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 |
Subgroup | Response 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 years | 26 / 43 (60.5) [44.4, 75.0] | 4 / 51 (7.8) [2.2, 18.9] | |
| Sex | Women | 22 / 32 (68.8) [50.0, 83.9] | 6 / 40 (15.0) [5.7, 29.8] |
| Men | 31 / 57 (54.4) [40.7, 67.6] | 13 / 76 (17.1) [9.4, 27.5] | |
| Region | North America | 16 / 28 (57.1) [37.2, 75.5] | 4 / 37 (10.8) [3.0, 25.4] |
| Other | 37 / 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 a | All grades % |
Grade≥3 % |
| Gastrointestinal disorders | ||
| Nausea | 82 | 6 |
| Vomiting | 68 | 6 |
| Diarrhea a | 54 | 8 |
| Abdominal pain a | 34 | 6 |
| Constipation | 29 | <> |
| Gastrointestinal hemorrhage a | 13 | 9 |
| General disorders and administration site conditions | ||
| Edema a | 40 | 7 |
| Fatigue a | 34 | 9 |
| Pyrexia | 27 | 4 |
| Infections and infestations | ||
| Upper respiratory tract infection a | 30 | 1 |
| Urinary tract infection a | 16 | 3 |
| Pneumonia a | 10 | 8 |
| Herpesvirus infection a | 10 | 1 |
| Musculoskeletal and connective tissue disorders | ||
| Musculoskeletal pain a | 35 | 4 |
| Arthralgia | 19 | 2 |
| Nervous system disorders | ||
| Headache a | 26 | 1 |
| Dizziness | 13 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea a | 23 | 7 |
| Cough a | 18 | <> |
| Pleural effusion | 13 | 4 |
| Epistaxis | 12 | 3 |
| Skin and subcutaneous disorders | ||
| Rash a | 14 | 3 |
| Investigations | ||
| QT prolonged | 11 | <> |
| Psychiatric disorders | ||
| Insomnia | 11 | 0 |
| Renal disorders | ||
| Renal insufficiency a | 11 | 5 |
| 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 |
||
|---|---|---|
| Test | All grades % |
Grade 3-5 % |
| Hematology | ||
| Anemia | 60 | 40 |
| Thrombocytopenia | 53 | 22 |
| Lymphopenia | 67 | 42 |
| Leukopenia | 61 | 18 |
| Neutropenia | 50 | 20 |
| Chemistry | ||
| Hyperglycemia a | 80 | 19 |
| Hypocalcemia | 39 | 2 |
| Hypoalbuminemia | 27 | 1 |
| Hyponatremia | 34 | 5 |
| Alk phos increase | 39 | 11 |
| Lipase increase | 37 | 18 |
| Hyperuricemia | 38 | 11 |
| ALT increase | 31 | 4 |
| AST increase | 32 | 3 |
| Hypomagnesemia | 23 | 0 |
| Hypokalemia | 25 | 6 |
| Hyperbilirubinemia | 29 | 4 |
| GGT increase | 35 | 7 |
| Bicarbonate decrease | 18 | <> |
| Creatinine increase | 25 | <> |
| Hyperkalemia | 23 | 4 |
| Hypophosphatemia | 25 | 2 |
| Amylase increase | 20 | 6 |
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 |
Women |
|---|---|---|
|
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=""> |
Age ≥ 65Years |
|---|---|---|
|
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
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
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
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 |
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.