Summary of published phase 1/2 trials investigating safety and efficacy of FLT3-TKI in combination with chemotherapy
| TKI . | Clinical phase . | Chemotherapy . | TKI therapy . | Patient number . | Age, y . | Prior therapy . | Cytogenetics . | FLT3 mutation status . | CR rate (%) . | OS . | Remarks . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Tandutinib (MLN518) | Phase 1/272 | Induction: AraC 200 mg/m2/d, days 1-7 Daunorubicin 60 mg/m2/d, days 1-3 | Cohort 1: 200 mg 2×/d continuously until 6 months after completion of therapy (7 pts); toxicity: GI intolerance | 29 | 26-83 (median: 60) | Newly diagnosed AML | 9 pts unfavorable | 5 pts had FLT3-ITD | Cohort 1: 5/7 pts | Not reported | AEs: mainly diarrhea, nausea, and vomiting |
| Consolidation: HD-AraC (3000 mg/m2 every 12 hours, days 1,3,5) elderly patients: 2000 mg/m2/d, days 1-5 | Cohort 2: 200 mg 2×/d, days 1-14 (8 pts); during induction and consolidation | Cohort 2: 6/8 pts | |||||||||
| Cohort 3: 500 mg 2×/d, days 1-14 (14 pts); during induction and consolidation | Not reported | ||||||||||
| Midostaurin (PKC412) | Phase 1b73 | Induction: AraC 100 mg/m2/d, days 1-7; Daunorubicin 60 mg/m2/d, days 1-3 | 100 mg or 50 mg 2×/d orally days 8-21 (sequentially) | Total N not reported; 40 pts on 50 mg 2×/d (20 each concomitantly or sequentially) | 20-65 (median: FLT3-mut 46 FLT3-wt 50) | Newly diagnosed AML (de novo) | FLT3-mut: 85% intermediate and 15% unfavorable | FLT3-mut: 13 pts (9 pts with FLT3-ITD) | 32/40 pts (80%) | FLT3-mut: 1 year 85% 2 years 62% | 100 mg 2×/d poorly tolerated (nausea and vomiting); 5 pts. received maintenance therapy (3 FLT3-mut, 2 FLT3-wt) |
| Consolidation: HD-AraC (3000 mg/m2 every 12 hours, days 1,3,5); 3 cycles | 100 mg or 50 mg 2×/d orally days 1-7 and 15-21 (concomitantly) | FLT3-wt: 45% intermediate, 26% unfavorable, 18,5% favorable, 11% unknown | FLT3-wt: 27 pts | FLT3-mut: 12/13 (92%) | FLT3-wt: 1 year 81% 2 years 59% | ||||||
| FLT3-wt: 20/27 (74%) | |||||||||||
| Sorafenib | Phase 1/274 | Induction: AraC 1.5 g/m2/d, days 1-4; Idarubicin 12 mg/m2/d, days 1-3 | Phase 1: Sorafenib 400 mg orally days 1-7 (a) every other day, (b) 400 mg daily, (c) 400 mg 2×/d | Phase 1: 10 | 21-59 (median: 34) | Phase 1: relapsed or refractory AML | 1/10 pts unfavorable | FLT3-mut: 3/7 | FLT3-wt: 1/3 | Overall: 12 months 74% | Difference in CR rate of FLT3-mut and FLT3-wt was statistically significant (P = .033) |
| Induction: AraC 1.5 g/m2/d, days 1-4; Idarubicin 12 mg/m2/d, days 1-3 | Phase 2: Sorafenib 400 mg orally 2×/d days 1-7 | Phase 2: 51 | Phase 2: 18-65 (median: 53) | Phase 2: newly diagnosed AML | 5/51 pts unfavorable | 15/51 | overall 75% | Short median follow-up (54 weeks) | |||
| Consolidation: AraC 0.75 g/m2, days 1-3; Idarubicin 8 mg/m2, days 1-2 | (Up to 5 cycles) Sorafenib 400 mg 2×/d up to 28 days during consolidation | FLT3-ITD: 92% (1/13 pts. CRp) | |||||||||
| Sorafenib 400 mg 2×/d maintenance for up to 1 year | FLT3-TKD: 100% | ||||||||||
| FLT3-WT: 66% (3/36 pts. CRp) | |||||||||||
| Lestaurtinib (CEP701) | Randomized phase 275 | Induction: Mitoxantrone plus etoposide plus cytarabine or HD-AraC | 80 mg 2×/d orally postchemotherapy (randomized) for 112 days, extension possible; cross-more than to TKI therapy possible if refractory to chemotherapy alone | 224 (220 receiving therapy) | Median age: 55 y | FLT3-mut AML in first relapse | Not reported | FLT3-ITD: 88% | Ctx only: 21% Ctx+TKI: 26% P = .35 | Ctx only: 4.57 months Ctx+TKI: 4.73 months | Duration of CR1 < 6 months in 47%; 7 pts crossed over from Ctx only to the TKI arm; 31 pts received TKI on the extension protocol; pts achieving > 85% target inhibition on day 15 had a superior CR/CRp rate compared with those not achieving this target (39% vs 9%, respectively) |
| FLT3-D835: 8% | |||||||||||
| Both: 4% |
