Efficacy and Safety of Midostaurin in Patients With Aggressive Systemic Mastocytosis or Mast Cell Leukemia

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00782067
• Collaborator: (none)
• Enrollment: 116
• Locations: 29
• Arm: 1
• Actual Duration (Months): 106.3
• Patients Per Site: 4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study was to determine the efficacy and safety of twice daily (bid) oral midostaurin in patients with Aggressive Systemic Mastocytosis (ASM) or Mast Cell Leukemia (MCL) with or without an Associated Hematological clonal Non-Mast cell lineage Disease (AHNMD).

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Midostaurin (PKC412)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 116 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single Arm, Phase II, Open-Label Study to Determine the Efficacy of 100mg Twice Daily Oral Dosing of Midostaurin Administered to Patients With Aggressive Systemic Mastocytosis or Mast Cell Leukemia +/- an Associated Hematological Clonal Non-Mast Cell Lineage Disease
• Actual Study Start Date: Oct 13, 2008
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Aug 24, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Midostaurin (PKC412) Midostaurin was administered at a dose of 100 mg twice daily (bid) in continuous cycles of 28 days until disease progression, intolerable toxicity or withdrawal due to any cause, whichever occurred first.	Drug: Midostaurin (PKC412); Midostaurin was provided as 25 mg soft gelatin capsules for oral administration.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Overall Response Rate (ORR) [6 months]

   Overall Response Rate (ORR) was defined as the percentage of participants who classified as confirmed responders (Major Response (MR) or Partial Response (PR)) by the adjudication of the SSC and based on a Modified Valent Criteria. A major responder had complete resolution of at least one C-Finding and no progression in other C-Findings. A partial responder showed a measurable improvement in one or more C-Finding(s) without confirmed progression in other C-Findings. A C-Finding was a Clinical Finding, which was considered by the investigator and corroborated by the Study Steering Committee (SSC) Chairperson or designee, attributable to the mast cell disease component and not the associated hematological clonal non-mast cell lineage disease (AHNMD) component or any other cause.

Secondary Outcome Measures

1. Median Time to Duration of Response (DoR) [Up 5 years]

   The Duration of response (DoR) was defined as the time from first onset of confirmed response (MR or PR) to the date of first documented and confirmed progression or death due to ASM/MCL.

2. Median Time to Response (TTR) [Up 5 years]

   The Time to response (TTR) was defined as the time from start of treatment until the date of onset of confirmed response (MR or PR).

3. Median Time to Progression-Free Survival (PFS) [Up 5 years]

   The Progression-free survival (PFS) is defined as the time from start of treatment to the date of the first documented and confirmed progression or death due to any cause.

4. Median Time to Overall Survival (OS) [Up 5 years]

   The Overall Survival (OS) is defined as the time from start of treatment to the date of death due to any cause.

5. Long-term Safety and Tolerability of Midostaurin [Up to 30 days after last dose of study treatment]

   Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC)

6. Histopathologic Response [Up 5 years]

   Histopathologic response was summarized to demonstrate the change from baseline in percentage of mast cell infiltrations in the Bone Marrow (BM) and related serum tryptase levels.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key inclusion criteria:

• Patients ≥ 18 years of age who provided written informed consent, Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 and a life expectancy of >12 weeks, electrocardiogram with a QTcF of ≤ 450 ms, with a diagnosis of SM and sub-variants based on WHO criteria.

• Patients with ASM or MCL were to have one or more measurable clinical findings (termed "C-findings") and defined as those attributable to the mast cell disease component and not to AHNMD or any other cause.

• Patients with MCL were to have BM aspirate smears with ≥ 20% immature MCs. Patients with AHNMD were eligible if it was not life-threatening or in an acute stage.

Key exclusion criteria:

• Patients with cardiovascular disease including congestive heart failure class III or IV according to the New York Heart Association classification, left ventricular ejection fraction (LVEF) of <50%, myocardial infarction within the previous 6 months, or poorly controlled hypertension.

• Patients with a heart block of any degree at screening (for Canada only).

• Patients with an AHNMD who required immediate cytoreductive therapy or targeted therapy (other than midostaurin).

• Patients who had demonstrated relapse after 3 or more prior regimens of SM treatment regardless of treatment regimen for supportive care (e.g., symptom-limiting therapies).

• Patients who had received any investigational agent, targeted therapy, chemotherapy, interferon-α, or 2 chlorodeoxyadenosine within 30 days prior to start of midostaurin treatment.

