Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

Sponsor

Alliance for Clinical Trials in Oncology (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT00651261

Collaborator

National Cancer Institute (NCI) (NIH), Novartis Pharmaceuticals (Industry)

717

Enrollment

176

Locations

Arms

4.1

Patients Per Site

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the effects, good and/or bad, of a standard chemotherapy regimen for AML that includes the drugs daunorubicin and cytarabine combined with or without midostaurin (also known as PKC412), to find out which is better. This research is being done because it is unknown whether the addition of midostaurin to chemotherapy treatment is better than chemotherapy treatment alone. Midostaurin has been tested in over 400 patients and is being studied in a number of illnesses, including AML, colon cancer, and lung cancer. Midostaurin blocks an enzyme, produced by a gene known as FLT3, that may have a role in the survival and growth of AML cells. Not all leukemia cells will have the abnormal FLT3 gene. This study will focus only on patients with leukemia cells with the abnormal FLT3 gene.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: cytarabine Drug: daunorubicin Drug: midostaurin Other: placebo Drug: dexamethasone acetate	Phase 3

Detailed Description

In this study, patients will receive either the experimental agent (midostaurin) or placebo combined with chemotherapy treatment. Patients are stratified according to FLT3 mutation status (internal tandem duplication [ITD] allelic ratio < 0.7 vs ITD allelic ratio ≥ 0.7 vs tandem kinase domain [TKD]). There are three parts to the study treatment: remission induction therapy, remission consolidation therapy and continuation therapy.

Remission Induction Therapy:

Cytarabine 200 mg/m2/day by continuous intravenous infusion on days 1-7
Daunorubicin 60 mg/m2/day by intravenous push or short infusion on days 1-3
Midostaurin 50 mg (two 25 mg capsules) or placebo for midostaurin (2 capsules) twice a day by mouth on days 8-21
A bone marrow aspiration will be performed in all patients on Day 21 to determine the need for a second induction cycle.

Remission Consolidation (Four Remission Consolidation Cycles):

High dose cytarabine 3000 mg/m2 will be given by intravenous infusion over 3 hours every 12 hours on days 1, 3 and 5. Serial neurologic evaluation will be performed before and following the infusion of high-dose cytarabine.
Dexamethasone 0.1% or other corticosteroid ophthalmic solution 2 drops to each eye once daily to begin 6-12 hours prior to the initiation of the cytarabine infusion and to continue for at least 24 hours after the last cytarabine dose.
Midostaurin 50 mg (two 25 mg capsules) or placebo for midostaurin (2 capsules) twice a day by mouth on days 8-21

Midostaurin/Placebo Continuation Therapy:

Midostaurin 50 mg (two 25 mg capsules) or placebo for midostaurin (2 capsules) by mouth twice a day for 28 days. Each cycle will be 28 days in length. Continuation therapy with midostaurin/placebo will continue until relapse or for 12 cycles maximum.

The primary and secondary objectives of this study are:

Primary objective:

To determine if the addition of midostaurin to daunorubicin/cytarabine induction, high-dose cytarabine consolidation, and continuation therapy improves overall survival (OS) in both the mutant FLT3-ITD and FLT3-TKD AML patients

Secondary objectives:

To compare the overall survival (OS) in the two groups using an analysis in which patients who receive a stem cell transplant are censored at the time of transplant
To compare the complete response (CR) rate between the two treatment groups
To compare the event-free survival (EFS) between the two treatment groups
To compare the disease free survival (DFS) of the two treatment groups
To compare the disease free survival rate one year after completion of the continuation phase of the two groups
To assess the toxicity of the experimental combination
To describe the interaction between treatment outcome and pretreatment characteristics such as age, performance status, white blood cell (WBC) count, morphology, cytogenetics, and molecular and pharmacodynamic features
To assess the population pharmacokinetics (popPK) of midostaurin and its two major metabolites (CGP52421 and CGP62221). The potential association(s) between PK exposure and FLT3 status, OS, EFS and clinical response will be explored

There is a pharmacokinetic sub-study (CALGB 60706) within CALGB 10603. This embedded companion study must be offered to all patients enrolled on CALGB 10603, although patients may opt not to participate in CALGB 60706.

After study entry, patients are followed periodically for up to 10 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

717 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

A Phase III Randomized, Double-Blind Study of Induction (Daunorubicin/Cytarabine) and Consolidation (High-Dose Cytarabine) Chemotherapy + Midostaurin (PKC412) (IND #101261) or Placebo in Newly Diagnosed Patients < 60 Years of Age With FLT3 Mutated Acute Myeloid Leukemia (AML)

Actual Study Start Date :

Apr 1, 2008

Actual Primary Completion Date :

Jul 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Induction and consolidation chemotherapy plus midostaurin Patients will receive a standard combination of chemotherapy drugs during remission induction therapy that includes cytarabine, daunorubicin, and the experimental drug midostaurin. Depending on the outcome of remission induction treatment, there may be a decision to discontinue the study treatment or a second remission induction cycle may be given. If remission induction therapy is successfully completed, patients will receive four courses of high-dose cytarabine consolidation chemotherapy plus dexamethasone together with the experimental drug midostaurin. All patients will undergo a bone marrow aspiration (and perhaps a biopsy) after the final course of remission consolidation chemotherapy. If the patient continues to respond to the treatment, the patient will receive continuation therapy with midostaurin for twelve (12) months.	Drug: cytarabine Given IV Drug: daunorubicin Given IV Drug: midostaurin Given orally Drug: dexamethasone acetate ocular medication administration
Active Comparator: Induction and consolidation chemotherapy plus placebo Patients will receive a standard combination of chemotherapy drugs during remission induction therapy that includes cytarabine, daunorubicin, and placebo. Depending on the outcome of remission induction treatment, there may be a decision to discontinue the study treatment or a second remission induction cycle may be given. If remission induction therapy is successfully completed, patients will receive four courses of high-dose cytarabine consolidation chemotherapy plus dexamethasone together with placebo. All patients will undergo a bone marrow aspiration (and perhaps a biopsy) after the final course of remission consolidation chemotherapy. If the patient continues to respond to the treatment, the patient will receive continuation therapy with placebo for twelve (12) months.	Drug: cytarabine Given IV Drug: daunorubicin Given IV Other: placebo Given orally Drug: dexamethasone acetate ocular medication administration

Arm

Intervention/Treatment

Experimental: Induction and consolidation chemotherapy plus midostaurin

Patients will receive a standard combination of chemotherapy drugs during remission induction therapy that includes cytarabine, daunorubicin, and the experimental drug midostaurin. Depending on the outcome of remission induction treatment, there may be a decision to discontinue the study treatment or a second remission induction cycle may be given. If remission induction therapy is successfully completed, patients will receive four courses of high-dose cytarabine consolidation chemotherapy plus dexamethasone together with the experimental drug midostaurin. All patients will undergo a bone marrow aspiration (and perhaps a biopsy) after the final course of remission consolidation chemotherapy. If the patient continues to respond to the treatment, the patient will receive continuation therapy with midostaurin for twelve (12) months.

Drug: cytarabine

Given IV

Drug: daunorubicin

Given IV

Drug: midostaurin

Given orally

Drug: dexamethasone acetate

ocular medication administration

Active Comparator: Induction and consolidation chemotherapy plus placebo

Patients will receive a standard combination of chemotherapy drugs during remission induction therapy that includes cytarabine, daunorubicin, and placebo. Depending on the outcome of remission induction treatment, there may be a decision to discontinue the study treatment or a second remission induction cycle may be given. If remission induction therapy is successfully completed, patients will receive four courses of high-dose cytarabine consolidation chemotherapy plus dexamethasone together with placebo. All patients will undergo a bone marrow aspiration (and perhaps a biopsy) after the final course of remission consolidation chemotherapy. If the patient continues to respond to the treatment, the patient will receive continuation therapy with placebo for twelve (12) months.