| TKI . | Clinical phase . | Chemotherapy . | TKI therapy . | Patient number . | Age, y . | Prior therapy . | Cytogenetics . | FLT3 mutation status . | CR rate (%) . | OS . | Remarks . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Tandutinib (MLN518) | Phase 1/272 | Induction: AraC 200 mg/m2/d, days 1-7 Daunorubicin 60 mg/m2/d, days 1-3 | Cohort 1: 200 mg 2×/d continuously until 6 months after completion of therapy (7 pts); toxicity: GI intolerance | 29 | 26-83 (median: 60) | Newly diagnosed AML | 9 pts unfavorable | 5 pts had FLT3-ITD | Cohort 1: 5/7 pts | Not reported | AEs: mainly diarrhea, nausea, and vomiting |
| Consolidation: HD-AraC (3000 mg/m2 every 12 hours, days 1,3,5) elderly patients: 2000 mg/m2/d, days 1-5 | Cohort 2: 200 mg 2×/d, days 1-14 (8 pts); during induction and consolidation | Cohort 2: 6/8 pts | |||||||||
| Cohort 3: 500 mg 2×/d, days 1-14 (14 pts); during induction and consolidation | Not reported | ||||||||||
| Midostaurin (PKC412) | Phase 1b73 | Induction: AraC 100 mg/m2/d, days 1-7; Daunorubicin 60 mg/m2/d, days 1-3 | 100 mg or 50 mg 2×/d orally days 8-21 (sequentially) | Total N not reported; 40 pts on 50 mg 2×/d (20 each concomitantly or sequentially) | 20-65 (median: FLT3-mut 46 FLT3-wt 50) | Newly diagnosed AML (de novo) | FLT3-mut: 85% intermediate and 15% unfavorable | FLT3-mut: 13 pts (9 pts with FLT3-ITD) | 32/40 pts (80%) | FLT3-mut: 1 year 85% 2 years 62% | 100 mg 2×/d poorly tolerated (nausea and vomiting); 5 pts. received maintenance therapy (3 FLT3-mut, 2 FLT3-wt) |
| Consolidation: HD-AraC (3000 mg/m2 every 12 hours, days 1,3,5); 3 cycles | 100 mg or 50 mg 2×/d orally days 1-7 and 15-21 (concomitantly) | FLT3-wt: 45% intermediate, 26% unfavorable, 18,5% favorable, 11% unknown | FLT3-wt: 27 pts | FLT3-mut: 12/13 (92%) | FLT3-wt: 1 year 81% 2 years 59% | ||||||
| FLT3-wt: 20/27 (74%) | |||||||||||
| Sorafenib | Phase 1/274 | Induction: AraC 1.5 g/m2/d, days 1-4; Idarubicin 12 mg/m2/d, days 1-3 | Phase 1: Sorafenib 400 mg orally days 1-7 (a) every other day, (b) 400 mg daily, (c) 400 mg 2×/d | Phase 1: 10 | 21-59 (median: 34) | Phase 1: relapsed or refractory AML | 1/10 pts unfavorable | FLT3-mut: 3/7 | FLT3-wt: 1/3 | Overall: 12 months 74% | Difference in CR rate of FLT3-mut and FLT3-wt was statistically significant (P = .033) |
| Induction: AraC 1.5 g/m2/d, days 1-4; Idarubicin 12 mg/m2/d, days 1-3 | Phase 2: Sorafenib 400 mg orally 2×/d days 1-7 | Phase 2: 51 | Phase 2: 18-65 (median: 53) | Phase 2: newly diagnosed AML | 5/51 pts unfavorable | 15/51 | overall 75% | Short median follow-up (54 weeks) | |||
| Consolidation: AraC 0.75 g/m2, days 1-3; Idarubicin 8 mg/m2, days 1-2 | (Up to 5 cycles) Sorafenib 400 mg 2×/d up to 28 days during consolidation | FLT3-ITD: 92% (1/13 pts. CRp) | |||||||||
| Sorafenib 400 mg 2×/d maintenance for up to 1 year | FLT3-TKD: 100% | ||||||||||
| FLT3-WT: 66% (3/36 pts. CRp) | |||||||||||
| Lestaurtinib (CEP701) | Randomized phase 275 | Induction: Mitoxantrone plus etoposide plus cytarabine or HD-AraC | 80 mg 2×/d orally postchemotherapy (randomized) for 112 days, extension possible; cross-more than to TKI therapy possible if refractory to chemotherapy alone | 224 (220 receiving therapy) | Median age: 55 y | FLT3-mut AML in first relapse | Not reported | FLT3-ITD: 88% | Ctx only: 21% Ctx+TKI: 26% P = .35 | Ctx only: 4.57 months Ctx+TKI: 4.73 months | Duration of CR1 < 6 months in 47%; 7 pts crossed over from Ctx only to the TKI arm; 31 pts received TKI on the extension protocol; pts achieving > 85% target inhibition on day 15 had a superior CR/CRp rate compared with those not achieving this target (39% vs 9%, respectively) |
| FLT3-D835: 8% | |||||||||||
| Both: 4% |
TKI indicates tyrosine kinase inhibitor; CR, complete response; CRp, complete response with incomplete platelet recovery; OS, overall survival; GI, gastrointestinal; pts., patients; AraC, cytarabine; HD-AraC, high-dose cytarabine; AML, acute myeloid leukemia; FLT3-mut, mutated FLT3-receptor (internal tandem duplication and/or tyrosine-kinase domain mutation); AE, adverse events; and Ctx, chemotherapy.