• Patients who had ASM with eosinophilia and known positivity for the FIP1L1- PDGFRα fusion unless they had demonstrated relapse or disease progression on prior imatinib therapy.

• Patients who had received any treatment with midostaurin prior to study entry.

• Patients who had received hematopoietic growth factor support within 14 days of Day 1 of midostaurin treatment.

• Patients who had any surgical procedure, excluding central venous catheter placement or other minor procedures (e.g. skin biopsy) within 14 days of Day 1 of midostaurin treatment.

• Patients with any pulmonary infiltrate, including those suspected to be of infectious origin. In particular, patients with resolution of clinical symptoms of pulmonary infection but with residual pulmonary infiltrates on chest x-ray were not eligible until the pulmonary infiltrates had completely resolved. Exception: patients with ASM/MCL ± AHNMD-related pleural effusion as judged by the Investigator and approved by the SSC Chairperson or designee were permitted to enter the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California at Los Angeles Dept. of Hematology Clinic	Los Angeles	California	United States	90095
2	Stanford University Medical Center Stanford University 2	Stanford	California	United States	94305-5750
3	Georgia Health Sciences University Dept.ofMedicalCollegeOfGeorgia	Augusta	Georgia	United States	30912
4	Dana Farber Cancer Institute Hematology / Oncology	Boston	Massachusetts	United States	02215
5	University of Michigan Comprehensive Cancer Center DeptofMichiganCancerCenter(3)	Ann Arbor	Michigan	United States	[phone]
6	Memorial Sloan Kettering Cancer Center Dept. of MSKCC (2)	New York	New York	United States	10021
7	Oregon Health and Science University Dept. Hematologic Malignancies	Portland	Oregon	United States	97239
8	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
9	Virginia Commonwealth University SC	Richmond	Virginia	United States	23284
10	Novartis Investigative Site	Camperdown	New South Wales	Australia	2050
11	Novartis Investigative Site	Prahran	Victoria	Australia	3181
12	Novartis Investigative Site	Wien		Austria	1090
13	Novartis Investigative Site	Leuven		Belgium	3000
14	Novartis Investigative Site	London	Ontario	Canada	N6A 4G4
15	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2M9
16	Novartis Investigative Site	Amiens		France	80054
17	Novartis Investigative Site	Paris cedex 15		France	75015
18	Novartis Investigative Site	Mannheim	Baden-Württemberg	Germany	68305
19	Novartis Investigative Site	Koeln	Nordrhein-Westfalen	Germany	50937
20	Novartis Investigative Site	Berlin		Germany	13353
21	Novartis Investigative Site	Hamburg		Germany	20246
22	Novartis Investigative Site	Leipzig		Germany	04103
23	Novartis Investigative Site	Groningen		Netherlands	9713 GZ
24	Novartis Investigative Site	Oslo		Norway	NO-0310
25	Novartis Investigative Site	Gdansk		Poland	80-952
26	Novartis Investigative Site	Istanbul		Turkey	34093
27	Novartis Investigative Site	Glasgow - Scotland		United Kingdom	G12 OYN
28	Novartis Investigative Site	Liverpool		United Kingdom	L7 8XP
29	Novartis Investigative Site	London		United Kingdom	SE1 7EH

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00782067
• Other Study ID Numbers: CPKC412D2201; 2008-000280-42
• First Posted: Oct 29, 2008
• Last Update Posted: Nov 15, 2018
• Last Verified: Oct 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Aggressive systemic mastocytosis; mast cell leukemia; C-Findings; tyrosine kinase inhibitor; KIT mutation; AHNMD; Systemic; Aggressive
• Additional relevant MeSH terms: Leukemia; Mastocytosis; Mastocytosis, Systemic; Leukemia, Mast-Cell; Aggression; Midostaurin

Study Results

Participant Flow

Recruitment Details	This study was conducted at 29 centers in 12 countries worldwide (Australia, Austria, Belgium, Canada, France, Germany, Netherlands, Norway, Poland, Turkey, United Kingdom, United States).
Pre-assignment Detail	The Participant Flow was on the Full Analysis Set (FAS), the Baseline Characteristics were done on the FAS and Primary Efficacy Population (PEP). The Efficacy analysis was done on the PEP (except for the Overall Survival which was done on FAS and PEP). The Safety analysis was done on the Safety Set (SS).