Drug: cytarabine

Given IV

Drug: daunorubicin

Given IV

Other: placebo

Given orally

Drug: dexamethasone acetate

ocular medication administration

Outcome Measures

Primary Outcome Measures

Overall Survival (OS) [Duration of study (Up to 10 years)]
Overall survival (OS) was defined as the time interval from randomization to death from any cause. The median OS with 95% CI was estimated using the Kaplan-Meier method.

Secondary Outcome Measures

Event- Free Survival [Duration of study (Up to 10 years)]
Event free survival (EFS) was defined as the time from randomization until the earliest qualifying event, including: failure to obtain a CR on or before 60 days of initiation of protocol therapy; relapse; or death from any cause. Patients alive and event free at the time of analysis were censored on the date of last clinical assessment. The median EFS with 95% CI was estimated using the Kaplan-Meier method. Due to a higher than expected transplant rate, EFS was promoted to be a key secondary endpoint.
Overall Survival, Censoring Participants Who Receive a Stem Cell Transplant at the Time of the Transplant [Duration of study (Up to 10 years)]
Overall survival (OS) was defined as the time interval from randomization to death from any cause. Any participants who received a stem cell transplant were censored at the time of transplant. The median OS with 95% CI was estimated using the Kaplan-Meier method.
Complete Response Rate [Induction therapy (up to 60 days)]
Percentage of participants who achieved a complete response (CR). A CR was defined as normalization of blood counts and a marrow showing less than 5% blasts occurring on or before day 60.
Disease-free Survival (DFS) [Duration of study (Up to 10 years)]
Disease free survival (DFS) is defined as the time from documentation of first CR at any time to the first of relapse or death from any cause in participants who achieved a CR.
DFS Rate One Year After Completing the Planned Continuation Phase [30 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 59 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Documentation of Disease:

Unequivocal diagnosis of AML ( > 20% blasts in the bone marrow based on the WHO classification), excluding M3 (acute promyelocytic leukemia). Patients with neurologic symptoms suggestive of CNS leukemia are recommended to have a lumbar puncture. Patients whose CSF is positive for AML blasts are not eligible.
Documented FLT3 mutation (ITD or point mutation), determined by analysis in a protocol- designated FLT3 screening laboratory.

Age Requirement:

Age ≥ 18 and < 60 years

Prior Therapy:

No prior chemotherapy for leukemia or myelodysplasia with the following exceptions:
emergency leukapheresis
emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 5 days
cranial RT for CNS leukostasis (one dose only)
growth factor/cytokine support
AML patients with a history of antecedent myelodysplasia (MDS) remain eligible for treatment on this trial, but must not have had prior cytotoxic therapy (e.g., azacitidine or decitabine)
Patients who have developed therapy related AML after prior RT or chemotherapy for another cancer or disorder are not eligible.

Cardiac Function: Patients with symptomatic congestive heart failure are not eligible.
Initial Laboratory Value: Total bilirubin < 2.5 x ULN (Upper Limit of Normal)
Pregnancy and Nursing Status:

