Abstract 3597: Experiences and lessons from innovative dose escalation designs in early-phase oncology

Abstract

Abstract Introduction: Since 2010, Roche-sponsored early development trials in oncology have successfully implemented innovative dose escalation (D/E) strategies including modified continual reassessment methods (CRM) and other Bayesian adaptive designs. Compared to standard 3+3 designs, these methods allow for flexibility to address a variety of clinical questions and to estimate more accurately a molecule’s maximum tolerated dose (MTD). However, CRM designs are sometimes considered as complex and difficult to implement and are not easily understood by clinicians (Le Tourneau et al., 2009, Iasonos et al. 2014). Here, we share our experiences and learnings from the initial exploration, introduction, and wide-spread implementation of CRM in early oncology clinical trials. Methods: We conducted a thorough internal review of the current statistical methods and clinical strategies used in CRM designs. In addition, we systematically collected feedback on the internal experience through surveys and interviews of participating biostatisticians, pharmacologists, clinicians and operations managers. Results: CRMs using two parameter logistic regression models and escalation with overdose control (Neuenschwander et al., 2008) are the most commonly used CRM designs in Roche-sponsored oncology D/E trials. Compared to trials in which 3+3 designs are used, we experienced significant advantages with CRM designs including: flexibility in cohort sizes; formal integration of relevant prior pre-clinical/clinical knowledge of the dose-toxicity relationship; and contribution of all dose limiting toxicities (DLTs) to an MTD determination. On the other hand, we learned about some limitations. The CRM designs modeled binary DLT events where the grade of an event was not considered. Thus, in a cohort where severe DLT event(s) were observed, clinical judgment typically superseded the CRM recommendation towards a lower dose; this decision rule was a priori defined in the protocol. In certain situations, inconsistent prior-information in the dose-toxicity relationship was observed. Therefore, prior assumptions had to be carefully assessed through simulations using multiple dose-toxicity scenarios. Conclusions: Overall, utilization of CRM designs was considered beneficial to Roche early development trials. Based on our experience, CRM designs are flexible and can be tailored to address a variety of clinical research questions. Trial simulation analyses were critical for us to understand the performance of CRM designs, including the accuracy of estimated MTD, trial duration/sample size, and sensitivity to prior assumptions. Furthermore, the introduction and implementation of CRM designs required and promoted strong multidisciplinary collaborations, especially during the design and study protocol set-up phases and the D/E recommendation phase. Citation Format: Jiawen Zhu, Ulrich Beyer, Somnath Sarkar, Gwen Nichols, William Pao, Daniel Sabanés Bové. Experiences and lessons from innovative dose escalation designs in early-phase oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3597. doi:10.1158/1538-7445.AM2017-3597