A Study of the Safety and Preliminary Efficacy of Oral Midostaurin (PKC412) in Relapsed or Refractory Pediatric Leukemia

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00866281
• Collaborator: (none)
• Enrollment: 22
• Locations: 8
• Arms: 2
• Duration (Months): 60
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a phase I/II pediatric dose-ranging study that will evaluate the safety, tolerability, clinical response, pharmacokinetics and pharmacodynamics of midostaurin in patients <18 years of age who have relapsed or refractory acute leukemias that may benefit from administration of midostaurin, including MLL-rearranged ALL and FLT3 positive AML.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia	Drug: midostaurin	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II, Open-label, Dose-escalating Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Twice Daily Oral Midostaurin and to Evaluate the Preliminary Clinical and Pharmacodynamic Response in Pediatric Patients With Relapsed or Refractory Leukemia
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 30 mg/m^2 bid Participants received bodyweight and body surface area (BSA) stratified dose of midostaurin 30 mg/m^2 twice daily (bid) through oral route. The total daily dose in 30 mg/m^2 bid cohort was 60 mg/m^2.	Drug: midostaurin; Midostaurin 25 mg/mL oral solution was provided in bottles of 50 mL, administered with water. The pediatric starting dose of midostaurin was set at 30 mg/m2 bid and was not to exceed 60 mg/m2 bid.; Other Names: PKC412
Experimental: 60 mg/m^2 bid Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m^2 bid through oral route. The total daily dose in 60 mg/m^2 bid cohort was 120 mg/m^2.	Drug: midostaurin; Midostaurin 25 mg/mL oral solution was provided in bottles of 50 mL, administered with water. The pediatric starting dose of midostaurin was set at 30 mg/m2 bid and was not to exceed 60 mg/m2 bid.; Other Names: PKC412

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of Midostaurin- Posterior Probability of DLT [Baseline, End of dose escalation phase (6 months)]

   MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced dose limiting toxicity (DLT), based on a Bayesian logistic regression model (BLRM) employing the escalation with overdose control (EWOC) principle. A DLT was defined as a grade 3 or 4 non-hematological adverse event (AE) or abnormal laboratory value related to study drug. Mean and the 95% posterior probability estimates of having a DLT by age strata and dose is presented. Estimation of MTD and/or recommended dose for expansion (RDE) at the dose-escalation phase of the study was based upon the estimation of the probability of DLT for participants in the dose-determining set (DDS).

Secondary Outcome Measures

1. Percentage of Participants With Best Overall Response by Indication [Baseline, Day 15 (Day 1 of Cycle 2), Day 22 (Day 8 of Cycle 2), Day 29(Day 1 of Cycle 9), End of treatment (up to 24 months after last dose or until death whichever occurred first)]

   The best overall clinical response was determined as per the clinical assessment done by the investigator. Responders were defined as all participants with a best clinical response of leukemia free state, morphological complete remission, incomplete morphological complete remission, partial remission, bone marrow blast response, bone marrow minor blast response, peripheral blood blast response, minor peripheral blood blast response. Participants with stable disease, progressive disease and with missing tumour assessment or who discontinued the study or who died before having their first assessment were considered as non-responders. Stable disease was defined as failure to achieve any of the above response. Progressive disease was defined as doubling of the bone marrow blast percentage from baseline in participants with <40% bone marrow blasts at baseline, or a 50% increase in bone marrow blast percentage from baseline in participants with >40% bone marrow blasts at baseline,

2. Time to Response With Midostaurin [Baseline, End of treatment (up to 24 months after last dose or until death whichever occurred first)]

   Time to response was defined as the time from the date of start of midostaurin treatment to the date of first response. The best overall clinical response was determined as per the clinical assessment done by the investigator. Responders were defined as all participants with a best clinical response of leukemia free state, morphological complete remission, incomplete morphological complete remission, partial remission, bone marrow blast response, bone marrow minor blast response, peripheral blood blast response, minor peripheral blood blast response. Time to response was calculated by using the formula = (date of first response -date of start of midostaurin) +1 day.