Non-pregnant and non-nursing due to the unknown teratogenic potential of midostaurin in humans, pregnant or nursing patients may not be enrolled.
Women of childbearing potential must have a negative serum or urine pregnancy test within a sensitivity of at least 50 mIU/mL within 16 days prior to registration.
Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or commit to TWO acceptable methods of birth control:
one highly effective method (eg, IUD, hormonal (non-oral contraceptive), tubal ligation, or partner's vasectomy) and
one additional effective method (e.g., latex condom, diaphragm or cervical cap)
The two acceptable methods of birth control must be used AT THE SAME TIME, before beginning midostaurin/placebo therapy and continuing for 12 weeks after completion of all therapy.
Note that oral contraceptives are not considered a high effective method because of the possibility of a drug interaction with midostaurin.
Women of childbearing potential is defined as a sexually active mature woman who has not undergone a hysterectomy or who has not had menses at any time in the preceding 24 consecutive months.
Men must agree not to father a child and must use a latex condom during any sexual contact with women of childbearing potential while taking midostaurin/placebo and for 12 weeks after therapy is stopped, even if they have undergone a successful vasectomy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UAB Comprehensive Cancer Center	Birmingham	Alabama	United States	35294
2	Arkansas Cancer Research Center at University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
3	University of California Davis Cancer Center	Sacramento	California	United States	95817
4	Aurora Presbyterian Hospital	Aurora	Colorado	United States	80012
5	Boulder Community Hospital	Boulder	Colorado	United States	80301-9019
6	Penrose Cancer Center at Penrose Hospital	Colorado Springs	Colorado	United States	80933
7	St. Anthony Central Hospital	Denver	Colorado	United States	80204
8	Porter Adventist Hospital	Denver	Colorado	United States	80210
9	Presbyterian - St. Luke's Medical Center	Denver	Colorado	United States	80218
10	St. Joseph Hospital	Denver	Colorado	United States	80218
11	Rose Medical Center	Denver	Colorado	United States	80220
12	CCOP - Colorado Cancer Research Program	Denver	Colorado	United States	80224-2522
13	Swedish Medical Center	Englewood	Colorado	United States	80110
14	North Colorado Medical Center	Greeley	Colorado	United States	80631
15	Sky Ridge Medical Center	Lone Tree	Colorado	United States	80124
16	Hope Cancer Care Center at Longmont United Hospital	Longmont	Colorado	United States	80501
17	McKee Medical Center	Loveland	Colorado	United States	80539
18	North Suburban Medical Center	Thornton	Colorado	United States	80229
19	Exempla Lutheran Medical Center	Wheat Ridge	Colorado	United States	80033
20	Helen and Harry Gray Cancer Center at Hartford Hospital	Hartford	Connecticut	United States	06102-5037
21	Tunnell Cancer Center at Beebe Medical Center	Lewes	Delaware	United States	19958
22	CCOP - Christiana Care Health Services	Newark	Delaware	United States	19713
23	University of Florida Shands Cancer Center	Gainesville	Florida	United States	32610-0232
24	Memorial Cancer Institute at Memorial Regional Hospital	Hollywood	Florida	United States	33021
25	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida	United States	32207
26	Florida Hospital Cancer Institute at Florida Hospital Orlando	Orlando	Florida	United States	32803-1273
27	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida	Tampa	Florida	United States	33612-9497
28	MBCCOP - Medical College of Georgia Cancer Center	Augusta	Georgia	United States	30912
29	Charles B. Eberhart Cancer Center at DeKalb Medical Center	Decatur	Georgia	United States	30033
30	Medical Center of Central Georgia	Macon	Georgia	United States	31208
31	Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler	Savannah	Georgia	United States	31405
32	Cancer Research Center of Hawaii	Honolulu	Hawaii	United States	96813
33	Queen's Cancer Institute at Queen's Medical Center	Honolulu	Hawaii	United States	96813
34	Illinois CancerCare - Bloomington	Bloomington	Illinois	United States	61701
35	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois	United States	60611-3013
36	University of Illinois Cancer Center	Chicago	Illinois	United States	60612-7243
37	University of Chicago Cancer Research Center	Chicago	Illinois	United States	60637-1470
38	Decatur Memorial Hospital Cancer Care Institute	Decatur	Illinois	United States	62526
39	Cardinal Bernardin Cancer Center at Loyola University Medical Center	Maywood	Illinois	United States	60153
40	BroMenn Regional Medical Center	Normal	Illinois	United States	61761
41	Oncology Hematology Associates of Central Illinois, PC - Peoria	Peoria	Illinois	United States	61615
42	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61636
43	Fort Wayne Medical Oncology and Hematology	Fort Wayne	Indiana	United States	46845
44	McFarland Clinic, PC	Ames	Iowa	United States	50010
45	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa	United States	52242-1002
46	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa	United States	51101
47	Mercy Medical Center - Sioux City	Sioux City	Iowa	United States	51104
48	St. Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
49	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky	United States	40536-0093
50	Tulane Cancer Center Office of Clinical Research	Alexandria	Louisiana	United States	71315-3198
51	Feist-Weiller Cancer Center at Louisiana State University Health Sciences	Shreveport	Louisiana	United States	71130-3932
52	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland	United States	21201
53	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
54	Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
55	Boston University Cancer Research Center	Boston	Massachusetts	United States	02118
56	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
57	Baystate Regional Cancer Program at D'Amour Center for Cancer Care	Springfield	Massachusetts	United States	01199
58	Battle Creek Health System Cancer Care Center	Battle Creek	Michigan	United States	49017
59	Mecosta County Medical Center	Big Rapids	Michigan	United States	49307
60	Butterworth Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
61	CCOP - Grand Rapids	Grand Rapids	Michigan	United States	49503
62	Lacks Cancer Center at Saint Mary's Health Care	Grand Rapids	Michigan	United States	49503
63	Borgess Medical Center	Kalamazoo	Michigan	United States	49001
64	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007-3731
65	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
66	Providence Cancer Institute at Providence Hospital - Southfield Campus	Southfield	Michigan	United States	48075
67	Munson Medical Center	Traverse City	Michigan	United States	49684
68	Metro Health Hospital	Wyoming	Michigan	United States	49519
69	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
70	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota	United States	55433
71	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
72	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota	United States	55432
73	HealthEast Cancer Care at St. John's Hospital	Maplewood	Minnesota	United States	55109
74	Minnesota Oncology Hematology, PA - Maplewood	Maplewood	Minnesota	United States	55109
75	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota	United States	55407
76	Hennepin County Medical Center - Minneapolis	Minneapolis	Minnesota	United States	55415
77	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota	United States	55455
78	Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota	United States	55422-2900
79	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
80	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
81	Park Nicollet Cancer Center	Saint Louis Park	Minnesota	United States	55416
82	Regions Hospital Cancer Care Center	Saint Paul	Minnesota	United States	55101
83	United Hospital	Saint Paul	Minnesota	United States	55102
84	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
85	Minnesota Oncology Hematology, PA - Woodbury	Woodbury	Minnesota	United States	55125
86	University of Mississippi Cancer Clinic	Jackson	Mississippi	United States	39216
87	Ellis Fischel Cancer Center at University of Missouri - Columbia	Columbia	Missouri	United States	65203
88	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
89	UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-6805
90	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
91	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
92	Sunrise Hospital and Medical Center	Las Vegas	Nevada	United States	89109
93	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756-0002
94	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87131-5636
95	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
96	Monter Cancer Center of the North Shore-LIJ Health System	Lake Success	New York	United States	11042
97	CCOP - North Shore University Hospital	Manhasset	New York	United States	11030
98	Don Monti Comprehensive Cancer Center at North Shore University Hospital	Manhasset	New York	United States	11030
99	Tucker Center for Cancer Care at Orange Regional Medical Center	Middletown	New York	United States	10940-4199
100	Winthrop University Hospital	Mineola	New York	United States	11501
101	Long Island Jewish Medical Center	New Hyde Park	New York	United States	11040
102	New York Weill Cornell Cancer Center at Cornell University	New York	New York	United States	10021
103	Mount Sinai Medical Center	New York	New York	United States	10029
104	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York	United States	14642
105	SUNY Upstate Medical University Hospital	Syracuse	New York	United States	13210
106	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599-7295
107	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina	United States	28232-2861
108	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
109	Leo W. Jenkins Cancer Center at ECU Medical School	Greenville	North Carolina	United States	27834
110	Kinston Medical Specialists	Kinston	North Carolina	United States	28501
111	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096
112	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio	United States	44309-2090
113	Barberton Citizens Hospital	Barberton	Ohio	United States	44203
114	Charles M. Barrett Cancer Center at University Hospital	Cincinnati	Ohio	United States	45267
115	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210-1240
116	St. Rita's Medical Center	Lima	Ohio	United States	45801
117	Cleo Craig Cancer Research Clinic	Lawton	Oklahoma	United States	73505
118	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma	United States	73104
119	Geisinger Cancer Institute at Geisinger Health	Danville	Pennsylvania	United States	17822-0001
120	Geisinger Hazleton Cancer Center	Hazleton	Pennsylvania	United States	18201
121	Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
122	Western Pennsylvania Cancer Institute at Western Pennsylvania Hospital	Pittsburgh	Pennsylvania	United States	15224-1791
123	UPMC Cancer Centers	Pittsburgh	Pennsylvania	United States	15232
124	Geisinger Medical Group - Scenery Park	State College	Pennsylvania	United States	16801
125	Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center	Wilkes-Barre	Pennsylvania	United States	18711
126	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina	United States	29425
127	Cancer Centers of the Carolinas - Easley	Easley	South Carolina	United States	29640
128	Cancer Centers of the Carolinas - Faris Road	Greenville	South Carolina	United States	29605
129	Cancer Centers of the Carolinas - Grove Commons	Greenville	South Carolina	United States	29605
130	Greenville Hospital Cancer Center	Greenville	South Carolina	United States	29605
131	CCOP - Greenville	Greenville	South Carolina	United States	29615
132	Self Regional Cancer Center at Self Regional Medical Center	Greenwood	South Carolina	United States	29646
133	Cancer Centers of the Carolinas - Greer Medical Oncology	Greer	South Carolina	United States	29650
134	Cancer Centers of the Carolinas - Seneca	Seneca	South Carolina	United States	29672
135	Cancer Centers of the Carolinas - Spartanburg	Spartanburg	South Carolina	United States	29307
136	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
137	Sanford Cancer Center at Sanford USD Medical Center	Sioux Falls	South Dakota	United States	57117-5039
138	University of Tennessee Cancer Institute - Memphis	Memphis	Tennessee	United States	38104
139	Tennessee Oncology, PLLC at Sarah Cannon Cancer Center	Nashville	Tennessee	United States	37203
140	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232-6838
141	Baylor University Medical Center - Houston	Houston	Texas	United States	77030
142	Ben Taub General Hospital	Houston	Texas	United States	77030
143	Veterans Affairs Medical Center - Houston	Houston	Texas	United States	77030
144	Mountainview Medical	Berlin	Vermont	United States	05602
145	Fletcher Allen Health Care - University Health Center Campus	Burlington	Vermont	United States	05401
146	Virginia Commonwealth University Massey Cancer Center	Richmond	Virginia	United States	23298-0037
147	West Virginia University Health Sciences Center - Charleston	Charleston	West Virginia	United States	25304
148	Mary Babb Randolph Cancer Center at West Virginia University Hospitals	Morgantown	West Virginia	United States	26506
149	Marshfield Clinic - Chippewa Center	Chippewa Falls	Wisconsin	United States	54729
150	Center for Cancer Treatment & Prevention at Sacred Heart Hospital	Eau Claire	Wisconsin	United States	54701
151	Marshfield Clinic Cancer Care at Regional Cancer Center	Eau Claire	Wisconsin	United States	54701
152	Green Bay Oncology, Limited at St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54301-3526
153	Green Bay Oncology, Limited at St. Mary's Hospital	Green Bay	Wisconsin	United States	54303
154	St. Mary's Hospital Medical Center - Green Bay	Green Bay	Wisconsin	United States	54303
155	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54307-3508
156	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center	Madison	Wisconsin	United States	53792-6164
157	Holy Family Memorial Medical Center Cancer Care Center	Manitowoc	Wisconsin	United States	54221-1450
158	Bay Area Cancer Care Center at Bay Area Medical Center	Marinette	Wisconsin	United States	54143
159	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin	United States	54449
160	Saint Joseph's Hospital	Marshfield	Wisconsin	United States	54449
161	Marshfield Clinic - Lakeland Center	Minocqua	Wisconsin	United States	54548
162	D.N. Greenwald Center	Mukwonago	Wisconsin	United States	53149
163	Regional Cancer Center at Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin	United States	53066
164	Ministry Medical Group at Saint Mary's Hospital	Rhinelander	Wisconsin	United States	54501
165	Marshfield Clinic - Indianhead Center	Rice Lake	Wisconsin	United States	54868
166	Marshfield Clinic at Saint Michael's Hospital	Stevens Point	Wisconsin	United States	54481
167	Waukesha Memorial Hospital Regional Cancer Center	Waukesha	Wisconsin	United States	53188
168	Marshfield Clinic - Weston Center	Weston	Wisconsin	United States	54476
169	Ministry Saint Clare's Hospital	Weston	Wisconsin	United States	54476
170	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin	United States	54494
171	Tom Baker Cancer Centre - Calgary	Calgary	Alberta	Canada	T2N 4N2
172	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
173	Nova Scotia Cancer Centre	Halifax	Nova Scotia	Canada	B3H 1V8
174	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
175	Maisonneuve-Rosemont Hospital	Montreal	Quebec	Canada	H1T 2M4
176	McGill Cancer Centre at McGill University	Montreal	Quebec	Canada	H2W 1S6