Arm/Group Title	Midostaurin (PKC412)
Arm/Group Description	Midostaurin was administered at a dose of 100 mg twice daily (bid) in continuous cycles of 28 days until disease progression, intolerable toxicity or withdrawal due to any cause, whichever occurred first.
Period Title: Overall Study
STARTED	116
Safety Set (SS)	116
Primary Efficacy Population (PEP)	89
COMPLETED	0
NOT COMPLETED	116

Baseline Characteristics

Arm/Group Title	Midostaurin (PKC412)
Arm/Group Description	Midostaurin was administered at a dose of 100 mg twice daily (bid) in continuous cycles of 28 days until disease progression, intolerable toxicity or withdrawal due to any cause, whichever occurred first.
Overall Participants	116
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.8 (11.76)
Sex: Female, Male (Count of Participants)
Female	40 34.5%
Male	76 65.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 1.7%
White	111 95.7%
More than one race	0 0%
Unknown or Not Reported	3 2.6%
Age Continuous (PEP) (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.0 (11.59)
Sex: Female, Male (PEP) (Number) [Number]
PEP (n=89) - Female	32 27.6%
PEP (n=89) - Male	57 49.1%
Race (PEP) (Number) [Number]
PEP (n=89) - Black	1 0.9%
PEP (n=89) - White	86 74.1%
PEP (n=89) - Other/Missing	2 1.7%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Overall Response Rate (ORR)
Description	Overall Response Rate (ORR) was defined as the percentage of participants who classified as confirmed responders (Major Response (MR) or Partial Response (PR)) by the adjudication of the SSC and based on a Modified Valent Criteria. A major responder had complete resolution of at least one C-Finding and no progression in other C-Findings. A partial responder showed a measurable improvement in one or more C-Finding(s) without confirmed progression in other C-Findings. A C-Finding was a Clinical Finding, which was considered by the investigator and corroborated by the Study Steering Committee (SSC) Chairperson or designee, attributable to the mast cell disease component and not the associated hematological clonal non-mast cell lineage disease (AHNMD) component or any other cause.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Primary Efficacy Population: participants assigned to study treatment who met diagnostic criteria for aggressive systemic mastocytosis or mast cell leukemia and presented with at least 1 measurable C-Finding at study entry and/or participants with transfusion dependent anemia due to their underlying disease at study entry as confirmed by the SCC.

Arm/Group Title	Midostaurin (PKC412)
Arm/Group Description	Midostaurin was administered at a dose of 100 mg twice daily (bid) in continuous cycles of 28 days until disease progression, intolerable toxicity or withdrawal due to any cause, whichever occurred first.
Measure Participants	89
Number (95% Confidence Interval) [Percentage of participants]	59.6 51.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Midostaurin (PKC412)
	Comments
	Type of Statistical Test	Other
	Comments	Single arm study
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Null hypothesis: ORR <= 30% Alternative hypothesis: ORR >= 50%
	Method	Exact Binomial Test
	Comments
Other Statistical Analysis		Exact Binomial 95% Confidence Interval

2. Secondary Outcome

Title	Median Time to Duration of Response (DoR)
Description	The Duration of response (DoR) was defined as the time from first onset of confirmed response (MR or PR) to the date of first documented and confirmed progression or death due to ASM/MCL.
Time Frame	Up 5 years

Outcome Measure Data

Analysis Population Description

Primary Efficacy Population (PEP), which consisted of all participants with a confirmed response, was considered.

Arm/Group Title	Midostaurin (PKC412)
Arm/Group Description	Midostaurin was administered at a dose of 100 mg twice daily (bid) in continuous cycles of 28 days until disease progression, intolerable toxicity or withdrawal due to any cause, whichever occurred first.
Measure Participants	89
Median (95% Confidence Interval) [Months]	31.4

3. Secondary Outcome

Title	Median Time to Response (TTR)
Description	The Time to response (TTR) was defined as the time from start of treatment until the date of onset of confirmed response (MR or PR).
Time Frame	Up 5 years

Outcome Measure Data

Analysis Population Description

Primary Efficacy Population (PEP), which consisted of all participants with a confirmed response, was considered.

