Table 5.

Simulation results for two agents, with multiple endpoints (DLT, response)

(True % DLT, true % rsp) Proportion combination recommended Avg number of pts treated on combination
Ibrutinib (mg per day)
ScenarioVenetoclax (mg per day)280420560Avg size, %-tiles% Stop% DLT% Rsp
1 “Ideal”400(0.07,0.55)(0.15,0.70)(0.25,0.95)19.10.216.474.2
0.120.120.6725th = 17
1.722.307.4650th = 18
200(0.05,0.40)(0.07,0.55)(0.15,0.80)75th = 20
0.070.080.1490th = 24
2.302.303.0695th = 27
2 “Worst”400(0.25,0.25)(0.30,0.40)(0.40,0.50)18.17.025.638.3
0.060.080.0625th = 16
2.542.181.6350th = 18
200(0.20,0.25)(0.25,0.40)(0.30,0.50)75th = 21
0.190.360.1790th = 25
3.815.083.0895th = 27
3 Best guess400(0.12,0.55)(0.18,0.80)(0.25,0.95)19.80.618.475.0
0.020.100.5825th = 17
1.972.776.7250th = 18
200(0.10,0.40)(0.15,0.55)(0.20,0.80)75th = 22
0.070.080.1690th = 26
2.572.773.1695th = 28
4 “Plateau”400(0.25,0.35)(0.30,0.50)(0.40,0.50)18.29.025.744.8
0.060.080.0325th = 17
2.552.191.4650th = 18
200(0.20,0.35)(0.25,0.50)(0.30,0.50)75th = 21
0.200.380.1590th = 25
3.835.472.9295th = 28
5 “Toxic”400(0.30,0.40)(0.40,0.50)(0.50,0.75)18.411.832.952.9
0.090.090.0325th = 16
2.942.201.1050th = 19
200(0.25,0.40)(0.30,0.50)(0.40,0.75)75th = 23
0.260.250.1790th = 26
4.414.593.1295th = 28
6 “Very toxic”400(0.75,0.40)(0.85,0.50)(0.95,0.75)4.3100.0074.042.5
0.000.000.0025th = 2
0.950.090.0050th = 2
200(0.70,0.40)(0.75,0.50)(0.85,0.75)75th = 6
0.000.000.0090th = 9
1.981.070.1795th = 11
  • NOTE: Optimal combinations are defined by an acceptable toxicity profile (≤25% DLT rate) and the highest clinical response rate. Stop when an 11th participant is recommended to a dose combination that already has 10 participants. Maximum total accrual set at 28, 1,000 simulations. For each scenario, 1,000 simulated trials were run, with the optimal combination(s) indicated in bold type.

  • Abbreviations: % DLT, percent of DLTs; % Rsp, percent of responses; % Stop, percent of trials stopped early for safety; %-tiles, percentiles; avg, average; avg size, average trial sample size; pts, patients.