Sponsors and Collaborators

Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
Novartis Pharmaceuticals

Investigators

Study Chair: Richard M. Stone, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Alliance for Clinical Trials in Oncology

ClinicalTrials.gov Identifier:

NCT00651261

Other Study ID Numbers:

CALGB-10603
CALGB-10603
EUDRACT-2006-006852-37
CDR0000590404

First Posted:

Apr 2, 2008

Last Update Posted:

Aug 18, 2021

Last Verified:

Aug 1, 2021

Keywords provided by Alliance for Clinical Trials in Oncology

adult acute basophilic leukemia

adult acute eosinophilic leukemia

adult acute lymphoblastic leukemia

adult acute megakaryoblastic leukemia (M7)

adult acute minimally differentiated myeloid leukemia (M0)

adult acute monoblastic leukemia (M5a)

adult acute monocytic leukemia (M5b)

adult acute myeloblastic leukemia with maturation (M2)

adult acute myeloblastic leukemia without maturation (M1)

adult acute myeloid leukemia with 11q23 (MLL) abnormalities

adult acute myeloid leukemia with inv(16)(p13;q22)

adult acute myeloid leukemia with t(16;16)(p13;q22)

adult acute myeloid leukemia with t(8;21)(q22;q22)

adult acute myelomonocytic leukemia (M4)

adult erythroleukemia (M6a)

adult pure erythroid leukemia (M6b)

untreated adult acute myeloid leukemia

Additional relevant MeSH terms:

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Cytarabine

Dexamethasone

Dexamethasone acetate

Daunorubicin

Midostaurin

BB 1101

Study Results

Participant Flow

Recruitment Details	Between May 2008 and October 2001, 3,277 participants were pre-registered. Of those, 900 participants had a documented FLT3 mutation. 717 participants were enrolled onto this study.
Pre-assignment Detail

Arm/Group Title	Induction and Consolidation Chemotherapy Plus Midostaurin	Induction and Consolidation Chemotherapy Plus Placebo
Arm/Group Description	Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
Period Title: Overall Study
STARTED	360	357
COMPLETED	69	51
NOT COMPLETED	291	306

Baseline Characteristics

Arm/Group Title	Induction and Consolidation Chemotherapy Plus Midostaurin	Induction and Consolidation Chemotherapy Plus Placebo	Total
Arm/Group Description	Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.	Total of all reporting groups
Overall Participants	360	357	717
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	47.1	48.6	47.9
Sex: Female, Male (Count of Participants)
Female	186 51.7%	212 59.4%	398 55.5%
Male	174 48.3%	145 40.6%	319 44.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 2.5%	7 2%	16 2.2%
Not Hispanic or Latino	103 28.6%	107 30%	210 29.3%
Unknown or Not Reported	248 68.9%	243 68.1%	491 68.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.3%	1 0.1%
Asian	8 2.2%	5 1.4%	13 1.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	8 2.2%	9 2.5%	17 2.4%
White	147 40.8%	128 35.9%	275 38.4%
More than one race	2 0.6%	1 0.3%	3 0.4%
Unknown or Not Reported	195 54.2%	213 59.7%	408 56.9%
Region of Enrollment (participants) [Number]
Canada	4 1.1%	9 2.5%	13 1.8%
United States	117 32.5%	106 29.7%	223 31.1%
Germany	148 41.1%	157 44%	305 42.5%
Belgium	3 0.8%	5 1.4%	8 1.1%
France	3 0.8%	2 0.6%	5 0.7%
Netherlands	3 0.8%	2 0.6%	5 0.7%
Australia	0 0%	2 0.6%	2 0.3%
Spain	7 1.9%	15 4.2%	22 3.1%
Austria	7 1.9%	5 1.4%	12 1.7%
Italy	61 16.9%	44 12.3%	105 14.6%
Czech Republic	5 1.4%	6 1.7%	11 1.5%
Slovakia	2 0.6%	2 0.6%	4 0.6%
Hungary	0 0%	2 0.6%	2 0.3%
FLT3 mutational subtype (participants) [Number]
TKD (No ITD)	81 22.5%	81 22.7%	162 22.6%
ITD Allelic ratio <0.7	171 47.5%	170 47.6%	341 47.6%
ITD Allelic ratio >=0.7	108 30%	106 29.7%	214 29.8%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	Overall survival (OS) was defined as the time interval from randomization to death from any cause. The median OS with 95% CI was estimated using the Kaplan-Meier method.
Time Frame	Duration of study (Up to 10 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Induction and Consolidation Chemotherapy Plus Midostaurin	Induction and Consolidation Chemotherapy Plus Placebo
Arm/Group Description	Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
Measure Participants	360	357
Median (95% Confidence Interval) [months]	74.7	25.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Induction and Consolidation Chemotherapy Plus Midostaurin, Induction and Consolidation Chemotherapy Plus Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	1-sided stratified log-rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95% 0.63 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Event- Free Survival
Description	Event free survival (EFS) was defined as the time from randomization until the earliest qualifying event, including: failure to obtain a CR on or before 60 days of initiation of protocol therapy; relapse; or death from any cause. Patients alive and event free at the time of analysis were censored on the date of last clinical assessment. The median EFS with 95% CI was estimated using the Kaplan-Meier method. Due to a higher than expected transplant rate, EFS was promoted to be a key secondary endpoint.
Time Frame	Duration of study (Up to 10 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Induction and Consolidation Chemotherapy Plus Midostaurin	Induction and Consolidation Chemotherapy Plus Placebo
Arm/Group Description	Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
Measure Participants	360	357
Median (95% Confidence Interval) [months]	8.2	3.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Induction and Consolidation Chemotherapy Plus Midostaurin, Induction and Consolidation Chemotherapy Plus Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0024
	Comments
	Method	1-sided stratified log rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95% 0.66 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Overall Survival, Censoring Participants Who Receive a Stem Cell Transplant at the Time of the Transplant
Description	Overall survival (OS) was defined as the time interval from randomization to death from any cause. Any participants who received a stem cell transplant were censored at the time of transplant. The median OS with 95% CI was estimated using the Kaplan-Meier method.
Time Frame	Duration of study (Up to 10 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Induction and Consolidation Chemotherapy Plus Midostaurin	Induction and Consolidation Chemotherapy Plus Placebo
Arm/Group Description	Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
Measure Participants	360	357
Median (95% Confidence Interval) [months]	NA	NA

