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April 28, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf

On April 28, 2017, the U.S. Food and Drug Administration approved midostaurin (RYDAPT®, Novartis Pharmaceuticals Corp.) for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive (FLT3+), as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.

The FDA also approved a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay (Invivoscribe Technologies Inc.), for use with midostaurin to test patients with AML for the FLT3 mutation.

Approval was based on a randomized, double-blind, placebo-controlled trial in 717 patients with previously untreated FLT3+ AML. This trial randomized patients to either placebo or midostaurin 50 mg orally twice daily on days 8-21 of each cycle of induction and consolidation chemotherapy followed by continuous daily midostaurin for up to 12 cycles. The trial demonstrated a statistically significant improvement in overall survival (OS) for patients receiving midostaurin compared with those on the placebo-containing arm (HR 0.77, p=0.016).

Common adverse reactions, occurring in at least 20% of patients, included febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infection. The most frequent serious adverse reaction was febrile neutropenia, occurring in 16% of patients on both arms.

FDA also approved midostaurin for the treatment of adults with aggressive systemic mastocytosis (SM), SM with associated hematological neoplasm, or mast cell leukemia. Approval was based on response rate and duration in a single-arm, open-label study of midostaurin 100 mg orally twice daily. With 6 cycles of midostaurin, the rates of confirmed complete remission (CR) plus incomplete remission (ICR) by modified Valent criteria were 38% for ASM and 16% for SM-AHN. One patient (5%) with mast cell leukemia achieved a CR. The most common adverse reactions included nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, fever, headache, and dyspnea.

The recommended dose of midostaurin in AML is 50 mg twice daily with food on days 8 to 21 of each cycle of induction and consolidation chemotherapy followed by 50 mg with food as a single agent for up to 12 months. The recommended dose for the treatment of adults with aggressive systemic mastocytosis (SM), SM with associated hematological neoplasm, or mast cell leukemia is 100 mg twice daily with food.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf .

FDA granted this application Breakthrough Therapy Designation (in AML), Fast Track Designation (in SM), and priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Midostaurin (Rydapt) for FMS-Like Tyrosine Kinase-3 (FLT3) Mutation–Positive Acute Myeloid Leukemia (AML)

Author: Sarah Schmidt, PharmD BCOP BCPS
Oncology Clinical Specialist, Bone Marrow Transplant and Hematology
Stephenson Cancer Center
Oklahoma City, OK

What is the potential role for midostaurin in the management of AML?

  • Activating mutations of the receptor tyrosine kinase FLT3 are the most common mutations found in AML; an internal tandem duplication (ITD) comprises 23% of all AML cases, and 7% of all cases contain an FLT3 mutation in the tyrosine kinase domain (TKD).1
  • Sorafenib, although it is not approved by the Food and Drug Administration (FDA) for AML, had previously been the only FLT3 inhibitor available for use in this patient population. Sorafenib has been studied in younger patients with AML in combination with idarubicin and cytarabine. A phase 2 study showed improved complete response (CR) rates in patients with FLT3 mutations compared to those without FLT3 mutations; however, results were not statistically significant (95% vs. 83%, p = 0.23).2
  • Sorafenib has also been studied in combination with azacitadine with improved survival and is recommended by the National Comprehensive Cancer Network guidelines for use in relapsed or refractory AML in combination with a hypomethylating agent for less aggressive therapy.3-4
  • Sorafenib has a tenfold lower inhibitory concentration 50 (IC50) than midostaurin in vitro. Although these two agents haven’t been compared in a clinical trial, fewer hematologic adverse effects have been seen with sorafenib when used in combination with chemotherapy.5
  • Midostaurin is the only FDA-approved medication for the treatment of AML patients with FLT3 mutations, approved in combination with daunorubicin + cytarabine (7+3) induction on days 8-21 and during consolidation with high-dose or intermediate-dose cytarabine consolidation on days 8-21. Monotherapy with midostaurin does not confer a clinical benefit.5-8
  • The study included only adults 18-59 years old; however, the FDA label contains no age restriction, and caution should be used in patients 60 years and older.
  • Two other FLT3 inhibitors, quizartinib and gilteritinib, are in clinical trials for patients with FLT3-positive AML.

What role can the pharmacist play in the management of patients on midostaurin?

