results may not be interpretable and therefore, unreportable (2–4).…”

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confidence: 99%

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The use of research biopsies in oncology trials: challenges and controversies

Ferry-Galow¹,

Chen²

2019

J Hosp Manag Health Policy

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“…There are many underlying reasons for this variability. Uneven sampling of tumor tissue may result in inconsistent tumor content, confounding the interpretation of assay results in preand post-drug treatment samples (17,18). When biopsies are converted to lysates this becomes an even greater challenge.…”

Section: Introductionmentioning

confidence: 99%

Effective implementation of novel MET pharmacodynamic assays in translational studies

et al. 2017

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MET tyrosine kinase (TK) dysregulation is significantly implicated in many types of cancer. Despite over 20 years of drug development to target MET in cancers, a pure anti-MET therapeutic has not yet received market approval. The failure of two recently concluded phase III trials point to a major weakness in biomarker strategies to identify patients who will benefit most from MET therapies. The capability to interrogate oncogenic mutations in MET via circulating tumor DNA (ctDNA) provides an important advancement in identification and stratification of patients for MET therapy. However, a wide range in type and frequency of these mutations suggest there is a need to carefully link these mutations to MET dysregulation, at least in proof-of-concept studies. In this review, we elaborate how we can utilize recently developed and validated pharmacodynamic biomarkers of MET not only to show target engagement, but more importantly to quantitatively measure MET dysregulation in tumor tissues. The MET assay endpoints provide evidence of both canonical and non-canonical MET signaling, can be used as "effect markers" to define biologically effective doses (BEDs) for molecularly targeted drugs, confirm mechanism-of-action in testing combination of drugs, and establish whether a diagnostic test is reporting MET dysregulation. We have established standard operating procedures for tumor biopsy collections to control preanalytical variables that have produced valid results in proof-of-concept studies. The reagents and procedures are made available to the research community for potential implementation on multiple platforms such as ELISA, quantitative immunofluorescence assay (qIFA), and immuno-MRM assays.

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The root causes of pharmacodynamic assay failure

Cited by 11 publications

References 21 publications

What Can Be Done to Improve Research Biopsy Quality in Oncology Clinical Trials?

What Can Be Done to Improve Research Biopsy Quality in Oncology Clinical Trials?

The use of research biopsies in oncology trials: challenges and controversies

Effective implementation of novel MET pharmacodynamic assays in translational studies

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