Arm/Group Title	Midostaurin (PKC412)
Arm/Group Description	Midostaurin was administered at a dose of 100 mg twice daily (bid) in continuous cycles of 28 days until disease progression, intolerable toxicity or withdrawal due to any cause, whichever occurred first.
Measure Participants	89
Median (Full Range) [Months]	0.3

4. Secondary Outcome

Title	Median Time to Progression-Free Survival (PFS)
Description	The Progression-free survival (PFS) is defined as the time from start of treatment to the date of the first documented and confirmed progression or death due to any cause.
Time Frame	Up 5 years

Outcome Measure Data

Analysis Population Description

Primary Efficacy Population (PEP), which consisted of all participants with a confirmed response, was considered.

Arm/Group Title	Midostaurin (PKC412)
Arm/Group Description	Midostaurin was administered at a dose of 100 mg twice daily (bid) in continuous cycles of 28 days until disease progression, intolerable toxicity or withdrawal due to any cause, whichever occurred first.
Measure Participants	89
Median (95% Confidence Interval) [Months]	17.0

5. Secondary Outcome

Title	Median Time to Overall Survival (OS)
Description	The Overall Survival (OS) is defined as the time from start of treatment to the date of death due to any cause.
Time Frame	Up 5 years

Outcome Measure Data

Analysis Population Description

Primary Efficacy Population (PEP), which consisted of all participants with a confirmed response and the Full Analysis Set (FAS), which consisted of all patients who received at least one dose of study drug were considered.

Arm/Group Title	Midostaurin (PKC412)
Arm/Group Description	Midostaurin was administered at a dose of 100 mg twice daily (bid) in continuous cycles of 28 days until disease progression, intolerable toxicity or withdrawal due to any cause, whichever occurred first.
Measure Participants	116
Primary Efficacy Population (PEP) (n=89)	26.8
Full Analysis Set (FAS) (n=116)	28.7

6. Secondary Outcome

Title	Long-term Safety and Tolerability of Midostaurin
Description	Analysis of frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC)
Time Frame	Up to 30 days after last dose of study treatment

Outcome Measure Data

Analysis Population Description

Safety Set (SS)

Arm/Group Title	Midostaurin (PKC412)
Arm/Group Description	Midostaurin was administered at a dose of 100 mg twice daily (bid) in continuous cycles of 28 days until disease progression, intolerable toxicity or withdrawal due to any cause, whichever occurred first.
Measure Participants	116
AEs by Primary System Organ Class (SOC) (n=116)	100 86.2%
SAEs by Primary System Organ Class (SOC) (n=88)	75.9 65.4%
Deaths by Primary System Organ Class (SOC) (n=25)	21.6 18.6%

7. Secondary Outcome

Title	Histopathologic Response
Description	Histopathologic response was summarized to demonstrate the change from baseline in percentage of mast cell infiltrations in the Bone Marrow (BM) and related serum tryptase levels.
Time Frame	Up 5 years

Outcome Measure Data

Analysis Population Description

Primary Efficacy Population (PEP); for each patient, the best improvement relative to Baseline was considered.

Arm/Group Title	Midostaurin (PKC412)
Arm/Group Description	Midostaurin was administered at a dose of 100 mg twice daily (bid) in continuous cycles of 28 days until disease progression, intolerable toxicity or withdrawal due to any cause, whichever occurred first.
Measure Participants	89
>50% decrease in mast cell (MC) (n=41)	46.1 39.7%
>0-<=50% decrease in mast cell (MC) (n=19)	21.3 18.4%
>50% decrease in serum tryptase (n=52)	58.4 50.3%
>0-<=50% decrease in serum tryptase (n=25)	28.1 24.2%

