RADIUS: Standard of Care +/- Midostaurin to Prevent Relapse Post Stem Cell Transplant in Patients With FLT3-ITD Mutated AML

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01883362
• Collaborator: (none)
• Enrollment: 60
• Locations: 19
• Arms: 2
• Actual Duration (Months): 50.7
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To determine if the addition of midostaurin (PKC412) to Standard of Care (SOC) therapy reduces relapse in FLT3-ITD mutated AML patients receiving an allogenetic hematopoietic stem cell transplant,

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Midostaurin; Other: Standard of Care	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Phase II, Randomized Trial of Standard of Care, With or Without Midostaruin to Prevent Relapse Following Allogeneic Hematopoietic Stem Cell Transplantation in Patients With FLT3-ITD Mutated Acute Myeloid Leukemia
• Actual Study Start Date: Feb 6, 2014
• Actual Primary Completion Date: Apr 30, 2018
• Actual Study Completion Date: Apr 30, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Standard of Care with Midostaurin Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles).	Drug: Midostaurin; Midostaurin was supplied in 25mg soft gelatin capsule taken orally twice a day for 28 days of each cycle. Patients will be treated for 12 cycles.; Other Names: PKC412
Active Comparator: Standard of Care Patients received standard of care alone in the post SCT setting	Other: Standard of Care; Standard of Care was not defined per protocol. The investigator prescribed based on the commonly used medications given in the post SCT setting.

Outcome Measures

Primary Outcome Measures

1. Proportion of Participants With Relapse Free Survival (RFS) up to 18 Months Post Transplant (Full Analysis Set) by Kaplan-Meier Analysis [date of transplant up to 18 months]

   Relapse-free survival assesses the clinical benefit of remaining in remission free from relapse or death due to the disease. It was defined as the time from transplant to relapse or death due to the disease. Relapse following complete response was defined as reappearance of leukemic blasts in the peripheral blood or finding more than 5% blasts in the bone marrow.

Secondary Outcome Measures

1. Proportion of Participants With Relapse Free Survival (RFS) - Time From Randomization up to 18 Months (Full Analysis Set) by Kaplan-Meier Analysis [Randomization to 18 months]

   Relapse-free survival assesses the clinical benefit of remaining in remission free from relapse or death due to the disease. It was defined as the time from transplant to relapse or death due to the disease. Relapse following complete response was defined as reappearance of leukemic blasts in the peripheral blood or finding more than 5% blasts in the bone marrow.

2. Proportion of Participants With Relapse Free Survival (RFS) - Time From Randomization up to 24 Months(Full Analysis Set) by Kaplan-Meier Analysis [date of transplant up to 24 months]

   DFS was defined as the time from transplant to relapse or death due to any cause. If a patient had more than 1 event (e.g., relapse then death) then the earliest date was taken into account.

3. Proportion of Participants With Relapse Free Survival (RFS) - Time From Transplant (Full Analysis Set) by Kaplan-Meier Analysis [date of transplant up to 24 months]

   Relapse-free survival was defined as the time from transplant to relapse or death due to the disease 24 months post-transplant. If a patient had more than one event (e.g., relapse then death) then the earliest date was taken into account.

4. Probability of Overall Survival - Date of Transplant up to 24 Months (Full Analysis Set) by Kaplan-Meier Analysis [date of transplant up to 24 months]

   Overall survival was defined as the time from transplant to death due to any cause.

5. Probability of Non-relapse Mortality (NRM) - Date of Transplant up to 24 Months (Full Analysis Set) by Kaplan-Meier Analysis [date of transplant up to 24 months]

   Non-relapse mortality (NRM) was defined as the time from transplant to death due to reasons other than relapse/progressive disease

6. FLT3-ITD Mutation Status Centrally in Archived Material From Diagnosis (if Available) Including Mutant:Wild Type Ratio. [up to 24 months from date of transplannt or at study completion]

   Unable to retrieve a sufficient amount of archived samples to perform an analysis therefore the study was not able to verify the FLT3-ITD mutation status

7. Plasma Pharmacokinetics (PK) of Midostaurin and the Metabolites: CGP62221 and CGP52421: Pre-dose Levels [Pre-dose on days 1 and 15 of Cycle 1, on day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12]

   Pre-dose levels (Cmin) will be directly determined from raw plasma concentration-time data. Values below the lower limit of quantification (LLOQ) will be treated as zero in any calculations of summary statistics.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients between 18 and 70 years of age

• Patients with ECOG Performance Status of ≤ 2

• Patients with a documented unequivocal diagnosis of AML according to WHO 2008 classification (>20% blasts in the bone marrow), excluding M3 (acute promyelocytic leukemia).