3. Overall Survival With Midostaurin [Baseline, End of treatment (up to 24 months after last dose or until death whichever occurred first)]

   Overall survival (OS) was defined as the time from start of treatment to date of death due to any cause. The percentage (%) event-free probability estimates were obtained from the Kaplan-Meier survival estimates.

4. Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221 [Day 1, Day 5, Day 7, Day 15 (Day 1 of Cycle 2), Day 29 (Day 1 of Cycle 3)]

   The plasma concentrations of midostaurin (PKC412) and its two major metabolites, CGP62221 and CGP52421 were determined by using a validated liquid chromatography/tandem mass spectrometry method.

5. Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs or SAEs and Death During the Study [Baseline (start of study treatment) up to End of treatment (up to 24 months after last dose or until death whichever occurred first)]

   An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalization, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the participant or require medical or surgical intervention to prevent one of the aforementioned outcomes. Treatment related AEs or SAEs were defined as AEs or SAEs that were suspected to be related to study treatment as per investigator. On treatment death was a fatal event leading to permanent cessations of all vital functions of the body.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Months to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Mixed-lineage leukemia (MLL) gene rearranged Acute Lymphoblastic Leukemia (ALL), that does not respond to treatment or has relapsed from prior treatment; or FLT3 mutated Acute Myeloid Leukemia (AML) that does not respond to a second treatment or has relapsed from 2 prior treatments

• Normal organ function, and chest x-ray

• Expected survival greater than 8 weeks

• Can care for most of personal needs and perform at least minimum activity

Exclusion Criteria:

• Patients with symptomatic leukemic central nervous system involvement or isolated extramedullary leukemia

• Patients must not have received other treatments for leukemia within a predefined time period, 72 hours for medications, 2 months for transplants

• Patients with heart function that is not normal

• Patients with HIV or hepatitis

• Patients with another severe disease or medical condition besides leukemia Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Seattle Children's Hospital CPKC412A2114	Seattle	Washington	United States	98105
2	Novartis Investigative Site	Paris Cedex 19		France	75935
3	Novartis Investigative Site	Genova	GE	Italy	16147
4	Novartis Investigative Site	Monza	MB	Italy	20900
5	Novartis Investigative Site	Roma	RM	Italy	00165
6	Novartis Investigative Site	Torino	TO	Italy	10126
7	Novartis Investigative Site	Rotterdam		Netherlands	3015 GJ
8	Novartis Investigative Site	Stockholm		Sweden	SE-171 76

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00866281
• Other Study ID Numbers: CPKC412A2114; 2008-006931-11
• First Posted: Mar 20, 2009
• Last Update Posted: Dec 22, 2015
• Last Verified: Nov 1, 2015

• Keywords provided by Novartis Pharmaceuticals: Acute Myeloid Leukemia; AML; Acute Lymphoblastic Leukemia; ALL; midostaurin; PKC412; Pediatric relapsed or refractory FLT3 positive Acute Myeloid Leukemia; Pediatric relapsed or refractory Mixed-lineage leukemia gene rearranged Acute Lymphoblastic leukemia
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Midostaurin

Study Results

Participant Flow

Recruitment Details	The study was conducted at 8 centers in 5 countries.
Pre-assignment Detail	A total of 22 participants were enrolled in the study.

Arm/Group Title	Cohort 1: Midostaurin (30 Milligrams/Meters^2)	Cohort 2: Midostaurin (60 mg/m^2)
Arm/Group Description	Participants received bodyweight and body surface area (BSA) stratified dose of midostaurin 30 mg/m^2 twice daily (bid) through oral route. The total daily dose in 30 mg/m^2 bid cohort was 60 mg/m^2.	Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m^2 bid through oral route. The total daily dose in 60 mg/m^2 bid cohort was 120 mg/m^2.
Period Title: Overall Study
STARTED	7	15
COMPLETED	0	0
NOT COMPLETED	7	15

