Milea Timbergen

31 Table 2. Overview of drugs used clinical trials targeting signalling pathways in DTF Drug Ref. Setting Tumour type N of DTF patients Efficacy in DTF Wnt/ ß-catenin signalling pathway Frizzled 9 receptor blocker Ipafricept (OMP- 54F28) 76 Phase 1 Advanced solid tumours (n = 26) 2 n = 2 SD ( > 6 months) Notch signalling pathway PF-03084014 77 Phase 1 DTF 7 ORR 71.4% (95%CI 29-96.3%) n = 5 PR, median TTR 9.9 months n = 1 PD 78 Phase 2 DTF 17 n = 5 PR (after a median of 32 cycles, 95 weeks), n=11 SD PI3K /AKT/ mTOR signalling pathway Receptor Tyrosin Kinase inhibitor Imatinib 79 Phase 2 DTF 40 n = 2 TS (<1 year) at 3 months: n=1 CR, n=3 PR, n=28 SD, n = 5 PD 3-months NPRR 91% (95% CI 77-96), 6-months NPRR 80%, 12- months NPRR 67% 80 Phase 2 DTF 51 At 2-months: n=48 SD 2-months PFS 94%, 4-months PFS 88%, 1 year PFS 66% 81 Phase 2 DTF 19 n = 3 PR, n = 4 SD (> 1 year), 1-year disease control rate 36.8%, TTF 325 days 82 Phase 2 Imatinib- sensitive tumours (n = 186) 20 DTF patients: n = 2 PR, n = 8 SD, n = 7 PD, n = 3 unknown. Median TTP 9.1 months (95%CI 2.9-17.0 months). Imatinib (+ nilotinib) 83 Phase 2 DTF 39 OS 100%, PAR at 6 months: 65% At 21 months: n = 7 PR, ORS 19% n = 8 imatinib + nilotinib due to PD under imatinib 3-months PAR 88% Imatinib + gemcitabine (I+G) or Imatinib+ doxorubicin (I+D) 84 Phase 1 solid tumours (n = 16) 1 (I+G) DTF patients: ceased treatment due to dose-limiting toxicity (grade 2 neutropenia) 2