• Patients with a documented FLT3 ITD mutation, determined by local laboratory for eligibility (historical tissue will be requested for central analysis confirmation)

• Patients who undersent allogeneic HSCT in CR1 from a matched related or matched unrelated donor. All of the following criteria had to be met: HLA typing to include available 8/8 or 7/8 allele HLA matched donor (at A,B,C, DRB1) Single allelic mismatch allowed

• Patients who had received a conditioning regimen which included one of the following:

Busulfan/Fludarabine (Bu/Flu) Busulfan (16 mg/kg PO or 12.8 mg/kg IV) Fludarabine (120-180 mg/m2) Fludarabine / Melphalan (Flu/Mel) Fludarabine (120-180 mg/m2) Melphalan (≤ 150 mg/m2) Busulfan/Cyclophosphamide (Bu/Cy) Busulfan (16 mg/kg PO or 12.8 mg/kg IV) Cyclophosphamide (120 mg/kg) Cyclophosphamide/Total Body Irradiation (Cy/TBI) Cyclophosphamide (120 mg/kg) TBI (1200-1420 cGy)

• Recovery of counts by day 42 and was able to start midostaurin by day 60 post-HSCT (first dose of midostaurin to start no earlier than 28 days post-HSCT); ANC >1000µL, platelets ≥20,000 without platelet transfusion

Exclusion Criteria:

Patients eligible for this study must not have met any of the following criteria:

• Patients who failed prior attempts at allogeneic HSCT

• Patients who had received an autologous transplant

• Patients with Acute GVHD Grade III-IV

• Patients with a known confirmed diagnosis of HIV infection or active viral hepatitis.

• Impaired cardiac function including any of the following:

• Screening ECG with a QTc > 450 msec. If QTc > 450 and electrolytes were not within normal ranges, electrolytes should be corrected and then the patient rescreened for QTc.

• Patients with congenital long QT syndrome

• History or presence of sustained ventricular tachycardia

• Any history of ventricular fibrillation or torsades de pointes

• Bradycardia defined as HR. < 50 bpm

• Right bundle branch block + left anterior hemiblock (bifascicular block)

• Patients with myocardial infarction or unstable angina < 6 months prior to starting study

• Congestive Heart Failure NY Heart Association class III or IV

• Patients with an ejection fraction < 45% assessed by MUGA or ---ECHO within 28 days prior to starting study cycle 1 (of midostaurin or control group)

• Patients with any pulmonary infiltrate including those suspected to be of infectious origin (unless resolves to ≤ Grade 1 within screening timeframe)

• Patient required treatment with strong CYP3A4 inhibitors or moderate or strong CYP3A4 inducers other than those required for GVH or infection prophylaxis or treatment

Pregnant or nursing (lactating) women, or women of child-bearing potential, must have used highly effective methods of contraception during dosing and for 30 days after treatment completion