Baseline Characteristics

Arm/Group Title	Cohort 1: Midostaurin (30 Milligrams/Meters^2)	Cohort 2: Midostaurin (60 mg/m^2)	Total
Arm/Group Description	Participants received body-weight and BSA stratified dose of midostaurin 30 mg/m^2 bid through oral route. The total daily dose in 30 mg/m^2 bid cohort was 60 mg/m^2.	Participants received body-weight and BSA stratified dose of midostaurin 60 mg/m^2 bid through oral route. The total daily dose in 60 mg/m^2 bid cohort was 120 mg/m^2.	Total of all reporting groups
Overall Participants	7	15	22
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.65 (7.479)	6.50 (6.903)	7.50 (7.070)
Age, Customized (participants) [Number]
Infants and toddlers (28 days-23 months)	2 28.6%	9 60%	11 50%
Children (2--11 years)	1 14.3%	1 6.7%	2 9.1%
Adolescents (12--17 years)	4 57.1%	5 33.3%	9 40.9%
Sex: Female, Male (Count of Participants)
Female	5 71.4%	10 66.7%	15 68.2%
Male	2 28.6%	5 33.3%	7 31.8%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Midostaurin- Posterior Probability of DLT
Description	MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced dose limiting toxicity (DLT), based on a Bayesian logistic regression model (BLRM) employing the escalation with overdose control (EWOC) principle. A DLT was defined as a grade 3 or 4 non-hematological adverse event (AE) or abnormal laboratory value related to study drug. Mean and the 95% posterior probability estimates of having a DLT by age strata and dose is presented. Estimation of MTD and/or recommended dose for expansion (RDE) at the dose-escalation phase of the study was based upon the estimation of the probability of DLT for participants in the dose-determining set (DDS).
Time Frame	Baseline, End of dose escalation phase (6 months)

Outcome Measure Data

Analysis Population Description

The analysis was performed in dose determining set (DDS) population. Here, 'n' signifies the number of evaluable participants for this measure.

Arm/Group Title	Cohort 1: Midostaurin (30 Milligrams/Meters^2)	Cohort 2: Midostaurin (60 mg/m^2)
Arm/Group Description	Participants received bodyweight and BSA stratified dose of midostaurin 30 mg/m^2 bid through oral route. The total daily dose in 30 mg/m^2 bid cohort was 60 mg/m^2.	Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m^2 bid through oral route. The total daily dose in 60 mg/m^2 bid cohort was 120 mg/m^2.
Measure Participants	6	11
Younger stratum (≥ 3months -≤ 2 years): (n=2, 5)	0.03	0.10
Older stratum (>2 years- <18years): (n=4,6)	0.03	0.08

2. Secondary Outcome

Title	Percentage of Participants With Best Overall Response by Indication
Description	The best overall clinical response was determined as per the clinical assessment done by the investigator. Responders were defined as all participants with a best clinical response of leukemia free state, morphological complete remission, incomplete morphological complete remission, partial remission, bone marrow blast response, bone marrow minor blast response, peripheral blood blast response, minor peripheral blood blast response. Participants with stable disease, progressive disease and with missing tumour assessment or who discontinued the study or who died before having their first assessment were considered as non-responders. Stable disease was defined as failure to achieve any of the above response. Progressive disease was defined as doubling of the bone marrow blast percentage from baseline in participants with <40% bone marrow blasts at baseline, or a 50% increase in bone marrow blast percentage from baseline in participants with >40% bone marrow blasts at baseline,
Time Frame	Baseline, Day 15 (Day 1 of Cycle 2), Day 22 (Day 8 of Cycle 2), Day 29(Day 1 of Cycle 9), End of treatment (up to 24 months after last dose or until death whichever occurred first)

Outcome Measure Data

Analysis Population Description

The analysis was performed in full analysis set (FAS) population, defined as all participants to whom study treatment was assigned.

