FDA Approves RYDAPT® (Midostaurin) with Chemotherapy for Newly Diagnosed Acute Myeloid Leukemia that is FLT3 Mutation Positive, and as a Single Agent for Aggressive Systemic Mastocytosis, Systemic Mastocytosis with Associated Hematological Neoplasm, or Mast Cell Leukemia
On April 28, 2017, the United States Food and Drug Administration (FDA) approved RYDAPT (midostaurin) for the treatment of adult patients with:
- Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation-positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. The recommended dose of RYDAPT for patients with AML is 50 mg twice daily with food on days 8 to 21 of each cycle of induction with cytarabine and daunorubicin and on days 8 to 21 of each cycle of consolidation with high-dose cytarabine. For a description of the experience with single-agent treatment with RYDAPT beyond induction and consolidation, refer to the full prescribing information (link below).
RYDAPT is not indicated as a single-agent induction therapy for the treatment of patients with AML.
- Aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL) [together referred to as advanced systemic mastocytosis (SM)]. The recommended dose for patients with advanced SM is 100 mg twice daily with food, until disease progression or unacceptable toxicity.
Pre-medicate patients with antiemetics to reduce the risk of nausea and vomiting. Monitor patients for pulmonary symptoms and discontinue RYDAPT in patients who experience signs or symptoms of interstitial lung disease or pneumonitis without an infectious etiology. Monitor patients with advanced SM for toxicity at least weekly for the first four weeks, every other week for the next eight weeks and monthly thereafter while on treatment. Dose modifications for patients with advanced SM with toxicity are described in the full prescribing information (link below).
Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)
- MOA: Midostaurin inhibits multiple receptor tyrosine kinases.
- Time Dependent Pharmacokinetics: Following twice-daily dosing, minimum concentrations (Cmin) increased to its highest Cmin during the first week followed by a decline to a steady-state after approximately 28 days for midostaurin, and its active metabolite, CGP62221. Midostaurin’s other active metabolite, CGP52421, continued to increase after one month of treatment. The highest Cmin and steady-state for midostaurin and its active metabolites were similar when RYDAPT was administered with food at a twice-daily dose of 50 mg or 100 mg.
- Effect of Food: Midostaurin AUC increased by 1.2-fold with a standard meal and by 1.6-fold with a high-fat meal compared to RYDAPT administered in the fasted state. Although food increases midostaurin exposure, RYDAPT is recommended to be administered with food to reduce the incidence of gastrointestinal toxicity.
- Plasma Protein Binding (midostaurin, CGP62221, and CGP52421): Greater than 99.8%.
- Terminal Half-Life (mean): 21 hours for midostaurin, 32 hours for CGP62221, and 482 hours for CGP52421.
- Metabolism: Primarily metabolized by CYP3A. Active metabolites, CGP62221 and CGP52421.
- Excretion: Approximately 95% of the total recovered radiolabeled midostaurin dose was eliminated in the feces and 5% was eliminated in the urine. Unchanged midostaurin recovery was negligible.
- Cardiac Electrophysiology: Midostaurin and its CGP62221 metabolite did not prolong the QT interval to any clinically relevant extent in a dedicated QTc study, while the effect of the CGP52421 metabolite is unknown. QTcF > 60 ms from baseline was observed in 6.3% of patients with advanced SM, and 18.4% (versus 10.7% for placebo) of patients with AML.
- Coadministration of a strong CYP3A4 inhibitor (i.e., ketoconazole) with a single dose of RYDAPT increased AUCinf of midostaurin by 10.4-fold and CGP62221 by 3.5-fold and AUC0-t of CGP52421 by 1.2-fold. Coadministration of a strong CYP3A4 inhibitor (i.e., itraconazole) with multiple doses of RYDAPT increased midostaurin Cmin by 2-fold, CGP62221 by 1.2-fold, and CGP52421 by 1.3-fold. Consider alternative therapies that do not strongly inhibit CYP3A activity. Alternatively, when RYDAPT is taken with strong CYP3A inhibitors, closely monitor patients for adverse reactions (AR), especially during the first week of consecutive RYDAPT administration in advanced SM population, and during first week of RYDAPT administration in each cycle of chemotherapy in AML population.
- Coadministration of a strong CYP3A4 inducer (i.e., rifampicin) with a single dose of RYDAPT decreased AUC of midostaurin by 96%, CGP62221 by 92%, and CGP52421 by 59%. Avoid coadministration of RYDAPT with strong CYP3A inducers.
Use in Specific Populations
The following population characteristics were not associated with a clinically significant effect on the pharmacokinetics of midostaurin: Age (20-94 years), sex, race, and mild (total bilirubin greater than 1.0 to 1.5 times the upper limit of normal (ULN) or aspartate aminotransferase (AST) greater than the ULN) or moderate (total bilirubin 1.5 to 3.0 times the ULN and any value for AST) hepatic impairment, or renal impairment (creatinine clearance (CLcr) > 30 mL/min). The effect of severe hepatic impairment (total bilirubin greater than 3.0 times the ULN and any value for AST) or severe renal impairment (CLcr 15 to 29 mL/min) on the pharmacokinetics of midostaurin is unknown.
Efficacy and Safety
Clinical efficacy and safety of RYDAPT for AML were demonstrated at the recommended dosage in a randomized, placebo-controlled trial that enrolled 717 patients with newly-diagnosed FLT3-mutated AML (Study 1). RYDAPT plus standard chemotherapy was superior compared to placebo plus standard chemotherapy in overall survival (HR 0.77; 95% CI: 0.63, 0.95; two-sided p=0.016). The most common ARs of RYDAPT plus chemotherapy were febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infection.
Clinical efficacy and safety of RYDAPT for advanced SM were demonstrated at the recommended dosage in two single-arm, open-label trials (Studies 2 and 3). Study 2 enrolled 116 patients with relapse or progression on 0, 1, or 2 prior regimens for advanced SM, of which 89 patients had measurable clinical findings and were evaluable. Confirmed complete remission (CR) plus incomplete remission (ICR) by 6 cycles of RYDAPT by modified Valent criteria occurred in 6 (38%) of 16 patients with ASM (95% CI: 15, 65) and in 9 (16%) of 57 patients with SM-AHN (95% CI: 7, 28). Overall response in 6 cycles of RYDAPT in 21 MCL patients based on the 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria using an algorithmic approach was 19% (95% CI: 5, 42). Study 3 enrolled 26 patients with advanced SM. By Valent criteria per investigator assessment of 17 patients with SM-AHN, 1 achieved a partial response and 9 achieved a major response by 2 cycles that was sustained for at least 8 weeks. Of 6 patients with MCL, 1 achieved partial response and 1 achieved major response. The most common ARs were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea. The most common serious ARs were infections and gastrointestinal disorders.
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.
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