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  1. Development & Approval Process | Drugs

Drug Trials Snapshot: RYDAPT

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race, and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to RYDAPT Prescribing Information for complete information.

RYDAPT (midostaurin)
rye-dapt
Novartis Pharmaceuticals Corp.
Approval date: April 28, 2017


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

RYDAPT is used to treat adults with advanced systemic mastocytosis (SM). It is to be used in patients who have:

  • aggressive SM,
  • SM with associated blood cancer, or
  • mast cell leukemia.

Advanced mastocytosis (SM) are group of rare and fatal disorders in which the body produces too many mast cells, a type of white blood cell.

How is this drug used?

RYDAPT is a capsule. Four capsules (a total of 100 mg) are taken two times a day with food.

What are the benefits of this drug?

After 6 cycles of treatment with RYDAPT, twenty one percent of 89 patients reached either complete and incomplete remission.

What are the benefits of this drug (results of trials used to assess efficacy)?

The table below summarizes efficacy results established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by 6 cycles of RYDAPT by modified Valent criteria for aggressive systemic mastocytosis (ASM) and systemic mastocytosis with associated hematological neoplasm (SM-AHN).

Table 2. Efficacy of RYDAPT in Systemic Mastocytosis per Modified Valent Criteria (Trial 1)

Modified Valent Criteria:All patients evaluated e
(N = 89)
ASM
(N = 16)
SM-AHN
(N = 57)
MCL
(N = 16)
CR+ICR by 6 cycles, n a,b
(95% CI, %)
19 (21%)
(13, 31)
6 (38%)
(15, 65)
9 (16%)
(7, 28)
4 (25%)
(7, 52)
Median Duration of CR+ICR (months) c
(95% CI)
Range d
NR
(24.1, NE)
6.6+, 65.8+
NR
(24.1, NE)
12.1+, 36.8+
NR
(7.4, NE)
6.6+, 52.1+
NR
(NE, NE)
19.1+, 65.8+
Median Time to CR+ICR (months)
Range
0.5
0.1, 3.0
0.7
0.3, 1.9
0.5
0.1, 3.0
0.3
0.1, 0.5
NE: Not Estimated; NR: Not Reached
a Per Study Steering Committee. Response confirmation after ≥ 8 weeks was required. No CRs were reported.
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.

Efficacy Results of Trial 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. 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 1.0+ to 79.2+ months in patients with SM-AHN and 0.6+ to 32.1+ months in patients with MCL.

RYDAPT Prescribing Information

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

  • Sex: RYDAPT worked similarly in men and women.
  • Race: The majority of participants in the clinical trials were White. Differences among races could not be determined due to small number of participants in other races.
  • Age: RYDAPT worked similarly in patients younger and older than 65 years of age.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

The table below summarizes efficacy results based on Objective Response Rate (ORR) by sex and age of patients in Trial 1. Racial subgroup differences were not investigated since the majority of patients were white.
Due to the small sample size, these exploratory analyses should be interpreted with caution.

Table 3. Overall Response Rate by Baseline Demographics-Trial 1

Demographic
Characteristic
SubgroupResponse Criteria
Modified Valent/Cheson
r/n, % [95% CI]
IWG
r/n, % [95% CI]
Age< 65="">27 / 46 (58.7) [43.2, 73.0]15 / 65 (23.1) [13.5, 35.2]
≥ 65 years26 / 43 (60.5) [44.4, 75.0]4 / 51 (7.8) [2.2, 18.9]
SexWomen22 / 32 (68.8) [50.0, 83.9]6 / 40 (15.0) [5.7, 29.8]
Men31 / 57 (54.4) [40.7, 67.6]13 / 76 (17.1) [9.4, 27.5]
RegionNorth America16 / 28 (57.1) [37.2, 75.5]4 / 37 (10.8) [3.0, 25.4]
Other37 / 61 (60.7) [47.3, 72.9]15 / 79 (19.0) [11.0, 29.4]

r / n: number of responders / number of eligible patients according to the respective response criteria;
SM: systemic mastocytosis; CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; IWG: International

Adapted from FDA Statistical review

What are the possible side effects?

RYDAPT can cause serious lung toxicity and harm to an unborn baby.

Common side effects of RYDAPT are nausea, vomiting, diarrhea, body swelling, musculoskeletal pain, abdominal pain, tiredness, upper respiratory tract infection, constipation, fever, headache, and shortness of breath.

