Stages of clinical development of midostaurin
| . | Stage 1 (1994-2000) . | Stage 2 (1998-2002) . | Stage 3 (2002-2017) . |
|---|---|---|---|
| Target(s) | PKC | VEGF; angiogenesis | FLT3; KIT |
| Indication(s) | Solid tumors; B-cell malignancies | Diabetic retinopathy | FLT3+ AML; advanced SM |
| Patient selection | No | No | Yes (AML: FLT3 mutations; advanced SM: KIT D816V mutations in >80% of patients, but unselected) |
| Treatment | Single agent; chemotherapy combination | Single agent | FLT3 mutant AML: combination with induction/consolidation chemotherapy + single-agent maintenance; advanced SM: single agent |
| Key findings | Favorable safety (mild/moderate GI toxicity and cytopenias); no MTD characterized; time-dependent PK; modest activity (in CLL) | Modest improvement in macular edema and visual acuity; limiting GI toxicity | FLT3-mutant AML (first line): improvement in OS and EFS, favorable safety profile; advanced SM (high overall response rate, durable responses, reduction in disease burden, improvement in quality of life; mild/moderate GI toxicity and cytopenias); PK: 3 active metabolites, DDI potential characterized |
| . | Stage 1 (1994-2000) . | Stage 2 (1998-2002) . | Stage 3 (2002-2017) . |
|---|---|---|---|
| Target(s) | PKC | VEGF; angiogenesis | FLT3; KIT |
| Indication(s) | Solid tumors; B-cell malignancies | Diabetic retinopathy | FLT3+ AML; advanced SM |
| Patient selection | No | No | Yes (AML: FLT3 mutations; advanced SM: KIT D816V mutations in >80% of patients, but unselected) |
| Treatment | Single agent; chemotherapy combination | Single agent | FLT3 mutant AML: combination with induction/consolidation chemotherapy + single-agent maintenance; advanced SM: single agent |
| Key findings | Favorable safety (mild/moderate GI toxicity and cytopenias); no MTD characterized; time-dependent PK; modest activity (in CLL) | Modest improvement in macular edema and visual acuity; limiting GI toxicity | FLT3-mutant AML (first line): improvement in OS and EFS, favorable safety profile; advanced SM (high overall response rate, durable responses, reduction in disease burden, improvement in quality of life; mild/moderate GI toxicity and cytopenias); PK: 3 active metabolites, DDI potential characterized |
Development included 22 phase 1 studies, 9 phase 2 studies, 1 phase 3 study, and 42 phase 4 studies, with >2600 patients enrolled to date. Development in solid tumors and ophthalmology was discontinued due to lack of prominent signs of efficacy. Development is ongoing for AML and advanced SM, with submission to the US Food and Drug Administration and European Medicines Agency in 2016 and approvals in 2017.
DDI, drug–drug interaction; GI, gastrointestinal; MTD, maximum tolerated dose; PK, pharmacokinetics; VEGF, vascular endothelial growth factor.