Emerging Trends in Clinical Trial Designs for Oncology Drug Development

Master protocols, seamless trials, and adaptive designs are revolutionizing oncology drug development. These innovative approaches involve multiple substudies with different objectives, evaluating investigational drugs across disease subtypes. Basket trials and umbrella trials offer flexibility in studying multiple therapies and diseases, targeting specific molecular characteristics. These strategies aim to expedite drug development by streamlining the evaluation process and maximizing the use of biomarkers.

• Clinical trials
• Oncology drug development
• Master protocols
• Adaptive designs
• Biomarkers

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1. The 3rdStat4Onc Annual Symposium Session Master Protocols and Seamless Trials Discussion Yihua Zhao, Boehringer Ingelheim Pharmaceuticals, Inc.

2. Larotrectinib & NTRK fusion positive solid tumors Master Protocols in Practice: Tumor Agnostic Approvals Dr. Nora Ku

3. Master Protocols A master protocol is defined as a protocol designed with multiple substudies, which may have different objectives and involves coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure (FDA draft guidance Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics , September 2018) Single investigational drug or investigational drug combination across multiple cancer populations basket trial Investigational drugs or investigational drug combination(s) in single cancer type: umbrella trials Multiple investigational drugs and/or drug combination regimens across multiple tumor types: platform trial 3rd Stat4Onc, "Master Protocols and Seamless Trials" April 27, 2019 3

4. Basket Trial Woodcock & LaVange Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both , NEJM 2017; 377: 62-70. No control Not randomized Usually multiple disease subtypes share similar molecular characteristics 3rd Stat4Onc, "Master Protocols and Seamless Trials" April 27, 2019 4

5. FWER vs. PWER Adaptive Multi-Arm Multi- Stage Design (aMAMS) Dr. Lingyun Liu

6. Umbrella Trial Can have one common control Randomized Usually different investigational drugs target different molecular characteristics of the same disease type 3rd Stat4Onc, "Master Protocols and Seamless Trials" April 27, 2019 6

7. In Common Can be adaptive, i.e. interim analysis to stop, expand or add a cohort Basket trial: expand, drop or add a disease cohort Umbrella trial: expand, drop or add an investigational drug arm Usually involve biomarker Basket trial: biomarkers that are common in different disease types Umbrella: different biomarkers to indicate different molecular characteristics targeted by different investigational drugs Precision medicine 3rd Stat4Onc, "Master Protocols and Seamless Trials" April 27, 2019 7

8. Challenges in Master Protocol Study Design and Analysis (1/2) Pooling of data in Go/NoGo decision making basket trial Bayesian Optimal Phase 2 (BOP2) design (Zhou, Lee and Yuan, 2017) Borrowing treatment information across indications o Bayesian hierarchical model Homogeneity vs. heterogeneity o Calibrated Bayesian hierarchical model (CBHM) (Chu & Yuan, 2018, A Bayesian Basket Trial Design Using a Calibrated Bayesian Hierarchical Model , Clinical Trials, 15: 149-158) o Bayesian latent subgroup trial (BLAST) design (Chu & Yuan, 2018, Bayesian Latent Subgroup Design for Basket Trials Accounting for Patient Heterogeneity , JRSS Series C, 67: 723-740) Control of type I error rate for multiple comparisons and interim analyses umbrella trial / aMAMS FWER vs. PWER Still open question Need simulations to evaluate 3rd Stat4Onc, "Master Protocols and Seamless Trials" April 27, 2019 8

9. Challenges in Master Protocol Study Design and Analysis (2/2) Randomization Imbalanced Response adaptive randomization (RAR), e.g. I-SPY 2, ADAPT Control Share one common control Temporal trend in control arm Use of historical data/external control, e.g. Bayesian Augmented Control (BAC) Adaptation Stop, expand, or add treatment arms/disease cohorts Bayesian simulation 3rd Stat4Onc, "Master Protocols and Seamless Trials" April 27, 2019 9

10. Success Stories of Master Protocols (1/3) Dr. Gideon Blumenthal Master Protocols: @FDAOncology View , DIA Master Protocol Workshop, Nov. 9, 2018 3rd Stat4Onc, "Master Protocols and Seamless Trials" April 27, 2019 10

11. Where we are and where we are going (2/3) Dr. Gideon Blumenthal Master Protocols: @FDAOncology View , DIA Master Protocol Workshop, Nov. 9, 2018 3rd Stat4Onc, "Master Protocols and Seamless Trials" April 27, 2019 11

12. Where we are and where we are going (3/3) Dr. Gideon Blumenthal Master Protocols: @FDAOncology View , DIA Master Protocol Workshop, Nov. 9, 2018 3rd Stat4Onc, "Master Protocols and Seamless Trials" April 27, 2019 12

13. Conclusions and Next Steps Master protocols have gained more and more popularity and research interest recently because of the flexibility in the trial designs and efficiency in trial conduct There are interesting/unresolved statistical issues that need to be tackled pooling of data control type I error rate control adaptation randomization & blinding Collaboration among multiple functions are needed to further understand the resolve these challenges 3rd Stat4Onc, "Master Protocols and Seamless Trials" April 27, 2019 13