Adverse Events

Time Frame	Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 8 years and 7 months.
Adverse Event Reporting Description	Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events fields "number of deaths resulting from adverse events" all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
Arm/Group Title	Midostaurin (PKC412)
Arm/Group Description	Midostaurin was administered at a dose of 100 mg twice daily (bid) in continuous cycles of 28 days until disease progression, intolerable toxicity or withdrawal due to any cause, whichever occurred first.
All Cause Mortality
	Midostaurin (PKC412)
	Affected / at Risk (%)	# Events
Total	25/116 (21.6%)
Serious Adverse Events
	Midostaurin (PKC412)
	Affected / at Risk (%)	# Events
Total	88/116 (75.9%)
Blood and lymphatic system disorders
Anaemia	8/116 (6.9%)
Coagulopathy	1/116 (0.9%)
Cytopenia	1/116 (0.9%)
Disseminated intravascular coagulation	1/116 (0.9%)
Eosinophilia	1/116 (0.9%)
Febrile neutropenia	6/116 (5.2%)
Granulocytopenia	1/116 (0.9%)
Leukocytosis	3/116 (2.6%)
Lymphadenopathy	1/116 (0.9%)
Mastocytosis	1/116 (0.9%)
Neutropenia	1/116 (0.9%)
Splenic infarction	2/116 (1.7%)
Thrombocytopenia	1/116 (0.9%)
Cardiac disorders
Acute myocardial infarction	1/116 (0.9%)
Angina pectoris	1/116 (0.9%)
Aortic valve stenosis	2/116 (1.7%)
Atrial fibrillation	2/116 (1.7%)
Bradycardia	1/116 (0.9%)
Cardiac arrest	2/116 (1.7%)
Cardiac failure	2/116 (1.7%)
Cardiac failure chronic	1/116 (0.9%)
Cardiac failure congestive	1/116 (0.9%)
Coronary artery disease	3/116 (2.6%)
Extrasystoles	1/116 (0.9%)
Heart valve incompetence	1/116 (0.9%)
Left ventricular failure	1/116 (0.9%)
Myocardial infarction	2/116 (1.7%)
Right ventricular failure	1/116 (0.9%)
Sinus tachycardia	1/116 (0.9%)
Tachycardia	1/116 (0.9%)
Ventricular tachycardia	2/116 (1.7%)
Congenital, familial and genetic disorders
Aplasia	1/116 (0.9%)
Ear and labyrinth disorders
Ear disorder	1/116 (0.9%)
Eye disorders
Papilloedema	1/116 (0.9%)
Retinopathy hypertensive	1/116 (0.9%)
Uveitis	1/116 (0.9%)
Gastrointestinal disorders
Abdominal discomfort	1/116 (0.9%)
Abdominal hernia	1/116 (0.9%)
Abdominal pain	1/116 (0.9%)
Abdominal pain upper	1/116 (0.9%)
Ascites	5/116 (4.3%)
Colitis	2/116 (1.7%)
Constipation	1/116 (0.9%)
Diarrhoea	8/116 (6.9%)
Gastric haemorrhage	1/116 (0.9%)
Gastric ulcer	2/116 (1.7%)
Gastric varices haemorrhage	1/116 (0.9%)
Gastritis	1/116 (0.9%)
Gastritis haemorrhagic	1/116 (0.9%)
Gastrointestinal disorder	2/116 (1.7%)
Gastrointestinal haemorrhage	7/116 (6%)
Gastrointestinal toxicity	1/116 (0.9%)
Gastrointestinal ulcer haemorrhage	1/116 (0.9%)
Haemorrhoids	1/116 (0.9%)
Intestinal haemorrhage	1/116 (0.9%)
Intestinal mass	1/116 (0.9%)
Lower gastrointestinal haemorrhage	1/116 (0.9%)
Melaena	1/116 (0.9%)
Nausea	1/116 (0.9%)
Oesophageal varices haemorrhage	2/116 (1.7%)
Pancreatitis acute	1/116 (0.9%)
Small intestinal obstruction	1/116 (0.9%)
Stomatitis	1/116 (0.9%)
Umbilical hernia	1/116 (0.9%)
Umbilical hernia, obstructive	1/116 (0.9%)
Upper gastrointestinal haemorrhage	3/116 (2.6%)
Varices oesophageal	1/116 (0.9%)
Vomiting	5/116 (4.3%)
General disorders
Asthenia	1/116 (0.9%)
Disease progression	2/116 (1.7%)
Fatigue	3/116 (2.6%)
General physical health deterioration	2/116 (1.7%)
Generalised oedema	1/116 (0.9%)