4. Secondary Outcome

Title	Complete Response Rate
Description	Percentage of participants who achieved a complete response (CR). A CR was defined as normalization of blood counts and a marrow showing less than 5% blasts occurring on or before day 60.
Time Frame	Induction therapy (up to 60 days)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Induction and Consolidation Chemotherapy Plus Midostaurin	Induction and Consolidation Chemotherapy Plus Placebo
Arm/Group Description	Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
Measure Participants	360	357
Number (95% Confidence Interval) [percentage of participants]	59 16.4%	54 15.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Induction and Consolidation Chemotherapy Plus Midostaurin, Induction and Consolidation Chemotherapy Plus Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.15
	Comments
	Method	Fisher Exact
	Comments

5. Secondary Outcome

Title	Disease-free Survival (DFS)
Description	Disease free survival (DFS) is defined as the time from documentation of first CR at any time to the first of relapse or death from any cause in participants who achieved a CR.
Time Frame	Duration of study (Up to 10 years)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Induction and Consolidation Chemotherapy Plus Midostaurin	Induction and Consolidation Chemotherapy Plus Placebo
Arm/Group Description	Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.	Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
Measure Participants	360	357
Median (95% Confidence Interval) [months]	26.7	15.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Induction and Consolidation Chemotherapy Plus Midostaurin, Induction and Consolidation Chemotherapy Plus Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.0049
	Comments
	Method	1-sided stratified log rank
	Comments

6. Secondary Outcome

Title	DFS Rate One Year After Completing the Planned Continuation Phase
Description
Time Frame	30 months

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title
Arm/Group Description

Adverse Events

	Induction and Consolidation Chemotherapy Plus Midostaurin		Induction and Consolidation Chemotherapy Plus Placebo
Time Frame
Adverse Event Reporting Description	709 participants were evaluated for adverse events.