What are the possible side effects (results of trials used to assess safety)?

The tables below summarize adverse reactions and laboratory abnormalities in the clinical trials.

Table 4. Adverse Reactions Reported in ≥ 10% of Patients with Advanced SM

 RYDAPT (100 mg twice daily)
N=142
Adverse Reaction aAll grades
%
Grade≥3
%
Gastrointestinal disorders
   Nausea826
   Vomiting686
   Diarrhea a548
   Abdominal pain a346
   Constipation29<>
   Gastrointestinal hemorrhage a139
General disorders and administration site conditions
   Edema a407
   Fatigue a349
   Pyrexia274
Infections and infestations
   Upper respiratory tract infection a301
   Urinary tract infection a163
   Pneumonia a108
   Herpesvirus infection a101
Musculoskeletal and connective tissue disorders
   Musculoskeletal pain a354
   Arthralgia192
Nervous system disorders
   Headache a261
   Dizziness130
Respiratory, thoracic and mediastinal disorders
   Dyspnea a237
   Cough a18<>
   Pleural effusion134
   Epistaxis123
Skin and subcutaneous disorders
   Rash a143
Investigations
   QT prolonged11<>
Psychiatric disorders
   Insomnia110
Renal disorders
   Renal insufficiency a115
Toxicity was graded per NCI CTCAE v3.
Represents adverse reactions, excluding laboratory terms, occurring up to 28 days after last midostaurin dose, regardless of baseline grade.
a Grouped terms
Upper respiratory tract infection: e.g. nasopharyngitis, upper respiratory tract infections
Urinary tract infection: e.g. urinary tract infection, cystitis
Pneumonia: e.g. pneumonia, lung infection
Herpesvirus infection: e.g. oral herpes, herpes zoster
Headache: e.g. headache, sinus headache
Dyspnea: e.g. dyspnea, bronchospasm, respiratory failure
Cough: e.g. cough, productive cough
Diarrhea: e.g. diarrhea, gastroenteritis, colitis
Abdominal pain: e.g. abdominal pain, abdominal pain upper
Gastrointestinal hemorrhage: e.g. gastrointestinal hemorrhage, hemorrhoidal hemorrhage, duodenal ulcer hemorrhage
Fatigue: e.g. fatigue, asthenia
Rash: e.g. rash, rash maculo-papular, erythema multiforme
Musculoskeletal pain: e.g. back pain, musculoskeletal pain, pain in extremity
Renal insufficiency: e.g. blood creatinine increased, renal failure, acute kidney injury
Edema: e.g. edema, edema peripheral

RYDAPT Prescribing Information

Table 5. Most Common (≥ 20%) New or Worsening Laboratory Abnormalities Reported in Patients with Advanced SM

 RYDAPT (100 mg twice daily)
N=142
TestAll grades
%
Grade 3-5
%
Hematology
Anemia6040
Thrombocytopenia5322
Lymphopenia6742
Leukopenia6118
Neutropenia5020
Chemistry
Hyperglycemia a8019
Hypocalcemia392
Hypoalbuminemia271
Hyponatremia345
Alk phos increase3911
Lipase increase3718
Hyperuricemia3811
ALT increase314
AST increase323
Hypomagnesemia230
Hypokalemia256
Hyperbilirubinemia294
GGT increase357
Bicarbonate decrease18<>
Creatinine increase25<>
Hyperkalemia234
Hypophosphatemia252
Amylase increase206

Includes abnormalities occurring up to 28 days after last midostaurin dose, if new or worsened from baseline or if baseline was unknown.
a Nonfasting
RYDAPT Prescribing Information

Were there any differences in side effects among sex, race and age?

  • Sex: The occurrence of side effects was similar in men and women.
  • Race: The majority of patients in the clinical trials were White. Differences in side effects among races could not be determined due to small number of patients in other races.
  • Age: The occurrence of side effects was similar in patients younger and older than 65 years of age.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

The table below summarizes adverse events during the clinical trials by sex, and age subgroup. Racial subgroup differences were not investigated since the majority of patients were white.
Because of the small sample size, these exploratory analyses should be interpreted with caution.