Malaise	2/116 (1.7%)
Multiple organ dysfunction syndrome	3/116 (2.6%)
Oedema peripheral	2/116 (1.7%)
Pyrexia	7/116 (6%)
Hepatobiliary disorders
Bile duct stenosis	1/116 (0.9%)
Cholecystitis	1/116 (0.9%)
Cholecystitis chronic	1/116 (0.9%)
Cholelithiasis	1/116 (0.9%)
Hepatic cirrhosis	1/116 (0.9%)
Hepatic failure	2/116 (1.7%)
Hepatorenal syndrome	1/116 (0.9%)
Immune system disorders
Anaphylactic shock	1/116 (0.9%)
Infections and infestations
Bronchitis	1/116 (0.9%)
Campylobacter colitis	1/116 (0.9%)
Cellulitis	1/116 (0.9%)
Clostridium difficile colitis	1/116 (0.9%)
Endocarditis	1/116 (0.9%)
Erysipelas	2/116 (1.7%)
Escherichia urinary tract infection	1/116 (0.9%)
Gastroenteritis	1/116 (0.9%)
Herpes zoster	1/116 (0.9%)
Infection	1/116 (0.9%)
Intervertebral discitis	1/116 (0.9%)
Lung infection	1/116 (0.9%)
Malaria	1/116 (0.9%)
Nocardiosis	1/116 (0.9%)
Otitis externa	1/116 (0.9%)
Otitis media	1/116 (0.9%)
Peritonitis	1/116 (0.9%)
Pneumonia	11/116 (9.5%)
Sepsis	10/116 (8.6%)
Sinusitis	1/116 (0.9%)
Skin bacterial infection	1/116 (0.9%)
Splenic infection	1/116 (0.9%)
Staphylococcal sepsis	1/116 (0.9%)
Upper respiratory tract infection	1/116 (0.9%)
Urethritis	1/116 (0.9%)
Urinary tract infection	5/116 (4.3%)
Wound infection	1/116 (0.9%)
Injury, poisoning and procedural complications
Lumbar vertebral fracture	1/116 (0.9%)
Muscle strain	1/116 (0.9%)
Post procedural haematoma	1/116 (0.9%)
Postoperative ileus	1/116 (0.9%)
Stoma site haemorrhage	1/116 (0.9%)
Subdural haematoma	1/116 (0.9%)
Transfusion reaction	1/116 (0.9%)
Transfusion related complication	1/116 (0.9%)
Wound dehiscence	1/116 (0.9%)
Investigations
Amylase increased	1/116 (0.9%)
Bleeding time prolonged	1/116 (0.9%)
Electrocardiogram QT prolonged	1/116 (0.9%)
Electrocardiogram ST segment depression	1/116 (0.9%)
Troponin increased	1/116 (0.9%)
Metabolism and nutrition disorders
Failure to thrive	1/116 (0.9%)
Gout	1/116 (0.9%)
Hypercalcaemia	1/116 (0.9%)
Hyperglycaemia	2/116 (1.7%)
Tumour lysis syndrome	1/116 (0.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/116 (0.9%)
Bone pain	1/116 (0.9%)
Intervertebral disc protrusion	1/116 (0.9%)
Muscle haemorrhage	1/116 (0.9%)
Musculoskeletal stiffness	1/116 (0.9%)
Myalgia	1/116 (0.9%)
Osteolysis	1/116 (0.9%)
Osteonecrosis of jaw	1/116 (0.9%)
Osteosclerosis	1/116 (0.9%)
Spinal pain	1/116 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia	2/116 (1.7%)
Acute myeloid leukaemia	5/116 (4.3%)
Adenocarcinoma of colon	1/116 (0.9%)
Haematological malignancy	1/116 (0.9%)
Lung neoplasm malignant	1/116 (0.9%)
Myelofibrosis	1/116 (0.9%)
Refractory cytopenia with unilineage dysplasia	1/116 (0.9%)
Squamous cell carcinoma	1/116 (0.9%)
Tumour compression	1/116 (0.9%)
Nervous system disorders
Cerebrovascular accident	1/116 (0.9%)
Headache	1/116 (0.9%)
Intracranial aneurysm	1/116 (0.9%)
Loss of consciousness	1/116 (0.9%)
Memory impairment	1/116 (0.9%)
Restless legs syndrome	1/116 (0.9%)
Seizure	3/116 (2.6%)
Psychiatric disorders
Anxiety	1/116 (0.9%)
Insomnia	1/116 (0.9%)
Mental status changes	1/116 (0.9%)
Renal and urinary disorders
Acute kidney injury	4/116 (3.4%)
Calculus urinary	1/116 (0.9%)
Renal failure	5/116 (4.3%)
Renal impairment	1/116 (0.9%)
Urethral stenosis	1/116 (0.9%)
Urinary retention	1/116 (0.9%)