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Diego Moores Cancer Center	La Jolla	California	United States	92093-0987
2	University of California at Los Angeles Oncology	Los Angeles	California	United States	90095
3	SCRI- Colorado Blood Cancer Institute	Denver	Colorado	United States	80218
4	H Lee Moffitt Cancer Center and Research Institute Oncology	Tampa	Florida	United States	33612
5	Northside Hospital	Atlanta	Georgia	United States	30342
6	University of Chicago Medical Center	Chicago	Illinois	United States	60637
7	Karmanos Cancer Institute Karmanos - Wayne State	Detroit	Michigan	United States	48201
8	Mayo Clinic - Rochester	Rochester	Minnesota	United States	55905
9	Washington University School Of Medicine-Siteman Cancer Ctr Washington U School of Med	Saint Louis	Missouri	United States	63110
10	Hackensack University Medical Center Hackensack Univ Med Ctr (32)	Hackensack	New Jersey	United States	07601
11	University of North Carolina at Chapel Hill University of North Carolina 6	Chapel Hill	North Carolina	United States	27599-9500
12	University Hospitals Case Medical Center	Cleveland	Ohio	United States	44106
13	Oregon Health Sciences University	Portland	Oregon	United States	97239
14	Tennessee Oncology Sarah Cannon Research Inst.	Nashville	Tennessee	United States	37203
15	Vanderbilt Univeristy Oncology	Nashville	Tennessee	United States	37232
16	Baylor Health Care System/Sammons Cancer Center Oncology	Dallas	Texas	United States	75246
17	Texas Transplant Physicians Group Oncology 2	San Antonio	Texas	United States	78229
18	Fred Hutchinson Cancer Research Center Oncology	Seattle	Washington	United States	98109
19	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2M9

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Brian Elliott, MD, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Jul 2, 2015
• Statistical Analysis Plan - Feb 7, 2018

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01883362
• Other Study ID Numbers: CPKC412AUS23
• First Posted: Jun 21, 2013
• Last Update Posted: Mar 17, 2021
• Last Verified: Mar 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: acute myeloid leukemia; AML; FLT3-ITD; midostaurin; PKC412; allogeneic hematopoeitic stem cell tranplant; SCT; HSCT; CR1; adult
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Midostaurin

Study Results

Participant Flow

Arm/Group Title	Standard of Care With Midostaurin	Standard of Care
Arm/Group Description	Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles).	Patients received standard of care alone in the post SCT setting
Period Title: Treatment
STARTED	30	30
COMPLETED	14	16
NOT COMPLETED	16	14
Period Title: Treatment
STARTED	26	27
COMPLETED	10	13
NOT COMPLETED	16	14

Baseline Characteristics

Arm/Group Title	Standard of Care With Midostaurin	Standard of Care	Total
Arm/Group Description	Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles).	Patients received standard of care alone in the post SCT setting	Total of all reporting groups
Overall Participants	30	30	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.8 (13.68)	46.0 (11.08)	48.4 (12.58)
Sex: Female, Male (Count of Participants)
Female	14 46.7%	12 40%	26 43.3%
Male	16 53.3%	18 60%	34 56.7%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	27 90%	27 90%	54 90%
Black	1 3.3%	0 0%	1 1.7%
Asian	1 3.3%	1 3.3%	2 3.3%
Other	1 3.3%	2 6.7%	3 5%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.9934 (7.11368)	26.6400 (5.27475)	26.8101 (6.17055)