Arm/Group Title	Induction and Consolidation Chemotherapy Plus Midostaurin		Induction and Consolidation Chemotherapy Plus Placebo
Arm/Group Description	Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and midostaurin 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and midostaurin at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of midostaurin 50 mg orally twice daily.		Patients will receive daunorubicin 60 mg/m^2 by IV push days 1-3 plus cytarabine 200 mg/m^2 IV days 1-7, and placebo 50 mg orally twice daily days 8-21. Participants achieving remission will receive four 28 day cycles of high dose cytarabine (3000 mg/m^2) days 1, 3, & 5 and placebo at 50 mg orally twice daily days 8-14. Maintenance therapy was given to participants who continued in remission for 12 28-day cycles of placebo 50 mg orally twice daily.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Induction and Consolidation Chemotherapy Plus Midostaurin		Induction and Consolidation Chemotherapy Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	157/355 (44.2%)		154/354 (43.5%)
Blood and lymphatic system disorders
Blood disorder	0/355 (0%)	0	1/354 (0.3%)	1
Bone marrow hypocellular	0/355 (0%)	0	1/354 (0.3%)	1
Disseminated intravascular coagulation	1/355 (0.3%)	1	0/354 (0%)	0
Febrile neutropenia	105/355 (29.6%)	144	110/354 (31.1%)	152
Hemoglobin decreased	154/355 (43.4%)	237	148/354 (41.8%)	230
Hemolysis	2/355 (0.6%)	2	0/354 (0%)	0
Lymph node pain	0/355 (0%)	0	1/354 (0.3%)	1
Lymphatic disorder	6/355 (1.7%)	6	4/354 (1.1%)	4
Cardiac disorders
Arrhythmia	1/355 (0.3%)	1	2/354 (0.6%)	2
Asystole	1/355 (0.3%)	1	0/354 (0%)	0
Atrial fibrillation	4/355 (1.1%)	4	6/354 (1.7%)	6
Atrial flutter	2/355 (0.6%)	2	2/354 (0.6%)	2
Atrial tachycardia	1/355 (0.3%)	1	2/354 (0.6%)	2
Cardiac disorder	4/355 (1.1%)	4	6/354 (1.7%)	6
Cardiac pain	3/355 (0.8%)	3	1/354 (0.3%)	1
Cardiopulmonary arrest	0/355 (0%)	0	1/354 (0.3%)	1
Conduction disorder	0/355 (0%)	0	2/354 (0.6%)	2
Left ventricular dysfunction	1/355 (0.3%)	1	0/354 (0%)	0
Left ventricular failure	8/355 (2.3%)	9	7/354 (2%)	7
Myocardial ischemia	3/355 (0.8%)	3	3/354 (0.8%)	3
Palpitations	0/355 (0%)	0	1/354 (0.3%)	1
Pericardial effusion	4/355 (1.1%)	4	5/354 (1.4%)	5
Pericarditis	3/355 (0.8%)	3	0/354 (0%)	0
Right ventricular dysfunction	1/355 (0.3%)	1	0/354 (0%)	0
Sinus arrhythmia	1/355 (0.3%)	1	0/354 (0%)	0
Sinus bradycardia	2/355 (0.6%)	2	2/354 (0.6%)	2
Sinus tachycardia	17/355 (4.8%)	20	15/354 (4.2%)	20
Supraventricular tachycardia	0/355 (0%)	0	2/354 (0.6%)	2
Ventricular fibrillation	0/355 (0%)	0	1/354 (0.3%)	1
Ventricular tachycardia	0/355 (0%)	0	3/354 (0.8%)	3
Ear and labyrinth disorders
Ear disorder	1/355 (0.3%)	1	2/354 (0.6%)	2
Ear pain	2/355 (0.6%)	2	3/354 (0.8%)	3
External ear pain	0/355 (0%)	0	1/354 (0.3%)	1
Middle ear inflammation	0/355 (0%)	0	1/354 (0.3%)	1
Tinnitus	0/355 (0%)	0	1/354 (0.3%)	1
Endocrine disorders
Endocrine disorder	0/355 (0%)	0	1/354 (0.3%)	1
Hyperthyroidism	0/355 (0%)	0	1/354 (0.3%)	1
Hypothyroidism	0/355 (0%)	0	1/354 (0.3%)	1
Eye disorders
Cataract	1/355 (0.3%)	1	0/354 (0%)	0
Conjunctivitis	2/355 (0.6%)	2	1/354 (0.3%)	1
Diplopia	1/355 (0.3%)	1	1/354 (0.3%)	1
Dry eye syndrome	3/355 (0.8%)	3	3/354 (0.8%)	3
Eye disorder	8/355 (2.3%)	9	12/354 (3.4%)	12
Eye pain	1/355 (0.3%)	1	1/354 (0.3%)	1
Eyelid function disorder	0/355 (0%)	0	2/354 (0.6%)	2
Flashing vision	1/355 (0.3%)	1	2/354 (0.6%)	2
Keratitis	5/355 (1.4%)	6	8/354 (2.3%)	9
Optic nerve edema	0/355 (0%)	0	1/354 (0.3%)	1
Photophobia	2/355 (0.6%)	2	1/354 (0.3%)	1
Retinal detachment	0/355 (0%)	0	1/354 (0.3%)	1
Scleral disorder	0/355 (0%)	0	1/354 (0.3%)	1
Vision blurred	2/355 (0.6%)	2	4/354 (1.1%)	4
Watering eyes	2/355 (0.6%)	2	3/354 (0.8%)	3
Gastrointestinal disorders
Abdominal distension	4/355 (1.1%)	4	2/354 (0.6%)	2
Abdominal pain	29/355 (8.2%)	33	28/354 (7.9%)	32
Anal fistula	1/355 (0.3%)	1	1/354 (0.3%)	1
Anal hemorrhage	1/355 (0.3%)	1	2/354 (0.6%)	2
Anal mucositis	2/355 (0.6%)	2	0/354 (0%)	0
Anal pain	7/355 (2%)	8	5/354 (1.4%)	5
Anal ulcer	0/355 (0%)	0	1/354 (0.3%)	1
Ascites	2/355 (0.6%)	2	2/354 (0.6%)	2
Colitis	9/355 (2.5%)	9	9/354 (2.5%)	9
Colonic hemorrhage	2/355 (0.6%)	2	0/354 (0%)	0
Colonic perforation	0/355 (0%)	0	1/354 (0.3%)	1
Constipation	16/355 (4.5%)	18	17/354 (4.8%)	18
Diarrhea	89/355 (25.1%)	111	89/354 (25.1%)	108
Dry mouth	2/355 (0.6%)	2	1/354 (0.3%)	1
Duodenal hemorrhage	0/355 (0%)	0	1/354 (0.3%)	1
Duodenal necrosis	1/355 (0.3%)	1	0/354 (0%)	0
Dyspepsia	10/355 (2.8%)	11	8/354 (2.3%)	8
Dysphagia	10/355 (2.8%)	10	10/354 (2.8%)	12
Ear, nose and throat examination abnormal	40/355 (11.3%)	52	42/354 (11.9%)	54
Endoscopy small intestine abnormal	1/355 (0.3%)	1	0/354 (0%)	0
Enteritis	2/355 (0.6%)	2	1/354 (0.3%)	1
Esophageal pain	1/355 (0.3%)	1	2/354 (0.6%)	2
Esophageal ulcer	1/355 (0.3%)	1	0/354 (0%)	0
Esophagitis	0/355 (0%)	0	2/354 (0.6%)	2
Flatulence	7/355 (2%)	8	5/354 (1.4%)	6
Gastric hemorrhage	2/355 (0.6%)	2	1/354 (0.3%)	1
Gastrointestinal disorder	10/355 (2.8%)	12	10/354 (2.8%)	10
Gastrointestinal pain	0/355 (0%)	0	1/354 (0.3%)	1
Gingival pain	1/355 (0.3%)	1	2/354 (0.6%)	2
Hemorrhoidal hemorrhage	1/355 (0.3%)	1	0/354 (0%)	0
Hemorrhoids	11/355 (3.1%)	14	7/354 (2%)	7
Ileal hemorrhage	0/355 (0%)	0	1/354 (0.3%)	1
Ileal necrosis	1/355 (0.3%)	1	0/354 (0%)	0
Ileus	2/355 (0.6%)	2	4/354 (1.1%)	4
Intestinal necrosis	2/355 (0.6%)	2	0/354 (0%)	0
Intra-abdominal hemorrhage	1/355 (0.3%)	1	0/354 (0%)	0
Jejunal necrosis	1/355 (0.3%)	1	0/354 (0%)	0
Lower gastrointestinal hemorrhage	2/355 (0.6%)	2	3/354 (0.8%)	3
Mucositis oral	23/355 (6.5%)	23	11/354 (3.1%)	13
Nausea	98/355 (27.6%)	149	91/354 (25.7%)	126
Oral hemorrhage	5/355 (1.4%)	6	10/354 (2.8%)	11
Oral pain	5/355 (1.4%)	5	5/354 (1.4%)	6
Periodontal disease	2/355 (0.6%)	2	1/354 (0.3%)	1
Proctitis	1/355 (0.3%)	1	1/354 (0.3%)	1
