Mechanism Of Action
Midostaurin is a small molecule that inhibits multiple receptor tyrosine kinases. In vitro biochemical or cellular assays
have shown that midostaurin or its major human active metabolites CGP62221 and CGP52421 inhibit the activity of wild
type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), PDGFRα/β, VEGFR2, as well as
members of the serine/threonine kinase PKC (protein kinase C) family.
Midostaurin demonstrated the ability to inhibit FLT3 receptor signaling and cell proliferation, and it induced apoptosis in
leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors.
Midostaurin also demonstrated the ability to inhibit KIT signaling, cell proliferation and histamine release and induce
apoptosis in mast cells.
The effect of RYDAPT (75 mg twice daily for 3 days) on the QTc interval was evaluated in a randomized, placebo and
moxifloxacin controlled, multiple-dose, blinded, parallel study. There was no clinically significant prolongation of QTc
interval or relationship between changes in QTc and concentrations for midostaurin and its active metabolites (CGP62221
and CGP52421). The study duration was not long enough to estimate the effects of the metabolite CGP52421 on the
In pooled clinical studies in patients with advanced SM, 4.7% patients had a post-baseline QTcF > 480 ms, no patients
had a QTcF > 500 ms, and 6.3% patients had a QTcF > 60 ms compared to baseline.
In a randomized placebo-controlled study in patients with AML, the proportion of patients with QTc prolongation was
higher in patients randomized to midostaurin as compared to placebo (QTcF > 480 ms: 10.1% vs 5.7%; QTcF > 500 ms:
6.2% vs 2.6%; QTcF > 60 ms: 18.4% vs 10.7%).
Midostaurin exhibits time-dependent pharmacokinetics with an initial increase in minimum concentrations (Cmin) that
reach the highest Cmin concentrations during the first week followed by a decline to a steady-state after approximately 28
days. The pharmacokinetics of the CGP62221 showed a similar trend. The plasma concentrations of CGP52421 continued
to increase after one month of treatment.
The highest Cmin and steady-state of midostaurin, CGP62221, and CGP52421 were similar when RYDAPT was
administered with food at a dose of 50 mg twice daily or 100 mg twice daily.
The time to maximal concentrations (Tmax) occurred between 1 to 3 hours post dose in the fasted state.
Effect of Food
Midostaurin exposure, represented by area under the curve over time to infinity (AUCinf), increased 1.2-fold when
RYDAPT was coadministered with a standard meal (457 calories, 50 g fat, 21 g proteins, and 18 g carbohydrates) and
1.6-fold when coadministered with a high-fat meal (1007 calories, 66 g fat, 32 g proteins, and 64 g carbohydrates)
compared to when RYDAPT was administered in a fasted state. Midostaurin maximum concentrations (Cmax) were
reduced by 20% with a standard meal and by 27% with a high-fat meal compared to a fasted state. Tmax was delayed when
RYDAPT was administered with a standard meal or a high-fat meal (median Tmax = 2.5 hrs to 3 hrs) [see DOSAGE AND ADMINISTRATION].
Midostaurin has an estimated geometric mean volume of distribution (% coefficient of variation) of 95.2 L (31%).
Midostaurin and its metabolites are distributed mainly in plasma in vitro. Midostaurin, CGP62221, and CGP52421 are
greater than 99.8% bound to plasma protein in vitro. Midostaurin is mainly bound to a1-acid glycoprotein in vitro.
The geometric mean terminal half-life (% coefficient of variation) is 21 hours (19%) for midostaurin, 32 hours (31%) for
CGP62221 and 482 hours (25%) for CGP52421
Midostaurin is primarily metabolized by CYP3A4. CGP62221 and CGP52421 (mean ± standard deviation) account for
28± 2.7% and 38 ± 6.6% respectively of the total circulating radioactivity.
Fecal excretion accounted for 95% of the recovered dose with 91% of the recovered dose excreted as metabolites and 4%
of the recovered dose as unchanged midostaurin. Only 5% of the recovered dose was found in urine.
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) did not have clinically
meaningful effects on the pharmacokinetics of midostaurin, CGP62221, or CGP52421. The pharmacokinetics of
midostaurin in patients with baseline 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) is unknown.
Drug Interaction Studies
Effect Of Strong CYP3A4 Inhibitors On Midostaurin
Coadministration of ketoconazole (400 mg daily for 10 days) with a single dose of RYDAPT (50 mg) on Day 6 increased
AUCinf of midostaurin by 10.4-fold and CGP62221 by 3.5-fold and area under the curve over time to last measurable
concentrations (AUC0-t) of CGP52421 by 1.2-fold compared to a single RYDAPT dose coadministered with placebo [see DRUG INTERACTIONS].
Coadministration of itraconazole (100 mg twice daily on Days 22-28 for 13 doses) with multiple doses of RYDAPT (100
mg twice daily on Days 1 to 2 and 50 mg twice daily on Days 3 to 28) increased Day 28 Cmin concentrations of
midostaurin by 2.1-fold, CGP62221 by 1.2-fold, and CGP52421 by 1.3-fold compared to the respective Day 21 Cmin
concentrations with RYDAPT alone [see DRUG INTERACTIONS].