Outcome Measures

1. Primary Outcome

Title	Proportion of Participants With Relapse Free Survival (RFS) up to 18 Months Post Transplant (Full Analysis Set) by Kaplan-Meier Analysis
Description	Relapse-free survival assesses the clinical benefit of remaining in remission free from relapse or death due to the disease. It was defined as the time from transplant to relapse or death due to the disease. Relapse following complete response was defined as reappearance of leukemic blasts in the peripheral blood or finding more than 5% blasts in the bone marrow.
Time Frame	date of transplant up to 18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard of Care With Midostaurin	Standard of Care
Arm/Group Description	Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles).	Patients received standard of care alone in the post SCT setting
Measure Participants	30	30
6 months	0.93 3.1%	0.93 3.1%
12 months	0.80 2.7%	0.93 3.1%
18 months	0.76 2.5%	0.89 3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Standard of Care With Midostaurin, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2655
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; 0.12 to 1.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Proportion of Participants With Relapse Free Survival (RFS) - Time From Randomization up to 18 Months (Full Analysis Set) by Kaplan-Meier Analysis
Description	Relapse-free survival assesses the clinical benefit of remaining in remission free from relapse or death due to the disease. It was defined as the time from transplant to relapse or death due to the disease. Relapse following complete response was defined as reappearance of leukemic blasts in the peripheral blood or finding more than 5% blasts in the bone marrow.
Time Frame	Randomization to 18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard of Care With Midostaurin	Standard of Care
Arm/Group Description	Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles).	Patients received standard of care alone in the post SCT setting
Measure Participants	30	30
6 months	0.93 3.1%	0.93 3.1%
12 months	0.80 2.7%	0.93 3.1%
18 months	0.76 2.5%	0.85 2.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Standard of Care With Midostaurin, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4297
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.17 to 2.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Proportion of Participants With Relapse Free Survival (RFS) - Time From Randomization up to 24 Months(Full Analysis Set) by Kaplan-Meier Analysis
Description	DFS was defined as the time from transplant to relapse or death due to any cause. If a patient had more than 1 event (e.g., relapse then death) then the earliest date was taken into account.
Time Frame	date of transplant up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard of Care With Midostaurin	Standard of Care
Arm/Group Description	Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles).	Patients received standard of care alone in the post SCT setting
Measure Participants	30	30
6 months	0.90 3%	0.93 3.1%
12 months	0.77 2.6%	0.89 3%
18 months	0.69 2.3%	0.85 2.8%
24 months	0.69 2.3%	0.81 2.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Standard of Care With Midostaurin, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2424
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; 0.20 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Proportion of Participants With Relapse Free Survival (RFS) - Time From Transplant (Full Analysis Set) by Kaplan-Meier Analysis
Description	Relapse-free survival was defined as the time from transplant to relapse or death due to the disease 24 months post-transplant. If a patient had more than one event (e.g., relapse then death) then the earliest date was taken into account.
Time Frame	date of transplant up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard of Care With Midostaurin	Standard of Care
Arm/Group Description	Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles).	Patients received standard of care alone in the post SCT setting
Measure Participants	30	30
6 months	0.93 3.1%	0.93 3.1%
12 months	0.80 2.7%	0.93 3.1%
18 months	0.76 2.5%	0.89 3%
24 months	0.76 2.5%	0.85 2.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Standard of Care With Midostaurin, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4297
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.17 to 2.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Probability of Overall Survival - Date of Transplant up to 24 Months (Full Analysis Set) by Kaplan-Meier Analysis
Description	Overall survival was defined as the time from transplant to death due to any cause.
Time Frame	date of transplant up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard of Care With Midostaurin	Standard of Care
Arm/Group Description	Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles).	Patients received standard of care alone in the post SCT setting
Measure Participants	30	30
6 months	0.96 3.2%	1.00 3.3%
12 months	0.89 3%	0.89 3%
18 months	0.76 2.5%	0.85 2.8%
24 months	0.76 2.5%	0.85 2.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Standard of Care With Midostaurin, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3418
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95%; 0.19 to 1.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Probability of Non-relapse Mortality (NRM) - Date of Transplant up to 24 Months (Full Analysis Set) by Kaplan-Meier Analysis
Description	Non-relapse mortality (NRM) was defined as the time from transplant to death due to reasons other than relapse/progressive disease
Time Frame	date of transplant up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard of Care With Midostaurin	Standard of Care
Arm/Group Description	Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles).	Patients received standard of care alone in the post SCT setting
Measure Participants	30	30
6 months	0.96 3.2%	1.00 3.3%
12 months	0.96 3.2%	0.96 3.2%
18 months	0.92 3.1%	0.96 3.2%
24 months	0.92 3.1%	0.96 3.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Standard of Care With Midostaurin, Standard of Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4169
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.50
	Confidence Interval	(2-Sided) 95%; 0.09 to 2.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	FLT3-ITD Mutation Status Centrally in Archived Material From Diagnosis (if Available) Including Mutant:Wild Type Ratio.
Description	Unable to retrieve a sufficient amount of archived samples to perform an analysis therefore the study was not able to verify the FLT3-ITD mutation status
Time Frame	up to 24 months from date of transplannt or at study completion

Outcome Measure Data

Analysis Population Description

Insufficient amount of samples to perform analysis

Arm/Group Title	Standard of Care With Midostaurin	Standard of Care
Arm/Group Description	Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles).	Patients received standard of care alone in the post SCT setting
Measure Participants	0	0

