Abstract
Investigating targeted therapies can be challenging due to diverse tumor mutations and slow patient accrual for clinical studies. The Signature Program is a series of 8 phase 2, agent-specific basket protocols using a rapid study start-up approach involving no predetermined study sites. Each protocol evaluated 1 agent (buparlisib, dovitinib, binimetinib, encorafenib, sonidegib, BGJ398, ceritinib, or ribociclib) in patients with solid or hematologic malignancies and an actionable mutation. The primary endpoint of each study was the clinical benefit rate (ie, complete or partial response, or stable disease) at 16 weeks. A total of 192 individual sites were opened in the United States, with a median start-up time of 3.6 weeks. The most common tumor types among the 595 treated patients were colorectal (9.2%), non-small cell lung adenocarcinoma (9.1%), and ovarian (8.4%). Frequent genetic alterations were in PIK3CA, RAS, p16, and PTEN. Overall, 30 partial or complete responses were observed with 6 compounds in 16 tumor types. The Signature Program presents a unique and successful approach for rapid signal finding across multiple tumors and allowed various agents to be evaluated in patients with rare alterations. Incorporating these program features in conventional studies could lead to improved trial efficiencies and patient outcomes.
Highlights
Genetic profiling has become readily accessible to oncologists in most practice settings in the United States
Patients were enrolled at 192 individual sites (396 protocol openings) including research networks, community sites, and academic institutions (Table 2)
The Signature Program is an industry-sponsored series of compound-specific protocols designed to operationalize an approach for rapid signal finding that could potentially improve patient outcomes and increase efficiencies for further development of the compounds involved
Summary
Genetic profiling has become readily accessible to oncologists in most practice settings in the United States This technology can identify potentially actionable genetic alterations in a tumor, allowing physicians to match individual patients with a targeted therapy [1, 2]. Agents targeting a wide range of molecules and pathways have been discovered, investigating these therapies can be challenging due to the diversity of molecular drivers, www.oncotarget.com even within tumors of the same histology, and the rarity of these patients at any one hospital or clinic. This results in operational inefficiencies, slow patient accrual, and long timelines for clinical trials [2,3,4]. Basket trials use a hypothesis-generating approach in which enrollment and treatment assignment are molecularly driven [3], and a single targeted agent is tested simultaneously in tumors of different histologies that have genetic alterations in the targeted pathway [5]
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