Table 2.
Summary of two drugs (targeted and cytotoxic) in combination
| Second drug at 100% dose percentage of FDA/RP2D/MTD | Lowest additive dose percentage of the combination | |
|---|---|---|
| One drug at 100% dose percentage of FDA/RP2D/MTD |
45% of studies (141/310) Note: 141 of the 372 total studies (38%) administered each drug at 100% dose |
117%a (cytotoxic agent 100%) 136%2 (targeted agent 100%) |
| Cytotoxic at 100% dose percentage of FDA/RP2D/MTD (N = 248 studies) | 57% (141/248) | 117%a |
| Targeted agent at 100% dose percentage of FDA/RP2D/MTD (N = 203 studies) | 69% (141/203) | 136%2 |
| No single drug at 100% of the FDA/RP2D/MTD (N = 51 studies)3 | Not applicable |
41%4
82%5 (without HDAC or PARP inhibitors) 97%6 (with antibody as targeted agent) |
Lowest dose percentage was 17% (targeted) plus 100% (cytotoxic): vorinostat (HDAC inhibitor) plus vinorelbine (Supporting Information Ref. S291); atrasentan (endothelin A receptor antagonist) and pegylated liposomal doxorubicin or docetaxel (Supporting Information Refs. S292–S293). However, cenersen (antisense against TP53) was given at 16% and idarubicin was at 100%, but dose was not chosen based on toxicity (Supporting Information Ref. S294). 2Combretastatin A4 phosphate (tubulin binder) was at 36% and bevacizumab was at 100% (Supporting Information Ref. S188). 3In the 51 studies where no single drug was given at 100% dose percentage, the most common grade 3 or 4 toxicities were as follows: (i) neutropenia (N = 24 (47%) studies); (ii) thrombocytopenia (N = 8 (16%) studies); (iii) anemia (N = 5 (10%) studies). For studies (N = 7) that included HDAC or PARP inhibitors, the most common toxicities leading to lowered doses were neutropenia and thrombocytopenia (57% and 29% of studies). 4Topotecan and veliparib (PARP inhibitor) (Supporting Information Ref. S345). 5Chlorambucil was at 46% and imatinib was at 36% (Supporting Information Ref. S339). 6Fludarabine was at 72% and alemtuzumab was at 25% (Supporting Information Refs. S336–S337).
Abbreviations: FDA: Food and Drug Administration‐approved dose; HDAC: histone deacetylase; MTD: maximum tolerable dose; PARP: poly‐ADP ribose polymerase; RP2D: recommended Phase 2 dose.