8. Secondary Outcome

Title	Plasma Pharmacokinetics (PK) of Midostaurin and the Metabolites: CGP62221 and CGP52421: Pre-dose Levels
Description	Pre-dose levels (Cmin) will be directly determined from raw plasma concentration-time data. Values below the lower limit of quantification (LLOQ) will be treated as zero in any calculations of summary statistics.
Time Frame	Pre-dose on days 1 and 15 of Cycle 1, on day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12

Outcome Measure Data

Analysis Population Description

number of samples available differed across time points

Arm/Group Title	PKC412	Metabolite CGP52421	Metabolite CGP62221
Arm/Group Description	Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles).	Metabolite of PKC412 (CGP52421)	Metabolite of PKC412 (CGP62221)
Measure Participants	29	29	29
Visit 2,Cycle1,Day 1	17.46 (76.806)	0.00 (0.000)	16.89 (61.212)
Visit 4,Cycle1, Day 15	932.46 (770.597)	1572.69 (684.955)	906.57 (747.836)
Visit 5,Cycle2,Day 1	769.92 (485.353)	1768.77 (849.580)	779.90 (400.244)
Visit 6,Cycle3,Day 1	907.20 (528.017)	2051.55 (765.758)	929.45 (311.841)
Visit 7,Cycle4,Day 1	548.45 (459.294)	1707.15 (810.143)	714.00 (610.925)
Visit 8,Cycle5,Day 1	525.73 (255.032)	1742.85 (658.905)	722.00 (320.977)
Visit 9,Cycle6,Day 1	519.10 (328.032)	1757.86 (685.740)	763.86 (408.290)
Visit 10,Cycle 7 Day 1	754.95 (497.976)	1717.35 (720.259)	780.65 (424.200)
Visit 11,Cycle 8 Day 1	537.95 (229.529)	1787.21 (733.162)	774.84 (326.583)
Visit 12,Cycle 9 Day 1	571.76 (311.764)	1889.76 (678.435)	850.47 (328.411)
Visit 13,Cycle 10 Day 1	643.07 (452.268)	1836.50 (632.894)	851.38 (347.311)
Visit 14,Cycle 11 Day 1	718.22 (538.208)	1857.33 (868.406)	983.94 (801.361)
Visit 15,Cycle 12 Day 1	564.69 (410.156)	1706.29 (643.326)	763.60 (387.685)

9. Post-Hoc Outcome

Title	All Collected Deaths
Description	On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 12.5 months (treatment duration ranged from 0.2 to 11.5 months). Deaths post treatment survival follow up were collected after the on treatment period, up to approximately 51 months.
Time Frame	approx. 12.5 months, approx. 51 months

Outcome Measure Data

Analysis Population Description

Clinical Database Population: all treated patients

Arm/Group Title	Standard of Care With Midostaurin	Standard of Care
Arm/Group Description	Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles).	Patients received standard of care alone in the post SCT setting
Measure Participants	30	30
Total Deaths	8 26.7%	4 13.3%
Deaths on-treatment	1 3.3%	0 0%

