Signature program: a platform of basket trials

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.

When should we order a next generation sequencing test in a patient with cancer?

“…Frequent genetic alterations were observed in PIK3CA, RAS, p16 , and PTEN . Overall, 30 partial or complete responses were observed with 6 of the compounds studied, in 16 tumor types [23] . The authors concluded that the Program was a successful approach, because it led to rapid signal finding, reduced patient exposure to toxicity, and substantially shortened trial start-up times .…”

Reporting of master protocols towards a standardized approach: A systematic review

“…While basket trial definitions (n = 35) [[1], [2], [3], [4], [5],11,13,15,18,[23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48]] were consistent on some aspects, such as that basket trials study multiple disease types (n = 34), other features such as the number of interventions to be studied were inconsistent. Approximately half of the reviewed publications (n = 18) [1,2,4,5,11,13,15,25,30,31,33,35,38,39,41,42,45,49] specified that basket trials are designed to evaluate a single intervention, while around a third (n = 10) [3,18,23,[26], [27], [28], [29],36,40,43] stated that they can evaluate multiple interventions. The remaining definitions (n = 7) specified both [37,44,47] or neither [32,34,46,48].…”

A Bayesian basket trial design accounting for uncertainties of homogeneity and heterogeneity of treatment effect among subpopulations

“…Since basket trials are considered an exploratory approach for signal finding on treatment effect across subpopulations, 12,32 prior information on the heterogeneity and homogeneity of treatment efficacy would be generally limited during trial planning. The proposed method does not require specification of prior information on the heterogeneity and homogeneity of treatment efficacy; however, it requires only two probabilities (eg, π 1 and π 2 ) corresponding to null and alternative models of the true response rates before beginning the trials.…”