Table 1.

Published clinical trials of midostaurin: single-agent trials and combination-agent trials

Reference	N	Study population	FLT3	Phase	Treatment (PO)	Key results	Comments
Single-agent trials
16	32	Refractory or unresponsive solid tumors	Not reported	I	Dose escalation (midostaurin 12.5 mg PO daily to 100 mg PO TID)	First to report Cmax, t1/2 in study subjects. Most common AEs: nausea, vomiting, fatigue, diarrhea. 225–300 mg/d considered too toxic for future study	First in human dose-escalation study Correlatives (PKC inhibition) reported separately
17	30	Advanced MDS Relapsed/refractory AML Newly diagnosed AML ineligible for induction chemotherapy	mut (90% ITD)	IIB 2-stage	Midostaurin 75 mg PO TID	Most common AEs: nausea, vomiting 3 fatal pulmonary events 70% had reduction of >50% in peripheral blast count; 30% had >50% reduction in BM blast count 2 went onto BMT after initial response	First trial in AML or MDS Correlative: pFLT3 was decreased in peripheral blood monocytes and bone marrow aspirate in the subset of patients tested (n=5); all responded
23	95	Relapsed/refractory AML Newly diagnosed AML ineligible for induction chemotherapy MDS (RAEB ± transformation or CML)	WT (63%) mut (37%) (76% ITD)	IIB	Midostaurin 50 PO BID or 100 mg PO BID	Best response: PR in 1% HI: 46% FLT3 mut, 35% FLT3-WT BR: 71% FLT3 mut, 42% FLT3-WT Higher BR in previously untreated patients ND in median onset of BR (29 days) or TTF between FLT3-WT and mut patients BR correlated to drug (and metabolite) concentrations in plasma	First trial to compare responses in WT versus mut FLT3 Trough concentrations of midostaurin (and metabolites) reported
Combination trials
20	69	Newly diagnosed AML, age 18–60 years	WT (72%) mut (28%)	IB	6 dose schedules of 50–100 mg BID midostaurin with standard daunorubicin and cytarabine induction (3+7)	Most common AEs: hematologic 100 mg BID: CR in 45% (35% WT, 83% mut); 79% discontinuation rate 50 mg BID: CR in 80% (74% WT, 92% mut) ND in OS at 1 and 2 years (WT vs mut) Superior tolerance with sequential vs concomitant administration Possible pharmacokinetic interaction with daunorubicin	First combination trial with 7+3 Defined dosing schedule for Phase III trial NCT00651261, in progress
13	16	Newly diagnosed AML, age ≥18 years, not eligible for std induction Relapsed/refractory AML, age ≥18 years	WT (87%) mut (13%)	I	Decitabine days 1–5 Midostaurin days 8–21 (25–50 mg PO BID) or days 1–28 (50 mg PO BID)	Most common AEs: hematologic 2 fatal complications of viral PNA 3 DLTs (cardiac or pulmonary) CR + CRi: 25% (duration 28–331 days) No detectable pharmacokinetic interaction with decitabine	First combination trial with decitabine Preclinical correlatives suggested synergy with decitabine (in apoptosis, FLT3 phosphorylation and downstream signaling)
18	54	Untreated and previously treated AML or high-risk MDS	WT (26%) mut (74%) (68% ITD, 6% ITD + D835Y)	I/II	Azacitidine (IV or SC) days 1–7 Midostaurin days 8–21 (25–50 mg BID) up to 12 cycles	Grade 3–4 hematological AEs in 100%; Grade 3–4 nonhematological toxicity in 70% BR: 84% (PB) 53% (BM) ORR 26% (33% in FLT3-ITD pts w/o prior exposure to FLT3 inhibitors), CR 2%, CRi 11%, MLFS 11%, PR 1% (74% were primary refractory) FLT3-ITD mut was not a/w ORR Median RD: 20 weeks No detectable pharmacokinetic interactions with azacitidine	First combination trial with azacytidine Correlative: pFLT3
24	17	Untreated AML, age ≥70 years Relapsed AML, any age	WT (100%) mut (0%)	I	Aza (75 mg/m2) days 1–7 Midostaurin days 8–21 (25, 50, or 75 mg PO BID)	Most common AEs: hematologic 3 G3 GI toxicities; 1 required hospitalization CR in 3 patients (12%; duration 7, 12, 12 m) RR 18%	Only study to report patient compliance (high)

Abbreviations: AE, adverse event; AML, acute myeloid leukemia; BM, bone marrow; BMT, bone marrow transplant; BR, blast response; CR, complete remission; CRi, CR with incomplete bone marrow recovery; DLT, dose limiting toxicity; FLT3, fms-like tyrosine kinase; G, grade; HI, hematologic improvement; ITD, internal tandem duplication; m, months; MDS, myelodysplastic syndrome; MLFS, morphologic leukemia free status; ORR, overall response rate; PB, peripheral blood; PNA, pneumonia; PR, partial response; TTF, time to treatment failure; WT, wild type; mut, mutation; Aza, azacitidine; PO, by mouth; PKC, protein kinase C; RAEB, refractory anemia with excess blasts; CML, chronic myeloid leukemia; ND, no difference; IV, intravenous; SC, subcutaneous; RD, response duration; a/w; associated with; GI, gastrointestinal; OS, overall survival; BID, twice daily; TID, three times daily; RR, response rate; std, standard; w/o, without.