  • Administration will begin during induction; a protocol should therefore be in place for procuring midostaurin, or it should be placed on the hospital’s formulary.
  • Prior to administration, female patients should have had a negative pregnancy test within 7 days of starting.5
  • Screening for drug-drug interactions and electrocardiogram monitoring for patients on other QTc-prolonging medications are recommended.
  • Midostaurin is a CYP3A4 substrate, and its concentration will be affected by CYP3A4 inhibitors (e.g., posaconazole) or inducers (e.g., rifampin). These medications should not be used concurrently with midostaurin if possible, especially during the first week of therapy.5
  • Pharmacists should counsel patients on the importance of taking this medication with food.5
    • Midostaurin’s area under the curve (AUC) increased to 1.2-fold when administered with a standard meal and to 1.6-fold when administered with a high-fat meal compared to being administered in a state of fasting.
    • Cmax was reduced by 20% when given with a standard meal and reduced by 27% with a high-fat meal compared to a state of fasting.
    • Tmax was delayed when given with a meal to 2.5-3 hours.
  • Because midostaurin is a moderately emetogenic medication, recommendations should be made regarding appropriate anti-emetics. 5HT-3 antagonists may be used with vigilant QTc monitoring.5
  • A patient support program, Rydapt Now, as well as financial assistance through Novartis, is available at https://www.us.rydapt.com/interested-in/patient-support/ .

Clinical Pearls

  • A companion diagnostic test, the LeukoStrat CDx FLT3 Mutation Assay to Invivoscribe Technologies Inc., was approved along with midostaurin, which has a turnaround time of 48-72 hours. Midostaurin must be used with an FDA-approved FLT3 mutation test.5
  • Midostaurin inhibits proliferation in all FLT3 activating loop (AL) mutants known to date with similar or sometimes greater potency compared to the FLT3/ITD cells.9
  • Midostaurin exhibits time-dependent pharmacokinetics; highest concentrations are seen during the first week, followed by a decline to steady state after about 28 days, due to auto-induction.10
  • Midostaurin was not approved by the FDA for maintenance; however, the Alliance trial, which included a maintenance phase, showed prolonged survival when compared with placebo when used in combination with daunorubicin/cytarabine induction and high-dose cytarabine consolidation followed by maintenance for a total of 12 months (patients ages 18-60 with FLT3 mutations).7,11,12
    • 57% of patients went on to receive an allogeneic transplant, and the trial was discontinued at the time of transplant; more patients in the midostaurin group received a transplant at first remission; the trial concluded that early transplant could have limited exposure of midostaurin.
  • Although midostaurin is FDA-approved for all adults, caution should be used in patients under 60 years because this patient population was not included in the clinical trial.

References

  1. Levis M. Midostaurin approved for FLT3-mutated AML. Blood 2007;129:3403-3406.
  2. Ravandi F, Arana Yi C, Cortes JE, et al. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia 2014;28:1543-1545.
  3. Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood 2013;121:4655-4662.
  4. Serve H, Krug U, Wagner R, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol 2013;31:3110-3118.
  5. Rydapt [package insert]. Novartis, East Hanover, NJ; April 2017.
  6. Gallogly MM, Lazarus HM. Midostaurin: an emerging treatment for acute myeloid leukemia patients. J Blood Med 2016;7:73-83.
  7. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017; [Epub ahead of print] June 23.
  8. Stone RM, Fischer T, Paquette R, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia 2012;26:2061-2068.
  9. Nguyen B, Williams AB, Young DJ, et al. FLT3 activating mutations display differential sensitivity to multiple tyrosine kinase inhibitors. Oncotarget 2017;8:10931-10944.
  10. Yin O, Wang Y, Scran H. A mechanism-based population pharmacokinetic model for characterizing time-dependent pharmacokinetics of midostaurin and its metabolites in human subjects. Clinical Pharmacokinetics 2008;42:807-816.
  11. Fischer T, Stone RM, Deangelo DJ, et al. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol 2010;28:4339-4345.
  12. Stone RM, Mandrekar S, Sanford BL, et al. The multi-kinase inhibitor midostaurin prolongs survival compared with placebo in combination with daunorubicin/cytarabine  induction, high-dose cytarabine consolidation, and as maintenance therapy in newly diagnosed acute myeloid leukemia patients age 18-60 with FLT3 mutations. Blood 2015;126:6.
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