Rectal hemorrhage	3/355 (0.8%)	3	3/354 (0.8%)	3
Rectal obstruction	2/355 (0.6%)	2	0/354 (0%)	0
Rectal pain	2/355 (0.6%)	2	1/354 (0.3%)	1
Salivary gland disorder	1/355 (0.3%)	1	2/354 (0.6%)	2
Stomach pain	8/355 (2.3%)	12	9/354 (2.5%)	9
Tooth disorder	1/355 (0.3%)	1	2/354 (0.6%)	2
Toothache	3/355 (0.8%)	3	4/354 (1.1%)	4
Typhlitis	1/355 (0.3%)	1	2/354 (0.6%)	2
Upper gastrointestinal hemorrhage	2/355 (0.6%)	2	1/354 (0.3%)	1
Vomiting	70/355 (19.7%)	101	65/354 (18.4%)	86
General disorders
Chest pain	6/355 (1.7%)	7	11/354 (3.1%)	12
Chills	16/355 (4.5%)	21	16/354 (4.5%)	24
Disease progression	1/355 (0.3%)	1	1/354 (0.3%)	1
Edema limbs	26/355 (7.3%)	32	21/354 (5.9%)	24
Facial pain	2/355 (0.6%)	2	2/354 (0.6%)	2
Fatigue	95/355 (26.8%)	136	98/354 (27.7%)	130
Fever	34/355 (9.6%)	38	33/354 (9.3%)	38
Flu-like symptoms	1/355 (0.3%)	1	1/354 (0.3%)	1
General symptom	11/355 (3.1%)	14	15/354 (4.2%)	16
Ill-defined disorder	1/355 (0.3%)	1	4/354 (1.1%)	4
Injection site reaction	14/355 (3.9%)	17	17/354 (4.8%)	22
Localized edema	5/355 (1.4%)	5	9/354 (2.5%)	11
Multi-organ failure	4/355 (1.1%)	4	5/354 (1.4%)	5
Pain	14/355 (3.9%)	17	18/354 (5.1%)	24
Sudden death	0/355 (0%)	0	1/354 (0.3%)	1
Visceral edema	1/355 (0.3%)	1	1/354 (0.3%)	1
Hepatobiliary disorders
Cholecystitis	1/355 (0.3%)	1	2/354 (0.6%)	2
Hepatic failure	1/355 (0.3%)	1	2/354 (0.6%)	2
Hepatobiliary disease	4/355 (1.1%)	4	1/354 (0.3%)	1
Immune system disorders
Cytokine release syndrome	0/355 (0%)	0	1/354 (0.3%)	1
Hypersensitivity	7/355 (2%)	8	14/354 (4%)	15
Immune system disorder	3/355 (0.8%)	3	3/354 (0.8%)	4
Infections and infestations
Abdominal infection	1/355 (0.3%)	1	3/354 (0.8%)	3
Anal infection	6/355 (1.7%)	9	5/354 (1.4%)	5
Anorectal infection	1/355 (0.3%)	1	0/354 (0%)	0
Appendicitis	0/355 (0%)	0	1/354 (0.3%)	1
Bladder infection	2/355 (0.6%)	2	3/354 (0.8%)	3
Bone infection	1/355 (0.3%)	1	1/354 (0.3%)	1
Bronchitis	1/355 (0.3%)	1	3/354 (0.8%)	4
Catheter related infection	29/355 (8.2%)	39	21/354 (5.9%)	26
Colitis, infectious (e.g., Clostridium difficile)	3/355 (0.8%)	3	2/354 (0.6%)	2
Conjunctivitis infective	4/355 (1.1%)	4	3/354 (0.8%)	3
Eye infection	1/355 (0.3%)	1	1/354 (0.3%)	1
Eye infection intraocular	1/355 (0.3%)	1	0/354 (0%)	0
Gallbladder infection	0/355 (0%)	0	1/354 (0.3%)	1
Gingival infection	1/355 (0.3%)	1	2/354 (0.6%)	3
Hepatic infection	2/355 (0.6%)	2	3/354 (0.8%)	3
Infection	30/355 (8.5%)	41	26/354 (7.3%)	33
Infectious colitis	8/355 (2.3%)	8	9/354 (2.5%)	10
Joint infection	0/355 (0%)	0	2/354 (0.6%)	2
Kidney infection	0/355 (0%)	0	1/354 (0.3%)	1
Lip infection	5/355 (1.4%)	5	8/354 (2.3%)	9
Lymph gland infection	1/355 (0.3%)	1	0/354 (0%)	0
Mucosal infection	1/355 (0.3%)	1	1/354 (0.3%)	1
Nail infection	3/355 (0.8%)	3	0/354 (0%)	0
Opportunistic infection	3/355 (0.8%)	3	1/354 (0.3%)	1
Otitis externa	1/355 (0.3%)	1	2/354 (0.6%)	2
Otitis media	0/355 (0%)	0	1/354 (0.3%)	1
Paranasal sinus infection	1/355 (0.3%)	1	3/354 (0.8%)	3
Penile infection	1/355 (0.3%)	1	0/354 (0%)	0
Pharyngitis	3/355 (0.8%)	4	2/354 (0.6%)	2
Phlebitis infective	2/355 (0.6%)	2	1/354 (0.3%)	1
Pleural infection	1/355 (0.3%)	1	0/354 (0%)	0
Pneumonia	25/355 (7%)	32	35/354 (9.9%)	39
Rhinitis infective	1/355 (0.3%)	1	1/354 (0.3%)	1
Salivary gland infection	1/355 (0.3%)	1	0/354 (0%)	0
Sepsis	23/355 (6.5%)	27	16/354 (4.5%)	17
Sinusitis	1/355 (0.3%)	1	0/354 (0%)	0
Skin infection	8/355 (2.3%)	9	8/354 (2.3%)	9
Small intestine infection	1/355 (0.3%)	1	0/354 (0%)	0
Soft tissue infection	0/355 (0%)	0	4/354 (1.1%)	4
Splenic infection	2/355 (0.6%)	2	1/354 (0.3%)	1
Tooth infection	1/355 (0.3%)	1	4/354 (1.1%)	5
Upper aerodigestive tract infection	1/355 (0.3%)	1	1/354 (0.3%)	1
Urinary tract infection	8/355 (2.3%)	10	15/354 (4.2%)	19
Vulval infection	1/355 (0.3%)	1	0/354 (0%)	0
Wound infection	4/355 (1.1%)	4	2/354 (0.6%)	2
Injury, poisoning and procedural complications
Bruising	1/355 (0.3%)	1	0/354 (0%)	0
Fracture	1/355 (0.3%)	1	0/354 (0%)	0
Gastrointestinal anastomotic leak	0/355 (0%)	0	1/354 (0.3%)	1
Intraoperative complications	2/355 (0.6%)	2	0/354 (0%)	0
Intraoperative gastrointestinal injury	1/355 (0.3%)	1	0/354 (0%)	0
Intraoperative gastrointestinal injury - Appendix	0/355 (0%)	0	1/354 (0.3%)	1
Intraoperative reproductive tract injury - Ovary	0/355 (0%)	0	1/354 (0.3%)	1
Intraoperative reproductive tract injury - Testis	0/355 (0%)	0	1/354 (0.3%)	1
Kidney anastomotic leak	1/355 (0.3%)	1	0/354 (0%)	0
Postoperative hemorrhage	0/355 (0%)	0	1/354 (0.3%)	1
Thermal burn	0/355 (0%)	0	1/354 (0.3%)	1
Vascular access complication	3/355 (0.8%)	3	3/354 (0.8%)	3
Wound dehiscence	1/355 (0.3%)	1	0/354 (0%)	0
Investigations
Activated partial thromboplastin time prolonged	9/355 (2.5%)	15	9/354 (2.5%)	11
Alanine aminotransferase increased	35/355 (9.9%)	41	35/354 (9.9%)	41
Alkaline phosphatase increased	8/355 (2.3%)	8	20/354 (5.6%)	24
Amylase increased	1/355 (0.3%)	1	0/354 (0%)	0
Aspartate aminotransferase increased	30/355 (8.5%)	33	29/354 (8.2%)	32
Blood bilirubin increased	25/355 (7%)	32	36/354 (10.2%)	42
CD4 lymphocytes decreased	1/355 (0.3%)	3	0/354 (0%)	0
Cardiac troponin T increased	2/355 (0.6%)	2	1/354 (0.3%)	1
Coagulopathy	8/355 (2.3%)	14	7/354 (2%)	11
Creatinine increased	15/355 (4.2%)	16	16/354 (4.5%)	17
Electrocardiogram QTc interval prolonged	17/355 (4.8%)	22	19/354 (5.4%)	22
Fibrinogen decreased	2/355 (0.6%)	2	7/354 (2%)	7
Gamma-glutamyltransferase increased	19/355 (5.4%)	25	22/354 (6.2%)	32
INR increased	8/355 (2.3%)	10	5/354 (1.4%)	5
Laboratory test abnormal	18/355 (5.1%)	33	28/354 (7.9%)	47
Leukocyte count decreased	41/355 (11.5%)	66	47/354 (13.3%)	78
Lipase increased	2/355 (0.6%)	2	1/354 (0.3%)	1
Lymphocyte count decreased	22/355 (6.2%)	30	36/354 (10.2%)	56
Neutrophil count decreased	145/355 (40.8%)	227	146/354 (41.2%)	224
Platelet count decreased	155/355 (43.7%)	239	146/354 (41.2%)	227