Arm/Group Title	AML Subjects	MLLr-ALL Subjects
Arm/Group Description	Subjects with acute myeloid leukemia (AML) and received body-weight stratified dosage midostaurin 30 or 60 mg/m^2.	Subjects with mixed lineage leukemia gene- rearranged acute lymphoblastic leukemia (MLLr-ALL) and received body-weight stratified dosage midostaurin 30 or 60 mg/m^2.
Measure Participants	9	13
Leukemia free state	0 0%	0 0%
Morphological complete remission	0 0%	0 0%
Incomplete morphological complete remission	11.1 158.6%	0 0%
Partial remission	0 0%	0 0%
Bone marrow blast response	22.2 317.1%	0 0%
Bone marrow minor blast response	0 0%	0 0%
Peripheral blood blast response	11.1 158.6%	23.1 154%
Minor peripheral blood blast response	11.1 158.6%	0 0%
Stable disease	44.4 634.3%	7.7 51.3%
Progressive disease	0 0%	61.5 410%
Not Done	0 0%	7.7 51.3%
Participants with response	55.6 794.3%	23.1 154%

3. Secondary Outcome

Title	Time to Response With Midostaurin
Description	Time to response was defined as the time from the date of start of midostaurin treatment to the date of first response. The best overall clinical response was determined as per the clinical assessment done by the investigator. Responders were defined as all participants with a best clinical response of leukemia free state, morphological complete remission, incomplete morphological complete remission, partial remission, bone marrow blast response, bone marrow minor blast response, peripheral blood blast response, minor peripheral blood blast response. Time to response was calculated by using the formula = (date of first response -date of start of midostaurin) +1 day.
Time Frame	Baseline, End of treatment (up to 24 months after last dose or until death whichever occurred first)

Outcome Measure Data

Analysis Population Description

The analysis was performed in FAS population. Here, "Number of participants analysed" signifies number of responders at specified time points for each arm, respectively.

Arm/Group Title	AML Subjects	MLLr-ALL Subjects
Arm/Group Description	Subjects with acute myeloid leukemia (AML) and received body-weight stratified dosage midostaurin 30 or 60 mg/m^2.	Subjects with mixed lineage leukemia gene- rearranged acute lymphoblastic leukemia (MLLr-ALL) and received body-weight stratified dosage midostaurin 30 or 60 mg/m^2.
Measure Participants	5	3
Median (Full Range) [Days]	14.0	8.0

4. Secondary Outcome

Title	Overall Survival With Midostaurin
Description	Overall survival (OS) was defined as the time from start of treatment to date of death due to any cause. The percentage (%) event-free probability estimates were obtained from the Kaplan-Meier survival estimates.
Time Frame	Baseline, End of treatment (up to 24 months after last dose or until death whichever occurred first)

Outcome Measure Data

Analysis Population Description

The analysis was performed in FAS population.

Arm/Group Title	AML Subjects	MLLr-ALL Subjects
Arm/Group Description	Subjects with acute myeloid leukemia (AML) and received body-weight stratified dosage midostaurin 30 or 60 mg/m^2.	Subjects with mixed lineage leukemia gene- rearranged acute lymphoblastic leukemia (MLLr-ALL) and received body-weight stratified dosage midostaurin 30 or 60 mg/m^2.
Measure Participants	9	13
Median (95% Confidence Interval) [Months]	3.68	1.35

5. Secondary Outcome

Title	Plasma Concentrations of Midostaurin and Its Metabolites CGP52421 and CGP62221
Description	The plasma concentrations of midostaurin (PKC412) and its two major metabolites, CGP62221 and CGP52421 were determined by using a validated liquid chromatography/tandem mass spectrometry method.
Time Frame	Day 1, Day 5, Day 7, Day 15 (Day 1 of Cycle 2), Day 29 (Day 1 of Cycle 3)

Outcome Measure Data

Analysis Population Description

The analysis was performed in pharmacokinetic (PK) set population defined as all safety set participants who had at least one valid (measurable) PK sample of midostaurin, and who had no significant restricted co-medications.

