Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia

Abstract

This phase 1b trial investigated several doses and schedules of midostaurin in combination with daunorubicin and cytarabine induction and high-dose cytarabine post-remission therapy in newly diagnosed patients with acute myeloid leukemia (AML). The discontinuation rate on the 50-mg twice-daily dose schedule was lower than 100 mg twice daily, and no grade 3/4 nausea or vomiting was seen. The complete remission rate for the midostaurin 50-mg twice-daily dose schedule was 80% (FMS-like tyrosine kinase 3 receptor (FLT3)-wild-type: 20 of 27 (74%), FLT3-mutant: 12 of 13 (92%)). Overall survival (OS) probabilities of patients with FLT3-mutant AML at 1 and 2 years (0.85 and 0.62, respectively) were similar to the FLT3-wild-type population (0.78 and 0.52, respectively). Midostaurin in combination with standard chemotherapy demonstrated high complete response and OS rates in newly diagnosed younger adults with AML, and was generally well tolerated at 50 mg twice daily for 14 days. A phase III prospective trial is ongoing (CALGB 10603, NCT00651261).

Conflict of interest statement

Authors’ Disclosures of Potential Conflicts of Interest

Employment or Leadership Position: Alice Huntsman-Labed, Novartis Pharma AG (C); Catherine Dutreix, Novartis Pharma AG (C); Adam del Corral, Novartis Pharmaceuticals Corporation (C) Consultant or Advisory Role: Richard M. Stone, Genzyme (C), Celgene (C), Ariad (C); Ronald Paquette, Novartis (C); Gary Schiller, Genzme (C); Charles A. Schiffer, Pfizer (C), Micromet (C), Celgene (C), Ambit (C), Ariad (C); Jorge Cortes, Novartis (C), Ariad (C), Ambit (U); Hagop M. Kantarjian, Novartis (C); Daniel J. DeAngelo, Novartis (C); Francis Giles, Novartis (C) Stock Ownership: Gerhard Ehninger, Novartis; Alice Huntsman-Labed, Novartis Honoraria: Thomas Fischer, Novartis; Ronald Paquette, Novartis; Gerhard Ehninger, Novartis Expert Testimony: None Other Remuneration:None

Figures

Fig 1

Schema of dose and schedule of midostaurin administration. Daunorubicin and cytarabine induction (3 + 7) and high-dose cytarabine post-remission therapy was administered on a standard schedule. In addition, patients received midostaurin (indicated by black bars) on one of three dose schedules: I. midostaurin 100 mg twice daily (BID) for 21 or 28 days; II. midostaurin 100 mg twice daily for 14 days; or III. midostaurin 50 mg twice daily for 14 days. Within each dose schedule, patients were assigned to receive midostaurin on day 1 (concomitant with chemotherapy, days 1-7; 14-21 in dose schedules II and III) or day 8 (sequential with chemotherapy; days 8-21 in dose schedules II and III). Open boxes represent values from patients on the concomitant arm (day 1-7 and day 15-22 dosing); closed circles represent values from patients on the sequential arm (day 8-22 dosing).

Fig 2

CONSORT flow diagram. Depicts patient numbers for enrollment, intervention allocation, and follow-up. Abbreviations: AE, adverse event; BID, twice daily. a Three patients (n= 2 from the sequential arm; n = 1 from the concomitant arm) discontinued in complete remission before completing consolidation and were considered as completers by investigators. Open boxes represent values from patients on the concomitant arm (day 1-7 and day 15-22 dosing); closed circles represent values from patients on the sequential arm (day 8-22 dosing).

Fig 3

a. Overall survival probability in patients with FLT3–wild-type and FLT3-mutant AML treated on dose schedule III. Overall survival was assessed without censoring for alternative therapies such as stem cell transplant. b. Disease-free survival probability in patients with FLT3–wild-type and FLT3-mutant AML treated on dose schedule III. Open boxes represent values from patients on the concomitant arm (day 1-7 and day 15-22 dosing); closed circles represent values from patients on the sequential arm (day 8-22 dosing).

Fig 4

a. Median trough concentration-time profile of midostaurin during the first cycle of induction therapy (midostaurin 50-mg twice-daily cohort). b. Median trough concentration-time profile of CGP62221 during the first cycle of induction therapy (midostaurin 50-mg twice-daily cohort). c. Median trough concentration-time profile of CGP52421 during the first cycle of induction therapy (midostaurin 50-mg twice-daily cohort). Open boxes represent values from patients on the concomitant arm (day 1-7 and day 15-22 dosing); closed circles represent values from patients on the sequential arm (day 8-22 dosing).