Reproductive system and breast disorders
Ovarian cyst	1/116 (0.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	6/116 (5.2%)
Epistaxis	3/116 (2.6%)
Orthopnoea	1/116 (0.9%)
Pleural effusion	5/116 (4.3%)
Pneumonitis	1/116 (0.9%)
Pulmonary haemorrhage	1/116 (0.9%)
Respiratory failure	2/116 (1.7%)
Tachypnoea	1/116 (0.9%)
Skin and subcutaneous tissue disorders
Angioedema	1/116 (0.9%)
Rash papular	1/116 (0.9%)
Skin ulcer	2/116 (1.7%)
Toxic skin eruption	3/116 (2.6%)
Surgical and medical procedures
Heart valve operation	1/116 (0.9%)
Vascular disorders
Arterial occlusive disease	1/116 (0.9%)
Flushing	1/116 (0.9%)
Haemodynamic instability	1/116 (0.9%)
Hypotension	2/116 (1.7%)
Peripheral artery stenosis	1/116 (0.9%)
Other (Not Including Serious) Adverse Events
	Midostaurin (PKC412)
	Affected / at Risk (%)	# Events
Total	115/116 (99.1%)
Blood and lymphatic system disorders
Anaemia	39/116 (33.6%)
Leukopenia	7/116 (6%)
Neutropenia	17/116 (14.7%)
Thrombocytopenia	23/116 (19.8%)
Ear and labyrinth disorders
Vertigo	6/116 (5.2%)
Gastrointestinal disorders
Abdominal distension	7/116 (6%)
Abdominal pain	34/116 (29.3%)
Abdominal pain upper	10/116 (8.6%)
Ascites	9/116 (7.8%)
Constipation	29/116 (25%)
Diarrhoea	62/116 (53.4%)
Dyspepsia	7/116 (6%)
Flatulence	6/116 (5.2%)
Nausea	94/116 (81%)
Vomiting	77/116 (66.4%)
General disorders
Chills	6/116 (5.2%)
Fatigue	33/116 (28.4%)
Oedema	6/116 (5.2%)
Oedema peripheral	41/116 (35.3%)
Pain	7/116 (6%)
Pyrexia	30/116 (25.9%)
Infections and infestations
Bronchitis	8/116 (6.9%)
Cystitis	7/116 (6%)
Oral herpes	6/116 (5.2%)
Pneumonia	6/116 (5.2%)
Sinusitis	6/116 (5.2%)
Upper respiratory tract infection	12/116 (10.3%)
Urinary tract infection	14/116 (12.1%)
Viral upper respiratory tract infection	20/116 (17.2%)
Injury, poisoning and procedural complications
Contusion	7/116 (6%)
Investigations
Alanine aminotransferase increased	6/116 (5.2%)
Amylase increased	7/116 (6%)
Blood alkaline phosphatase increased	9/116 (7.8%)
Blood creatinine increased	6/116 (5.2%)
Electrocardiogram QT prolonged	12/116 (10.3%)
Gamma-glutamyltransferase increased	11/116 (9.5%)
Lipase increased	11/116 (9.5%)
Weight decreased	10/116 (8.6%)
Metabolism and nutrition disorders
Decreased appetite	11/116 (9.5%)
Hyperglycaemia	8/116 (6.9%)
Hyperkalaemia	7/116 (6%)
Hypocalcaemia	6/116 (5.2%)
Hypokalaemia	11/116 (9.5%)
Hypomagnesaemia	7/116 (6%)
Musculoskeletal and connective tissue disorders
Arthralgia	24/116 (20.7%)
Back pain	26/116 (22.4%)
Muscle spasms	13/116 (11.2%)
Musculoskeletal pain	19/116 (16.4%)
Myalgia	8/116 (6.9%)
Pain in extremity	9/116 (7.8%)
Nervous system disorders
Disturbance in attention	8/116 (6.9%)
Dizziness	16/116 (13.8%)
Headache	29/116 (25%)
Paraesthesia	6/116 (5.2%)
Psychiatric disorders
Anxiety	8/116 (6.9%)
Depression	13/116 (11.2%)
Insomnia	11/116 (9.5%)
Respiratory, thoracic and mediastinal disorders
Cough	22/116 (19%)
Dyspnoea	17/116 (14.7%)
Epistaxis	14/116 (12.1%)
Oropharyngeal pain	6/116 (5.2%)
Pleural effusion	9/116 (7.8%)
Skin and subcutaneous tissue disorders
Alopecia	7/116 (6%)
Hyperhidrosis	6/116 (5.2%)
Night sweats	10/116 (8.6%)
Pruritus	24/116 (20.7%)
Rash	7/116 (6%)
Vascular disorders
Flushing	8/116 (6.9%)
Haematoma	6/116 (5.2%)
Hypotension	11/116 (9.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.