Arm/Group Title	Cohort 1: Midostaurin (30 Milligrams/Meters^2)	Cohort 2: Midostaurin (60 mg/m^2)
Arm/Group Description	Participants received bodyweight and body surface area (BSA) stratified dose of midostaurin 30 mg/m^2 bid through oral route. The total daily dose in 30 mg/m^2 bid cohort was 60 mg/m^2.	Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m^2 bid through oral route. The total daily dose in 60 mg/m^2 bid cohort was 120 mg/m^2.
Measure Participants	7	15
PKC412-Cycle 1/Day 1 (1 hour)	1678 (652.817)	2330.88 (1290.136)
PKC412-Cycle 1/Day 1 (2 hour)	1762.5 (226.771)	2449.09 (936.039)
PKC412-Cycle 1/Day 1 (3 hour)	1891.67 (505.941)	2287.5 (1421.365)
PKC412-Cycle 1/Day 1 (12 hour)	939.17 (347.925)	2068.85 (2183.946)
PKC412-Cycle 1/Day 5 (0 hour)	2444 (936.659)	2610.1 (2480.716)
PKC412-Cycle 1/Day 7 (0 hour)	1945 (643.467)	2028 (2071.949)
PKC412-Cycle 2/Day 1 (0 hour)	1832.5 (773.881)	726 (379.953)
PKC412-Cycle 3/Day 1 (0 hour)	962 (505.146)	674 (340.776)
CGP62221-Cycle 1/Day 1 (1 hour)	106.18 (89.473)	228.33 (148.469)
CGP62221-Cycle 1/Day 1 (2 hour)	208.95 (183.22)	458.75 (281.882)
CGP62221-Cycle 1/Day 1 (3 hour)	333.4 (227.863)	563.63 (276.938)
CGP62221-Cycle 1/Day 1 (12 hour)	424.35 (299.416)	730.31 (385.698)
CGP62221-Cycle 1/Day 5 (0 hour)	3182 (1756.778)	3360.3 (2002.498)
CGP62221-Cycle 1/Day 7 (0 hour)	3390 (1400.071)	2895 (1893.347)
CGP62221-Cycle 2/Day 1 (0 hour)	2380 (728.331)	1614.14 (1057.585)
CGP62221-Cycle 3/Day 1 (0 hour)	1140.67 (189.16)	1759.2 (923.668)
CGP52421-Cycle 1/Day 1 (1 hour)	71.64 (42.325)	111.58 (78.187)
CGP52421-Cycle 1/Day 1 (2 hour)	113.23 (54.831)	189.65 (128.879)
CGP52421-Cycle 1/Day 1 (3 hour)	152.18 (78.405)	236.19 (144.723)
CGP52421-Cycle 1/Day 1 (12 hour)	139.27 (68.198)	259.52 (148.943)
CGP52421-Cycle 1/Day 5 (0 hour)	1018 (259.014)	1581 (509.208)
CGP52421-Cycle 1/Day 7 (0 hour)	1269 (453.963)	2129 (341.97)
CGP52421-Cycle 2/Day 1 (0 hour)	2350 (1110.465)	2640 (541.018)
CGP52421-Cycle 3/Day 1 (0 hour)	2386.67 (277.909)	3488 (1511.529)

6. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs or SAEs and Death During the Study
Description	An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalization, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the participant or require medical or surgical intervention to prevent one of the aforementioned outcomes. Treatment related AEs or SAEs were defined as AEs or SAEs that were suspected to be related to study treatment as per investigator. On treatment death was a fatal event leading to permanent cessations of all vital functions of the body.
Time Frame	Baseline (start of study treatment) up to End of treatment (up to 24 months after last dose or until death whichever occurred first)

Outcome Measure Data

Analysis Population Description

The analysis was performed in safety set population, defined as the participants who received at least one dose of midostaurin.

Arm/Group Title	Cohort 1: Midostaurin (30 Milligrams/Meters^2)	Cohort 2: Midostaurin (60 mg/m^2)
Arm/Group Description	Participants received bodyweight and BSA stratified dose of midostaurin 30 mg/m^2 bid through oral route. The total daily dose in 30 mg/m^2 bid cohort was 60 mg/m^2.	Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m^2 bid through oral route. The total daily dose in 60 mg/m^2 bid cohort was 120 mg/m^2.
Measure Participants	7	15
AEs	6 85.7%	15 100%
AEs suspected to be drug related	1 14.3%	2 13.3%
On-treatment death	2 28.6%	3 20%
SAEs	3 42.9%	6 40%
SAEs suspected to be drug related	0 0%	1 6.7%