Adverse Events

Time Frame	Adverse events were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 12.5 months (treatment duration ranged from 0.2 to 11.5 months).
Adverse Event Reporting Description	AE: Any sign or symptom that occurs during the study treatment plus the 30 days post treatment
Arm/Group Title	Standard of Care With Midostaurin		Standard of Care		ALL Patients
Arm/Group Description	Patients received standard of care in the post stem cell transplant (SCT) setting in addition to Midostaurin 50mg twice a day for 12 months (cycles).		Patients received standard of care alone in the post SCT setting		ALL Patients combined
All Cause Mortality
	Standard of Care With Midostaurin		Standard of Care		ALL Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Serious Adverse Events
	Standard of Care With Midostaurin		Standard of Care		ALL Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/30 (30%)		15/30 (50%)		24/60 (40%)
Blood and lymphatic system disorders
Anaemia	2/30 (6.7%)		1/30 (3.3%)		3/60 (5%)
Febrile neutropenia	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)
Neutropenia	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Pancytopenia	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Cardiac disorders
Arteriosclerosis coronary artery	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Myocarditis	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Pericarditis	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Gastrointestinal disorders
Abdominal pain	1/30 (3.3%)		1/30 (3.3%)		2/60 (3.3%)
Diarrhoea	4/30 (13.3%)		2/30 (6.7%)		6/60 (10%)
Dysphagia	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Gastritis	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Lower gastrointestinal haemorrhage	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Nausea	1/30 (3.3%)		3/30 (10%)		4/60 (6.7%)
Oesophageal perforation	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Pancreatitis acute	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Vomiting	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)
General disorders
Chills	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Pyrexia	2/30 (6.7%)		2/30 (6.7%)		4/60 (6.7%)
Immune system disorders
Chronic graft versus host disease in intestine	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Chronic graft versus host disease in liver	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Graft versus host disease	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Infections and infestations
Appendicitis	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Cellulitis	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Cytomegalovirus infection	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Cytomegalovirus viraemia	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Device related infection	1/30 (3.3%)		1/30 (3.3%)		2/60 (3.3%)
Encephalitis	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Enterovirus infection	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Herpes zoster disseminated	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Lung infection	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Mycobacterium fortuitum infection	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Nocardiosis	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Parainfluenzae virus infection	1/30 (3.3%)		1/30 (3.3%)		2/60 (3.3%)
Pneumonia	1/30 (3.3%)		1/30 (3.3%)		2/60 (3.3%)
Pulmonary mycosis	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Rhinovirus infection	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Staphylococcal infection	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Urinary tract infection	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Investigations
Alanine aminotransferase increased	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Amylase increased	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Aspartate aminotransferase increased	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Lipase increased	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Neutrophil count decreased	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Platelet count decreased	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Staphylococcus test positive	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Transaminases increased	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
