Table 2.
Selected clinical trials combining direct/indirect PI3K inhibitors or DNA damage response inhibitors with chemotherapy or hypomethylating agents
| Compound | Direct/indirect PI3Ki | DDRi | Study design | Indication | Combination therapy | Clinical trial Ref. | Clinical outcome |
| Quizartinib | FLT3 inhibitor | - | Phase I | de novo FLT3mut AML | Q + standard CT vs. standard CT | NCT 01390337[70] | ORR 84% (16/19 patients, 14 patients CRc + 2 patients MLFS). No additional toxicity. |
| Midostaurin | FLT3 inhibitor | - | Phase III | de novo FLT3mut AML | M + standard CT vs. standard CT | NCT00651261[68] | OS 74.7 months (midostaurin) vs. 25.6 months (placebo), P = 0.009), median EFS 8.2 mo (midostaurin) and 3.0 mo (placebo) P = 0.002) |
| Idelalisib | PI3K delta inhibitor | - | Phase III | R/R chronic lymphocytic leukaemia | I + bendamustine/rituximab vs. bendamustine/rituximab | NCT01569295[71] | Median PFS 20.8 months (idelalisib) vs. 11.1 months (placebo), P < 0.0001 |
| Tucatinib | HER2 inhibitor | - | Phase II | HER2-positive metastatic breast cancer | T + trastuzumab/capecitabine vs. trastuzumab/capecitabine | NCT02614794[72] | 2-year OS at 2 44.9% (tucatinib) vs. 26.6% (placebo), P < 0.005 |
| Berzosertib (VX-970, M6620) | - | ATR inhibitor | Phase II | Platinum-resistant high-grade serous ovarian cancer | B + gemcitabine vs. gemcitabine | NCT02595892[66] | Median PFS 22.9 weeks (berzosertib) vs. 14.7 weeks (placebo), P = 0.044 |
| AZD1775 | - | Wee1 inhibitor | Phase II | TP53mut ovarian cancer, R/R to first-line platinum-based therapy | A + carboplatin | NCT01164995[65] | Median PFS 5.3 months, OS 12.6 months. Clinical proof that Wee1 inhibitor enhances carboplatin efficacy in TP53-mutated tumors |
ATR: ATR serine/threonine kinase; FLT3: rms telated teceptor tyrosine Kinase 3; HER2: human epidermal growth factor receptor 2; PI3K: phosphoinositide 3-kinase; R/R: relapsed/refractory; TP53: tumor protein P53; WEE1: WEE1 G2 checkpoint kinase; CRc: composite complete remission; EFS: event-free survival; ORR: overall response rate; MLFS: morphological leukemia-free state; OS: overall survival; PFS: progression-free survival.