Adverse Events

Time Frame	Serious Adverse Events are monitored from date of First Participant First Visit (FPFV) up to Last Participant Last Visit (LPLV), 24 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) up to LPLV, 20 weeks
Arm/Group Title	Cohort 1: Midostaurin (30 Milligrams/Meters^2)		Cohort 2: Midostaurin (60 mg/m^2)
Arm/Group Description	Participants received bodyweight and BSA stratified dose of midostaurin 30 mg/m^2 bid through oral route. The total daily dose in 30 mg/m^2 bid cohort was 60 mg/m^2.		Participants received bodyweight and BSA stratified dose of midostaurin 60 mg/m^2 bid through oral route. The total daily dose in 60 mg/m^2 bid cohort was 120 mg/m^2.
All Cause Mortality
	Cohort 1: Midostaurin (30 Milligrams/Meters^2)		Cohort 2: Midostaurin (60 mg/m^2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort 1: Midostaurin (30 Milligrams/Meters^2)		Cohort 2: Midostaurin (60 mg/m^2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/7 (42.9%)		6/15 (40%)
Blood and lymphatic system disorders
Febrile Neutropenia	1/7 (14.3%)		1/15 (6.7%)
Neutropenia	1/7 (14.3%)		0/15 (0%)
Gastrointestinal disorders
Diarrhoea	1/7 (14.3%)		1/15 (6.7%)
Tongue Oedema	0/7 (0%)		1/15 (6.7%)
Vomiting	1/7 (14.3%)		1/15 (6.7%)
General disorders
Pyrexia	1/7 (14.3%)		0/15 (0%)
Immune system disorders
Cytokine Release Syndrome	0/7 (0%)		1/15 (6.7%)
Infections and infestations
Infection	1/7 (14.3%)		0/15 (0%)
Pneumonia	0/7 (0%)		1/15 (6.7%)
Injury, poisoning and procedural complications
Tongue Injury	0/7 (0%)		1/15 (6.7%)
Investigations
Alanine Aminotransferase Increased	0/7 (0%)		1/15 (6.7%)
Blast Cell Count Increased	0/7 (0%)		1/15 (6.7%)
Metabolism and nutrition disorders
Hypophagia	1/7 (14.3%)		0/15 (0%)
Malnutrition	0/7 (0%)		1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Bone Pain	0/7 (0%)		1/15 (6.7%)
Nervous system disorders
Headache	1/7 (14.3%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1: Midostaurin (30 Milligrams/Meters^2)		Cohort 2: Midostaurin (60 mg/m^2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/7 (85.7%)		15/15 (100%)
Blood and lymphatic system disorders
Anaemia	0/7 (0%)		5/15 (33.3%)
Febrile Neutropenia	0/7 (0%)		1/15 (6.7%)
Leukopenia	0/7 (0%)		1/15 (6.7%)
Lymphopenia	0/7 (0%)		2/15 (13.3%)
Neutropenia	0/7 (0%)		3/15 (20%)
Thrombocytopenia	0/7 (0%)		9/15 (60%)
Cardiac disorders
Sinus Tachycardia	0/7 (0%)		1/15 (6.7%)
Tachycardia	0/7 (0%)		1/15 (6.7%)
Gastrointestinal disorders
Abdominal Distension	0/7 (0%)		1/15 (6.7%)
Abdominal Pain	0/7 (0%)		1/15 (6.7%)