White blood cell count decreased	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Metabolism and nutrition disorders
Hyponatraemia	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Musculoskeletal and connective tissue disorders
Back pain	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Myositis	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Nervous system disorders
Depressed level of consciousness	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Ischaemic cerebral infarction	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Posterior reversible encephalopathy syndrome	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Syncope	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Transient ischaemic attack	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Psychiatric disorders
Psychogenic seizure	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Renal and urinary disorders
Acute kidney injury	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Pulmonary embolism	0/30 (0%)		1/30 (3.3%)		1/60 (1.7%)
Vascular disorders
Deep vein thrombosis	1/30 (3.3%)		0/30 (0%)		1/60 (1.7%)
Other (Not Including Serious) Adverse Events
	Standard of Care With Midostaurin		Standard of Care		ALL Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/30 (93.3%)		26/30 (86.7%)		54/60 (90%)
Blood and lymphatic system disorders
Anaemia	5/30 (16.7%)		5/30 (16.7%)		10/60 (16.7%)
Eosinophilia	2/30 (6.7%)		0/30 (0%)		2/60 (3.3%)
Leukopenia	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Neutropenia	4/30 (13.3%)		2/30 (6.7%)		6/60 (10%)
Thrombocytopenia	2/30 (6.7%)		3/30 (10%)		5/60 (8.3%)
Cardiac disorders
Sinus tachycardia	3/30 (10%)		1/30 (3.3%)		4/60 (6.7%)
Tachycardia	1/30 (3.3%)		3/30 (10%)		4/60 (6.7%)
Ear and labyrinth disorders
Tinnitus	2/30 (6.7%)		1/30 (3.3%)		3/60 (5%)
Endocrine disorders
Cushingoid	2/30 (6.7%)		1/30 (3.3%)		3/60 (5%)
Hypothyroidism	2/30 (6.7%)		1/30 (3.3%)		3/60 (5%)
Eye disorders
Dry eye	5/30 (16.7%)		5/30 (16.7%)		10/60 (16.7%)
Lacrimation increased	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)
Vision blurred	4/30 (13.3%)		2/30 (6.7%)		6/60 (10%)
Gastrointestinal disorders
Abdominal pain	4/30 (13.3%)		3/30 (10%)		7/60 (11.7%)
Constipation	4/30 (13.3%)		2/30 (6.7%)		6/60 (10%)
Diarrhoea	9/30 (30%)		4/30 (13.3%)		13/60 (21.7%)
Dry mouth	5/30 (16.7%)		4/30 (13.3%)		9/60 (15%)
Dyspepsia	3/30 (10%)		1/30 (3.3%)		4/60 (6.7%)
Flatulence	3/30 (10%)		0/30 (0%)		3/60 (5%)
Nausea	19/30 (63.3%)		5/30 (16.7%)		24/60 (40%)
Oral pain	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Stomatitis	0/30 (0%)		3/30 (10%)		3/60 (5%)
Vomiting	20/30 (66.7%)		5/30 (16.7%)		25/60 (41.7%)
General disorders
Asthenia	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)
Catheter site pain	2/30 (6.7%)		0/30 (0%)		2/60 (3.3%)
Chest discomfort	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Chest pain	2/30 (6.7%)		0/30 (0%)		2/60 (3.3%)
Chills	1/30 (3.3%)		3/30 (10%)		4/60 (6.7%)
Fatigue	7/30 (23.3%)		7/30 (23.3%)		14/60 (23.3%)
Malaise	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Mucosal inflammation	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Oedema peripheral	6/30 (20%)		10/30 (33.3%)		16/60 (26.7%)
Pain	2/30 (6.7%)		0/30 (0%)		2/60 (3.3%)
Pyrexia	3/30 (10%)		4/30 (13.3%)		7/60 (11.7%)
Immune system disorders
Graft versus host disease	2/30 (6.7%)		1/30 (3.3%)		3/60 (5%)
Graft versus host disease in eye	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Graft versus host disease in skin	2/30 (6.7%)		0/30 (0%)		2/60 (3.3%)
Infections and infestations
Cytomegalovirus infection	0/30 (0%)		4/30 (13.3%)		4/60 (6.7%)
Folliculitis	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Influenza	2/30 (6.7%)		0/30 (0%)		2/60 (3.3%)
Rhinovirus infection	2/30 (6.7%)		1/30 (3.3%)		3/60 (5%)
Sinusitis	2/30 (6.7%)		0/30 (0%)		2/60 (3.3%)
Upper respiratory tract infection	3/30 (10%)		6/30 (20%)		9/60 (15%)
Injury, poisoning and procedural complications
Contusion	2/30 (6.7%)		1/30 (3.3%)		3/60 (5%)
Procedural pain	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Investigations
Alanine aminotransferase increased	5/30 (16.7%)		6/30 (20%)		11/60 (18.3%)
Aspartate aminotransferase increased	5/30 (16.7%)		7/30 (23.3%)		12/60 (20%)
Blood alkaline phosphatase increased	3/30 (10%)		5/30 (16.7%)		8/60 (13.3%)
Blood bilirubin increased	2/30 (6.7%)		1/30 (3.3%)		3/60 (5%)