Effect Of Strong CYP3A4 Inducers On Midostaurin
Coadministration of rifampicin (600 mg daily on Days 1 to 14) with a single dose of RYDAPT (50 mg) on Day 9
decreased AUCinf of midostaurin by 96% and CGP62221 by 92% and AUC0-t of CGP52421 by 59% [see DRUG INTERACTIONS].
Effect Of Midostaurin On Sensitive CYP3A Substrates
Midazolam (sensitive CYP3A substrate) AUCinf was not affected following 4 days of RYDAPT administration. The
clinical relevance of this interaction is unknown as the RYDAPT was administered for only 4 days.
Effects Of Midostaurin
Midostaurin, CGP52421 and CGP62221 inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1, and
induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A in vitro.
Midostaurin inhibits organic anion transporter polypeptide (OATP) 1A1 and induces multidrug resistance protein (MRP)
2 in vitro.
Acute Myeloid Leukemia
RYDAPT in combination with chemotherapy was investigated in a randomized, double-blind placebo-controlled trial of
717 patients with newly-diagnosed FLT3-mutated AML. In this study, FLT3 mutation status was determined
prospectively with a clinical trial assay and verified retrospectively using the companion diagnostic LeukoStrat® CDx
FLT3 Mutation Assay, which is an FDA-approved test for selection of patients with AML for RYDAPT treatment.
Patients were stratified by FLT3 mutation status: TKD, ITD with allelic ratio less than 0.7, and ITD with allelic ratio
greater than or equal to 0.7. Patients with acute promyelocytic leukemia or therapy-related AML were not eligible.
Patients were randomized (1:1) to receive RYDAPT 50 mg twice daily (n=360) or placebo (n=357) with food on Days 8-
21 in combination with daunorubicin (60 mg/m2 daily on Days 1 to 3) /cytarabine (200 mg/m2 daily on Days 1 to 7) for up
to two cycles of induction and high dose cytarabine (3 g/m2 every 12 hours on Days 1, 3 and 5) for up to four cycles of
consolidation, followed by continuous RYDAPT or placebo treatment according to initial assignment for up to 12
additional 28-day cycles. There was no re-randomization at the start of post consolidation therapy. Patients who
proceeded to hematopoietic stem cell transplantation (SCT) stopped receiving study treatment.
The randomized patients had a median age of 47 years (range, 18-60 years), 44% were male, and 88% had a performance
status of 0-1. AML was de novo onset in 95%. The percentage of patients with FLT3-ITD allelic ratio < 0.7, FLT3-ITD
allelic ratio ≥ 0.7, and FLT3-TKD mutations were identical (per randomized FLT3 stratum) on both arms (48%, 30%, and
23%, respectively). Of the 563 patients with NPM1 testing, 58% had an NPM1 mutation. The two treatment groups were
generally balanced with respect to the baseline demographics and disease characteristics, except that the placebo arm had
a higher percentage of females (59%) than in the midostaurin arm (52%). NPM1 mutations were identified in 55% of
patients tested on the midostaurin arm and 60% of patients tested on the placebo arm.
A second course of induction was administered to 25% of the patients, 62% initiated at least one cycle of consolidation,
29% initiated maintenance, and 17% completed all 12 planned cycles of maintenance; 21% of the patients underwent SCT
in first CR. The overall rate of SCT (induction failure, first CR or salvage after relapse) was 59% (214/360) of patients in
the RYDAPT plus standard chemotherapy arm vs. 55% (197/357) in the placebo plus standard chemotherapy arm. All
patients were followed for survival.
Efficacy was established on the basis of overall survival (OS), measured from the date of randomization until death by
any cause. The primary analysis was conducted after a minimum follow-up of approximately 3.5 years after the
randomization of the last patient. RYDAPT plus standard chemotherapy was superior to placebo plus standard
chemotherapy in OS (HR 0.77; 95% CI 0.63, 0.95; 2 sided p=0.016) (Figure 1). Because survival curves plateaued before
reaching the median, median survival could not be reliably estimated.
Figure 1: Kaplan-Meier Curve for Overall Survival in Study 1
The analysis of event-free survival (EFS), defined as a failure to obtain a complete remission (CR) within 60 days of
initiation of protocol therapy, or relapse, or death from any cause, showed a statistically significant improvement with a
median of 8.2 months for RYDAPT plus standard chemotherapy versus 3.0 months for placebo plus standard
chemotherapy with HR 0.78 (95% CI 0.66, 0.93) and 2 sided p=0.005. In an exploratory analysis of EFS defined as a
failure to obtain a CR any time during induction, or relapse, or death from any cause with failures assigned as an event on
study day 1, the median EFS was 10.6 months for RYDAPT plus standard chemotherapy versus 5.6 months for placebo
plus standard chemotherapy with HR 0.72 (95% CI 0.61, 0.86).
