Enabling Precision Medicine The Role of Genetics in Clinical Drug Development: Proceedings of a Workshop (2017) / Chapter Skim
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3 Case Studies in Precision Drug Development
3 Case Studies in Precision Drug Development
Pages 23-42
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From page 23... ...
(Herbst, Hornby) • Novel designs for genetically enabled oncology studies include umbrella trials, which test the impact of different drugs on dif ferent mutations in a single type of cancer, and basket trials, which test the effect of a drug or drugs on one or more muta tions in a variety of cancer types.
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clinical trial, an innovative basket study of a drug to treat solid tumors with specific gene rearrangements. John Staropoli, associate medical director at Biogen, discussed genetic testing and clinical drug development for spinal muscular atrophy (SMA)
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Searching for New Cancer Treatments for Lung Cancer In 1998, ZD1839, an epidermal growth factor receptor (EGFR) yrosine t kinase inhibitor later known in its generic form as gefitinib, was evaluated in a Phase 1 clinical trial in patients with metastatic non-small cell lung, head and neck, prostate, and colorectal cancer that was refractory to conventional chemotherapy or hormonal therapy (Herbst et al., 2002)
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The challenge, he explained, was to match those mutations with a targeted drug. Researchers identified squamous cell carcinoma of the lung, which accounts for about 30 percent of NSCLC, as an area with a therapeutic unmet need and launched the Lung-MAP umbrella trial to address it.
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In addition, industry partners Pfizer, Genentech/Roche, AstraZeneca, MedImmmune, Amgen, Bristol–Myers Squibb, and Foundation Medicine provide funding and therapeutics for the trials as well as advisory contributions. Working with the NCI clinical trials cooperative groups allowed for maximum efficiency in enrolling patients with uncommon or rare, targetable mutations to facilitate analysis and FDA approval, Herbst said.
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, two immunotherapy agents were approved by FDA for the treatment of squamous cell lung cancer. Lung-MAP was adapted to take these agents FIGURE 3-1 Design of Lung-MAP clinical trial.
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To address this, the Lung-MAP leadership created an accrual enhancement committee to help existing sites recruit additional participants and to provide additional support to high-accruing sites through innovative outreach, such as the use of social media, webinars, or promotional videos (see Figure 3-2)
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This allows researchers to reach underserved areas, engage patients and physicians, and bring the therapies under study to the patients, Herbst said. STARTRK-2: A BASKET TRIAL OF ENTRECTINIB FOR THE TREATMENT OF SOLID TUMORS WITH SPECIFIC GENE REARRANGEMENTS As discussed by Herbst, there are two key frameworks for biomarkerenabled clinical trials: umbrella and basket, with Lung-MAP representing the former.
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In other words, he said, entrectinib is active against multiple cancer types, as long as the relevant mechanism is present. Multifactorial Design of the STARTRK-2 Basket Trial A challenge for precision drug development, Hornby said, is how to design a registration-enabling clinical program and accompanying IVD approach that can identify and enroll genetically identified patients who are individually rare within a given tumor histology but collectively numerous.
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working to enable academic medical centers throughout the United States, Europe, and Asia to perform high-sensitivity fusion testing. In developing an IVD, Hornby emphasized, it is important to interact with regulatory agencies very early on in the drug development process.
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At the time of the workshop, there were more than 150 clinical sites across 14 countries on four continents, including more than 70 established clinical sites in the United States and an additional 150 clinical trial sites in the United States that can be activated "just in time" when a new patient is detected in that area. This is facilitated via a site management organization using a central institutional review board (IRB)
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Patient and Provider Awareness Ignyta is working with disease and patient advocacy groups to raise awareness of the STARTRK-2 study and of the potential importance of genetic testing. Outreach strategies include presenting and sharing live data updates at conferences; issuing newsletters, banner ads, and blast emails; conducting search engine optimization to provide informed patients with genetic diagnoses an avenue for finding the study; and maintaining an upto-date clinical trial website tailored to both providers and patients.
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• Design clinical trials to match the underlying disease biology and the mechanism that the drug targets. • Engage regulatory agencies early, and work collaboratively, if possible.
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. Subsequent clinical trials showed results that were comparable to the preclinical animal studies -- specifically that presymptomatic intervention yielded better outcomes than post-ymptomatic s intervention.
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Recommended Uniform Screening Panel, supported by preclinical and clinical data showing that earlier treatment yields better outcomes. USING GENETICS IN CLINICAL TRIALS FOR MITOCHONDRIAL DISEASES Mitochondrial diseases are highly heterogeneous genetic diseases, whose pathogenesis results from a dysfunction in respiratory chain activity and corresponding reduced cellular energy production.
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. These resources are important for collating genomic data in a central location, where they can serve as an invaluable tool for elucidating the underlying genetic causes of mitochondrial disease, identifying modifiers of disease severity, guiding drug discovery efforts, and informing clinical drug development programs, Falk said.
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Biopharmaceutical companies are engaged in drug development and clinical trials, and there are numerous medical centers, clinicians, and esearchers also engaged in drug discovery and clinical research efforts, she r said. Govern ent research agencies, including NIH and the U.S.
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, drugs may behave differently than they would in non-diseased cells or across different disease subtypes, she said. A better understanding of the molecular aberrations underpinning mitochondrial disease and the subsequent mechanistic defects at play could also facilitate preclinical in vitro laboratory drug testing and inform the design of targeted clinical trials in molecularly defined participants.
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SOURCE: Marni Falk, National Academies of Sciences, Engineering, and Medicine workshop presentation, March 8, 2017. Enrolling sufficient numbers of participants in trials for rare diseases can be challenging, Falk said, pointing out that FDA has produced guidance on this issue.9 To address challenges presented by conducting traditional clinical research in rare diseases, Falk described the emerging concept of performing separate single-patient, or "N-of-1," clinical trials.
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The opportunity exists to improve outcomes for rare disease patients by using precision medicine to target underlying molecular aberrations, Falk said, and she provided her perspective on what is needed to make advances in this area: • Train clinicians to diagnose, care for, and effectively manage com plex patients. • Validate common biomarkers to diagnose and monitor disease in subgroups.
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