Table 6. Subgroup Analysis of Adverse Events by Sex

 

Men
N=91
n (%)

Women
N=51
n (%)

Any grade event

91 (100)

51(100)

Grade ≥3  event

76 (84)

43 (84)

Any SAE

65 (71)

32 (63)

Grade ≥3  SAE

60 (66)

30 (59)

SAE=serious adverse event

Table 7. Subgroup Analysis of Adverse Events by Age

 

Age < 65="">
N=78
n (%)

Age ≥ 65Years
N=64
n (%)

Any grade event

78 (100)

64 (100)

Grade ≥3  event

64 (82)

55 (86)

Any SAE

55 (71)

42 (66)

Grade ≥3  SAE

49 (63)

41 (64)

SAE=serious adverse event
Adapted from Clinical trial report

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved RYDAPT based on evidence from two clinical trials of 142 patients total with advanced mastocytosis. The trials were conducted in 31 centers in Europe, North America, and Australia.

Presented below are patients from both trials who took at least one dose of RYDAPT. This is called the safety population.

Figure 1 summarizes how many men and women were in the clinical trials.

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were in the clinical trials. In total, 91 men (64%) and 51 women (36%) participated in the clinical trials.

Clinical trial data

Figure 2 and Table 1 below summarize the percentage of patients by race in the clinical trials.

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race enrolled in the clinical trials. In total, 132 Whites (93%), 2 Black or African American ( 1%) and 8 unknown(6%) participated in the clinical trials.

Clinical trial data

Table 1. Baseline Demographics by Race

Race

Number of Patients

Percentage

White

132

93

Black or African American

2

1

Unknown

8

6

Clinical trial data

Figure 3 summarizes how many patients of a certain age were enrolled in the clinical trials.

Figure 3. Baseline Demographics by Age

Pie chart summarizing how many individuals of certain age groups were in the clinical trial.  In total, 78 patients were younger than 65 years (55%) and 64 were 65 years and older. (45%).

Clinical trial data

Who participated in the trials?

The table below summarizes demographics of safety population patients in the clinical trials.

Table 8. Baseline Demographics of Patients in the Clinical Trials-safety population

Demographics parameters

Trial 1
(N=116)

Trial 2
(N=26)
 Total
(N=142)
Age 
       Median (range)
       < 65="" years,="" n="">
       ≥ 65 years, n (%)
       ≥ 70 years, n (%)

63 (25‐82)
65  (66)
51 (44)
34 (29)

64 (24‐79)
13 (50)
13 (50)
5 (19)

63 (24-82)
78 (55)
64 (45)
39 (27)
 Sex
       Men, n (%)
       Women, n (%)

76(66)
40 (34)

15 (58)
11 (42)

91 (64)
51 (36)
Race
       White, n (%)
       Black or African American n (%)
       Other or unknown, n (%)

111 (96)
2 (2)
3 (3)

21 (81)
0 (0)
5 (19)

132 (93)
2 (1)
8 (6)
Ethnicity
       Hispanic or Latino, n (%)
       Not Hispanic or Latino, n (%)
       Missing

3 (3)
110 (95)
3 (3)

1 (4)
24 (92)
1 (4)

4 (3)
134 (94)
4 (3)

Adapted from FDA Clinical review

How were the trials designed?

There were two trials that evaluated benefit and side effects of RYDAPT. All patients had advanced mastocytosis and received RYDAPT two times a day until progression of the disease or unacceptable side effects.

In Trial 1, the benefit of RYDAPT was evaluated after 6 cycles of therapy by measuring how well the patients responded and by how long that response lasted. In Trial 2, the benefit of RYDAPT was evaluated after 2 cycles of therapy by measuring how well the patients responded and by how long that response lasted.

How were the trials designed?

The safety and efficacy of RYDAPT were established in two trials of patients with advanced mastocytosis.

Trial 1 was a multicenter, single-arm, open-label trial in patients with advanced SM. RYDAPT was administrated orally at 100 mg twice daily until disease progression or intolerable toxicity. The primary endpoint was confirmed complete remission (CR) plus incomplete remission (ICR) by 6 cycles of RYDAPT by modified Valent criteria for ASM and SM-AHN.

Supportive evidence was assessed from a second trial that was a multicenter, single-arm, open-label trial of patients with advanced SM. The primary endpoint was ORR assessed by investigators after 2 cycles of treatment based on the original Valent criteria.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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