Abdominal Pain Upper	0/7 (0%)		1/15 (6.7%)
Constipation	0/7 (0%)		1/15 (6.7%)
Diarrhoea	1/7 (14.3%)		6/15 (40%)
Mouth Haemorrhage	1/7 (14.3%)		0/15 (0%)
Nausea	0/7 (0%)		7/15 (46.7%)
Oral Mucosal Exfoliation	0/7 (0%)		1/15 (6.7%)
Oral Pain	0/7 (0%)		1/15 (6.7%)
Oral Pruritus	0/7 (0%)		1/15 (6.7%)
Tongue Discolouration	0/7 (0%)		1/15 (6.7%)
Tooth Loss	0/7 (0%)		1/15 (6.7%)
Vomiting	3/7 (42.9%)		12/15 (80%)
General disorders
Asthenia	0/7 (0%)		1/15 (6.7%)
Catheter Site Inflammation	0/7 (0%)		1/15 (6.7%)
Catheter Site Pain	0/7 (0%)		1/15 (6.7%)
Crying	0/7 (0%)		1/15 (6.7%)
Fatigue	0/7 (0%)		2/15 (13.3%)
Feeling Abnormal	0/7 (0%)		1/15 (6.7%)
Generalised Oedema	0/7 (0%)		1/15 (6.7%)
Non-Cardiac Chest Pain	0/7 (0%)		1/15 (6.7%)
Pain	0/7 (0%)		2/15 (13.3%)
Pyrexia	1/7 (14.3%)		7/15 (46.7%)
Hepatobiliary disorders
Hepatosplenomegaly	0/7 (0%)		1/15 (6.7%)
Hyperbilirubinaemia	1/7 (14.3%)		2/15 (13.3%)
Immune system disorders
Hypogammaglobulinaemia	0/7 (0%)		1/15 (6.7%)
Infections and infestations
Bronchopulmonary Aspergillosis	0/7 (0%)		1/15 (6.7%)
Enterobacter Infection	1/7 (14.3%)		0/15 (0%)
Enterobacter Sepsis	1/7 (14.3%)		0/15 (0%)
Febrile Infection	1/7 (14.3%)		0/15 (0%)
Fungal Infection	1/7 (14.3%)		0/15 (0%)
Herpes Zoster	1/7 (14.3%)		0/15 (0%)
Infection	1/7 (14.3%)		1/15 (6.7%)
Influenza	0/7 (0%)		1/15 (6.7%)
Lung Infection	0/7 (0%)		1/15 (6.7%)
Staphylococcal Infection	0/7 (0%)		1/15 (6.7%)
Upper Respiratory Tract Infection	1/7 (14.3%)		0/15 (0%)
Urinary Tract Infection	0/7 (0%)		1/15 (6.7%)
Viral Infection	0/7 (0%)		1/15 (6.7%)
Injury, poisoning and procedural complications
Allergic Transfusion Reaction	0/7 (0%)		1/15 (6.7%)
Lower Limb Fracture	0/7 (0%)		1/15 (6.7%)
Investigations
Activated Partial Thromboplastin Time Prolonged	0/7 (0%)		1/15 (6.7%)
Alanine Aminotransferase Increased	1/7 (14.3%)		4/15 (26.7%)
Aspartate Aminotransferase Increased	1/7 (14.3%)		4/15 (26.7%)
Blood Albumin Decreased	0/7 (0%)		1/15 (6.7%)
Blood Alkaline Phosphatase Increased	0/7 (0%)		1/15 (6.7%)
Blood Creatinine Increased	0/7 (0%)		1/15 (6.7%)
Blood Fibrinogen Decreased	0/7 (0%)		1/15 (6.7%)
Blood Lactate Dehydrogenase Increased	0/7 (0%)		1/15 (6.7%)
Blood Phosphorus Decreased	0/7 (0%)		1/15 (6.7%)
Cardiac Murmur	0/7 (0%)		1/15 (6.7%)
Electrocardiogram Qt Prolonged	0/7 (0%)		2/15 (13.3%)
Haemoglobin Decreased	0/7 (0%)		1/15 (6.7%)
Heart Sounds Abnormal	0/7 (0%)		1/15 (6.7%)
Lipase Increased	0/7 (0%)		1/15 (6.7%)
Weight Decreased	0/7 (0%)		2/15 (13.3%)
Weight Increased	0/7 (0%)		1/15 (6.7%)
