Indication Determination and Patients Stratification Case Show

  • A domestic company (marked as BIOTECH) in China discovered a candidate small molecule (upper left), which demonstrated good efficacy in one of the tumor type (marked as Type A) in cell-derived xenografts (CDXs) in pre-clinical stage (upper right). To extend potential indications in phase I trial, three more indications (marked as Type B, Type C, and Type D) were selected via literature searching and/or in vitro validation (bottom left), and the phase I trial was launched (bottom right). However, no conclusive results were generated in the first milestone of the trial, which drove BIOTECH to find more supporting data in pre-clinical stage in order to be more confident to move the project forward.

 Indication Determination and Patients Stratification Case Show
 

  • LIDE proposed a solution that using fresh patient tumor samples from either of the four indications to do MiniPDX mouse trial, with 10 cases for each, as well as K cell DNA/RNA library for each case. WES and RNAseq can be done for selected cases in future.
    68.1 Indication Determination and Patients Stratification Case Show
     
  • The first milestone was defined as completion of 10 cases enrollment in either of the four indications. In Type A, none of the patients were responded to the treatment (T/C%<40%), whereas there were several responders and non-responders (T/C%>80%) in both Type B and D indications. If this is a real clinical trial, 31 patients were enrolled with only 5 of them had response, whereas the objective response rate was only 16%, which indicated a failed trial.
    68.1 Indication Determination and Patients Stratification Case Show
     
  • However, modification can be done freely in a pre-clinical trial. We abandoned Type A and had done another round of enrollment for Type B to increase the sample size. At the end of the milestone 2, we may find significant two populations, 7 responders and 6 non-responders when rearranging the data into a waterfall figure. In this case, if we only recruit Type B patients, we may achieve 35% ORR, which could be a successful trial.
    68.1 Indication Determination and Patients Stratification Case Show
     
  • When we go into the 3rd milestone, we determined specific gene mutation in E1 or E2 sub-type unit were occurred only in 7 responders, rather than the 6 non-responders. The sub-type gene E1 or E2 are the downstream of the drug’s target. In another word, if the E1/E2 mutant patients in the indication of Type B can be picked out, we’re likely to achieve 100% of ORR in theory.
    68.1 Indication Determination and Patients Stratification Case Show