A single-arm, open-label, multicenter trial evaluated the efficacy of RYDAPT as a single agent in ASM, SM-AHN, and
MCL, collectively referred to as advanced SM. The study enrolled 116 adult patients with relapse or progression to 0, 1,
or 2 prior regimens for SM. The study excluded patients with serum creatinine > 2.0 mg/dL, hepatic transaminases > 2.5 x
upper limit of normal (ULN) or > 5 x ULN if disease-related, total bilirubin > 1.5 x ULN or > 3 x ULN if disease-related,
QTc > 450 msec, cardiovascular disease including left-ventricular ejection fraction < 50%, or any pulmonary infiltrates. In
addition, the study excluded patients with acute-stage or life-threatening AHN. Patients received RYDAPT 100 mg orally
twice daily in 28-day cycles until disease progression or intolerable toxicity.
Of the 116 patients treated, a study steering committee identified 89 patients who had measurable C-findings and were
evaluable for response. The median age in this group was 64 years (range: 25 to 82), 64% of patients were male, and
nearly all patients (97%) were Caucasian. Among these patients, 36% had prior therapy for SM, and 82% had the KIT
D816V mutation detected at baseline. Their median duration of treatment was 11 months (range: < 1 to 68 months), with
treatment ongoing in 17%.
Efficacy was established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by 6 cycles
of RYDAPT by modified Valent criteria for ASM and SM-AHN (Table 7). Table 7 shows responses to RYDAPT
according to modified Valent criteria. Confirmed major or partial responses occurred in 46 of 73 patients with a
documented KIT D816V mutation, 7 of 16 with wild-type or unknown status with respect to KIT D816V mutation, and 21
of 32 having prior therapy for SM.
Table 7: Efficacy of RYDAPT in Systemic Mastocytosis per Modified Valent Criteria (Study 2)
|Modified Valent Criteria:
||All patients evaluated e
(N = 89)
(N = 16)
(N = 57)
(N = 16)
|CR+ICR by 6 cycles, n a,b
| (95% CI, %)
|Median Duration of CR+ICR (months) c
| (95% CI)
| Range d
|Median Time to CR+ICR (months)
NE Not Estimated; NR Not Reached
a Per Study Steering Committee. Response confirmation after ≥ 8 weeks was required. No CRs were
b Patients who received concomitant high-dose corticosteroids were considered unevaluable and were
excluded from response assessment.
c Among patients with a response of CR or ICR. The estimated median follow-up for duration of response
was 35.4 months overall.
d A + sign indicates a censored value.
e 25 patients were not assessable for the presence of MCL on central histopathology review, and 11 patients
with unconfirmed presence of AHN were regarded as not having AHN.
As a post-hoc exploratory analysis, efficacy was also assessed per the 2013 International Working Group-
Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRTECNM)
consensus criteria. Response after 6 cycles of RYDAPT was determined using a computational algorithm. The
efficacy of RYDAPT for MCL was based on the CR results by IWG-MRT-ECNM. There were 115 patients evaluable for
response assessment, of whom 47 (41%) had prior therapy for SM, and 93 (81%) had a documented D816V mutation at
baseline. Table 8 provides the results of this analysis. Overall response by IWG-MRT-ECNM criteria was reported for 16
(17%) of 93 patients with a documented D816V mutation, and in 8 (17%) of 47 patients having prior therapy for SM.
Table 8: Efficacy of RYDAPT in Systemic Mastocytosis per IWG-MRT-ECNM Consensus Criteria Using an
Algorithmic Approach (Study 2)
(N = 115) b, c
(N = 16)
(N = 72)
(N = 21)
(N = 6)
|Overall Response in 6 cycles, n a
| (95% CI)
|Best Overall Response, n
| Complete Remission
| Partial Remission
|Duration of Response (months) d
a Determined with 12-week confirmation. Patients who received high-dose corticosteroids were considered
evaluable for response.
b Median exposure to midostaurin was 11.5 (range: 0.3, 68.3) months.
c 31 patients were not assessable for MCL on central review, and 15 patients with unconfirmed AHN were
classified as not having AHN.
d Median DOR was not reached in any subtype. Median follow up for DOR, among all responders, was 35.0
Study 3 was a single-arm, multicenter, open-label trial of 26 patients with advanced SM. RYDAPT was administered
orally at 100 mg twice daily with food. The median age in this group was 64 years, 58% of patients were male and most
were Caucasian (81%). Eligibility criteria were similar to Study 2. By Valent criteria per investigator assessment, of 17
patients with SM-AHN, 10 achieved a response (1 partial, 9 major) by 2 cycles that was sustained for at least 8 weeks.
Patients who received concomitant corticosteroids were included. Of the 6 patients with MCL, 1 achieved partial response
and 1 achieved major response. Median DOR for either group had not been reached, with DOR ranging from 3.4+ to
79.2+ months in patients with SM-AHN and 28.6+ to 32.1+ months in patients with MCL. The subtype of SM in the
remaining 3 patients was unconfirmed.