White Blood Cell Count Decreased	0/7 (0%)		2/15 (13.3%)
White Blood Cell Count Increased	1/7 (14.3%)		0/15 (0%)
Metabolism and nutrition disorders
Decreased Appetite	1/7 (14.3%)		3/15 (20%)
Dehydration	0/7 (0%)		1/15 (6.7%)
Fluid Retention	0/7 (0%)		1/15 (6.7%)
Hyperglycaemia	1/7 (14.3%)		1/15 (6.7%)
Hyperkalaemia	1/7 (14.3%)		1/15 (6.7%)
Hypernatraemia	0/7 (0%)		1/15 (6.7%)
Hyperphosphataemia	0/7 (0%)		1/15 (6.7%)
Hyperuricaemia	0/7 (0%)		1/15 (6.7%)
Hypoalbuminaemia	0/7 (0%)		1/15 (6.7%)
Hypocalcaemia	1/7 (14.3%)		3/15 (20%)
Hypoglycaemia	0/7 (0%)		1/15 (6.7%)
Hypokalaemia	0/7 (0%)		4/15 (26.7%)
Hypomagnesaemia	0/7 (0%)		2/15 (13.3%)
Hyponatraemia	0/7 (0%)		3/15 (20%)
Hypophosphataemia	0/7 (0%)		1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Bone Pain	1/7 (14.3%)		0/15 (0%)
Pain In Extremity	0/7 (0%)		1/15 (6.7%)
Pain In Jaw	0/7 (0%)		1/15 (6.7%)
Nervous system disorders
Dizziness	0/7 (0%)		1/15 (6.7%)
Headache	0/7 (0%)		4/15 (26.7%)
Tremor	0/7 (0%)		1/15 (6.7%)
Psychiatric disorders
Agitation	0/7 (0%)		1/15 (6.7%)
Anxiety	0/7 (0%)		5/15 (33.3%)
Depression	0/7 (0%)		2/15 (13.3%)
Insomnia	0/7 (0%)		1/15 (6.7%)
Mood Altered	0/7 (0%)		3/15 (20%)
Nightmare	0/7 (0%)		1/15 (6.7%)
Reproductive system and breast disorders
Breast Haematoma	0/7 (0%)		1/15 (6.7%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm	0/7 (0%)		1/15 (6.7%)
Cough	0/7 (0%)		3/15 (20%)
Dyspnoea	0/7 (0%)		2/15 (13.3%)
Epistaxis	0/7 (0%)		2/15 (13.3%)
Hypoxia	0/7 (0%)		1/15 (6.7%)
Lung Disorder	0/7 (0%)		1/15 (6.7%)
Lung Infiltration	0/7 (0%)		1/15 (6.7%)
Nasal Congestion	0/7 (0%)		1/15 (6.7%)
Oropharyngeal Pain	0/7 (0%)		1/15 (6.7%)
Rales	0/7 (0%)		1/15 (6.7%)
Rhinalgia	0/7 (0%)		1/15 (6.7%)
Tachypnoea	0/7 (0%)		1/15 (6.7%)
Skin and subcutaneous tissue disorders
Alopecia	0/7 (0%)		2/15 (13.3%)
Ecchymosis	0/7 (0%)		1/15 (6.7%)
Erythema	0/7 (0%)		1/15 (6.7%)
Petechiae	0/7 (0%)		1/15 (6.7%)
Pruritus	0/7 (0%)		1/15 (6.7%)
Rash	1/7 (14.3%)		1/15 (6.7%)
Rash Erythematous	0/7 (0%)		1/15 (6.7%)
Rash Papular	0/7 (0%)		1/15 (6.7%)
Skin Disorder	0/7 (0%)		1/15 (6.7%)
Skin Lesion	0/7 (0%)		2/15 (13.3%)
Swelling Face	0/7 (0%)		1/15 (6.7%)
Vascular disorders
Capillary Leak Syndrome	0/7 (0%)		1/15 (6.7%)
Haematoma	0/7 (0%)		1/15 (6.7%)
Hyperaemia	0/7 (0%)		1/15 (6.7%)

Limitations/Caveats

The study was terminated early since despite considerable efforts to boost recruitment, no new participants were enrolled in the final year of this study.

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 (i.e, data from all sites) in the clinical trial.