Blood cholesterol increased	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Blood creatinine increased	3/30 (10%)		3/30 (10%)		6/60 (10%)
Blood triglycerides increased	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Lipase increased	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)
Lymphocyte count decreased	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)
Neutrophil count decreased	7/30 (23.3%)		3/30 (10%)		10/60 (16.7%)
Platelet count decreased	4/30 (13.3%)		3/30 (10%)		7/60 (11.7%)
Transaminases increased	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Weight decreased	2/30 (6.7%)		3/30 (10%)		5/60 (8.3%)
White blood cell count decreased	6/30 (20%)		2/30 (6.7%)		8/60 (13.3%)
Metabolism and nutrition disorders
Decreased appetite	3/30 (10%)		5/30 (16.7%)		8/60 (13.3%)
Dehydration	1/30 (3.3%)		4/30 (13.3%)		5/60 (8.3%)
Hyperglycaemia	4/30 (13.3%)		3/30 (10%)		7/60 (11.7%)
Hyperkalaemia	2/30 (6.7%)		4/30 (13.3%)		6/60 (10%)
Hypernatraemia	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Hypertriglyceridaemia	3/30 (10%)		1/30 (3.3%)		4/60 (6.7%)
Hypoalbuminaemia	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Hypocalcaemia	1/30 (3.3%)		4/30 (13.3%)		5/60 (8.3%)
Hypokalaemia	1/30 (3.3%)		3/30 (10%)		4/60 (6.7%)
Hypomagnesaemia	3/30 (10%)		2/30 (6.7%)		5/60 (8.3%)
Hypophosphataemia	2/30 (6.7%)		1/30 (3.3%)		3/60 (5%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/30 (10%)		6/30 (20%)		9/60 (15%)
Back pain	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)
Muscle spasms	1/30 (3.3%)		3/30 (10%)		4/60 (6.7%)
Muscle tightness	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)
Muscular weakness	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)
Musculoskeletal pain	1/30 (3.3%)		4/30 (13.3%)		5/60 (8.3%)
Myalgia	2/30 (6.7%)		3/30 (10%)		5/60 (8.3%)
Neck pain	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Pain in extremity	1/30 (3.3%)		5/30 (16.7%)		6/60 (10%)
Nervous system disorders
Dizziness	3/30 (10%)		6/30 (20%)		9/60 (15%)
Dizziness postural	2/30 (6.7%)		1/30 (3.3%)		3/60 (5%)
Dysgeusia	1/30 (3.3%)		3/30 (10%)		4/60 (6.7%)
Headache	8/30 (26.7%)		5/30 (16.7%)		13/60 (21.7%)
Hyperaesthesia	2/30 (6.7%)		0/30 (0%)		2/60 (3.3%)
Hypoaesthesia	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Neuropathy peripheral	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)
Peripheral sensory neuropathy	2/30 (6.7%)		1/30 (3.3%)		3/60 (5%)
Tremor	5/30 (16.7%)		3/30 (10%)		8/60 (13.3%)
Psychiatric disorders
Anxiety	3/30 (10%)		2/30 (6.7%)		5/60 (8.3%)
Depression	2/30 (6.7%)		2/30 (6.7%)		4/60 (6.7%)
Insomnia	4/30 (13.3%)		6/30 (20%)		10/60 (16.7%)
Renal and urinary disorders
Acute kidney injury	2/30 (6.7%)		0/30 (0%)		2/60 (3.3%)
Haematuria	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Pollakiuria	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Renal failure	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)
Reproductive system and breast disorders
Vulvovaginal dryness	2/30 (6.7%)		1/30 (3.3%)		3/60 (5%)
Respiratory, thoracic and mediastinal disorders
Cough	8/30 (26.7%)		6/30 (20%)		14/60 (23.3%)
Dyspnoea	3/30 (10%)		6/30 (20%)		9/60 (15%)
Dyspnoea exertional	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)
Epistaxis	2/30 (6.7%)		1/30 (3.3%)		3/60 (5%)
Hiccups	0/30 (0%)		2/30 (6.7%)		2/60 (3.3%)
Nasal congestion	2/30 (6.7%)		2/30 (6.7%)		4/60 (6.7%)
Oropharyngeal pain	1/30 (3.3%)		4/30 (13.3%)		5/60 (8.3%)
Rhinorrhoea	1/30 (3.3%)		3/30 (10%)		4/60 (6.7%)
Upper-airway cough syndrome	4/30 (13.3%)		0/30 (0%)		4/60 (6.7%)
Skin and subcutaneous tissue disorders
Dry skin	3/30 (10%)		2/30 (6.7%)		5/60 (8.3%)
Erythema	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)
Melanocytic naevus	2/30 (6.7%)		0/30 (0%)		2/60 (3.3%)
Night sweats	2/30 (6.7%)		1/30 (3.3%)		3/60 (5%)
Pruritus	5/30 (16.7%)		5/30 (16.7%)		10/60 (16.7%)
Rash	5/30 (16.7%)		6/30 (20%)		11/60 (18.3%)
Rash erythematous	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)
Rash maculo-papular	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)
Skin discolouration	2/30 (6.7%)		1/30 (3.3%)		3/60 (5%)
Skin hyperpigmentation	4/30 (13.3%)		2/30 (6.7%)		6/60 (10%)
Vascular disorders
Hypertension	2/30 (6.7%)		6/30 (20%)		8/60 (13.3%)
Hypotension	1/30 (3.3%)		2/30 (6.7%)		3/60 (5%)

Limitations/Caveats

[Not Specified]

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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.