Serum cholesterol increased	1/355 (0.3%)	1	0/354 (0%)	0
Weight gain	3/355 (0.8%)	3	3/354 (0.8%)	3
Weight loss	1/355 (0.3%)	1	11/354 (3.1%)	13
Metabolism and nutrition disorders
Acidosis	2/355 (0.6%)	2	1/354 (0.3%)	1
Anorexia	21/355 (5.9%)	30	26/354 (7.3%)	29
Blood glucose increased	17/355 (4.8%)	23	22/354 (6.2%)	31
Blood uric acid increased	6/355 (1.7%)	10	4/354 (1.1%)	4
Dehydration	1/355 (0.3%)	1	0/354 (0%)	0
Glucose intolerance	0/355 (0%)	0	2/354 (0.6%)	2
Serum albumin decreased	19/355 (5.4%)	28	22/354 (6.2%)	26
Serum calcium decreased	20/355 (5.6%)	25	26/354 (7.3%)	30
Serum calcium increased	2/355 (0.6%)	2	1/354 (0.3%)	1
Serum glucose decreased	1/355 (0.3%)	1	2/354 (0.6%)	3
Serum magnesium decreased	15/355 (4.2%)	19	15/354 (4.2%)	22
Serum phosphate decreased	7/355 (2%)	9	12/354 (3.4%)	13
Serum potassium decreased	31/355 (8.7%)	37	47/354 (13.3%)	53
Serum potassium increased	8/355 (2.3%)	9	4/354 (1.1%)	4
Serum sodium decreased	20/355 (5.6%)	22	20/354 (5.6%)	22
Serum sodium increased	5/355 (1.4%)	5	5/354 (1.4%)	5
Serum triglycerides increased	3/355 (0.8%)	4	0/354 (0%)	0
Tumor lysis syndrome	1/355 (0.3%)	1	2/354 (0.6%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	8/355 (2.3%)	8	6/354 (1.7%)	6
Arthritis	1/355 (0.3%)	1	2/354 (0.6%)	2
Back pain	15/355 (4.2%)	19	13/354 (3.7%)	13
Bone pain	7/355 (2%)	8	4/354 (1.1%)	5
Buttock pain	1/355 (0.3%)	1	0/354 (0%)	0
Chest wall pain	1/355 (0.3%)	1	2/354 (0.6%)	2
Joint effusion	1/355 (0.3%)	1	1/354 (0.3%)	1
Muscle weakness	3/355 (0.8%)	3	2/354 (0.6%)	3
Musculoskeletal disorder	4/355 (1.1%)	4	4/354 (1.1%)	4
Myalgia	7/355 (2%)	7	4/354 (1.1%)	5
Neck pain	7/355 (2%)	8	4/354 (1.1%)	5
Pain in extremity	5/355 (1.4%)	6	6/354 (1.7%)	9
Trismus	0/355 (0%)	0	1/354 (0.3%)	1
Nervous system disorders
Ataxia	1/355 (0.3%)	1	3/354 (0.8%)	3
Depressed level of consciousness	2/355 (0.6%)	2	1/354 (0.3%)	1
Dizziness	19/355 (5.4%)	23	20/354 (5.6%)	25
Dysgeusia	4/355 (1.1%)	4	7/354 (2%)	9
Encephalopathy	1/355 (0.3%)	1	1/354 (0.3%)	1
Extrapyramidal disorder	1/355 (0.3%)	1	1/354 (0.3%)	1
Headache	41/355 (11.5%)	54	42/354 (11.9%)	63
Intracranial hemorrhage	3/355 (0.8%)	3	6/354 (1.7%)	6
Ischemia cerebrovascular	0/355 (0%)	0	1/354 (0.3%)	1
Memory impairment	2/355 (0.6%)	2	0/354 (0%)	0
Neuralgia	0/355 (0%)	0	1/354 (0.3%)	1
Neurological disorder NOS	9/355 (2.5%)	11	4/354 (1.1%)	4
Nystagmus	1/355 (0.3%)	1	0/354 (0%)	0
Peripheral motor neuropathy	1/355 (0.3%)	1	0/354 (0%)	0
Peripheral sensory neuropathy	5/355 (1.4%)	5	6/354 (1.7%)	11
Seizure	1/355 (0.3%)	1	1/354 (0.3%)	1
Speech disorder	4/355 (1.1%)	4	1/354 (0.3%)	1
Syncope	6/355 (1.7%)	6	4/354 (1.1%)	4
Syncope vasovagal	1/355 (0.3%)	1	1/354 (0.3%)	1
Tremor	4/355 (1.1%)	4	3/354 (0.8%)	3
Psychiatric disorders
Agitation	3/355 (0.8%)	5	3/354 (0.8%)	3
Anxiety	5/355 (1.4%)	5	9/354 (2.5%)	11
Confusion	4/355 (1.1%)	4	3/354 (0.8%)	3
Depression	2/355 (0.6%)	2	12/354 (3.4%)	12
Euphoria	0/355 (0%)	0	1/354 (0.3%)	1
Insomnia	11/355 (3.1%)	14	7/354 (2%)	11
Personality change	0/355 (0%)	0	1/354 (0.3%)	1
Psychosis	4/355 (1.1%)	4	2/354 (0.6%)	2
Renal and urinary disorders
Bladder hemorrhage	0/355 (0%)	0	1/354 (0.3%)	1
Bladder pain	1/355 (0.3%)	1	0/354 (0%)	0
Cystitis	1/355 (0.3%)	1	0/354 (0%)	0
Glomerular filtration rate decreased	2/355 (0.6%)	2	1/354 (0.3%)	1
Hemorrhage urinary tract	2/355 (0.6%)	2	6/354 (1.7%)	6
Proteinuria	0/355 (0%)	0	1/354 (0.3%)	1
Renal failure	13/355 (3.7%)	13	9/354 (2.5%)	9
Renal hemorrhage	1/355 (0.3%)	1	0/354 (0%)	0
Ureteric obstruction	1/355 (0.3%)	1	0/354 (0%)	0
Urethral pain	0/355 (0%)	0	1/354 (0.3%)	1
Urinary frequency	1/355 (0.3%)	1	2/354 (0.6%)	2
Urinary incontinence	2/355 (0.6%)	2	1/354 (0.3%)	1
Urinary retention	2/355 (0.6%)	2	3/354 (0.8%)	3
Urine discoloration	0/355 (0%)	0	1/354 (0.3%)	1
Urogenital disorder	15/355 (4.2%)	21	11/354 (3.1%)	15
Reproductive system and breast disorders
Breast pain	0/355 (0%)	0	2/354 (0.6%)	2
Penile pain	0/355 (0%)	0	1/354 (0.3%)	1
Perineal pain	1/355 (0.3%)	1	0/354 (0%)	0
Reproductive tract disorder	1/355 (0.3%)	1	0/354 (0%)	0
Uterine hemorrhage	4/355 (1.1%)	5	3/354 (0.8%)	4
Vaginal hemorrhage	5/355 (1.4%)	5	9/354 (2.5%)	9
Vaginal mucositis	1/355 (0.3%)	1	1/354 (0.3%)	1
Vaginal pain	0/355 (0%)	0	1/354 (0.3%)	1
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	9/355 (2.5%)	9	5/354 (1.4%)	5
Allergic rhinitis	1/355 (0.3%)	1	3/354 (0.8%)	4
Aspiration	1/355 (0.3%)	1	0/354 (0%)	0
Atelectasis	0/355 (0%)	0	1/354 (0.3%)	1
Bronchopulmonary hemorrhage	1/355 (0.3%)	1	0/354 (0%)	0
Bronchospasm	1/355 (0.3%)	1	2/354 (0.6%)	2
Cough	17/355 (4.8%)	21	19/354 (5.4%)	20
Dyspnea	20/355 (5.6%)	22	24/354 (6.8%)	24
Epistaxis	24/355 (6.8%)	26	22/354 (6.2%)	24
Hiccups	2/355 (0.6%)	2	0/354 (0%)	0
Hypoxia	8/355 (2.3%)	8	12/354 (3.4%)	12
Laryngeal edema	0/355 (0%)	0	1/354 (0.3%)	1
Laryngeal mucositis	1/355 (0.3%)	1	0/354 (0%)	0
Laryngeal pain	1/355 (0.3%)	1	0/354 (0%)	0
Laryngoscopy abnormal	0/355 (0%)	0	1/354 (0.3%)	1
Nasal congestion	1/355 (0.3%)	1	0/354 (0%)	0
Pharyngeal examination abnormal	3/355 (0.8%)	3	2/354 (0.6%)	2
Pharyngeal mucositis	2/355 (0.6%)	2	0/354 (0%)	0
Pharyngolaryngeal pain	6/355 (1.7%)	6	11/354 (3.1%)	12
Pleural effusion	8/355 (2.3%)	8	8/354 (2.3%)	8
Pleuritic pain	1/355 (0.3%)	1	1/354 (0.3%)	1
Pneumonitis	27/355 (7.6%)	28	17/354 (4.8%)	19
Pneumothorax	2/355 (0.6%)	2	1/354 (0.3%)	1
Pulmonary hemorrhage	1/355 (0.3%)	1	1/354 (0.3%)	1
Pulmonary hypertension	2/355 (0.6%)	2	0/354 (0%)	0
Respiratory disorder	12/355 (3.4%)	12	9/354 (2.5%)	9
Respiratory tract hemorrhage	2/355 (0.6%)	2	1/354 (0.3%)	1
Retinoic acid syndrome	1/355 (0.3%)	1	0/354 (0%)	0
Tracheal stenosis	1/355 (0.3%)	1	0/354 (0%)	0
Voice alteration	2/355 (0.6%)	2	0/354 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	6/355 (1.7%)	8	4/354 (1.1%)	4
Decubitus ulcer	1/355 (0.3%)	1	2/354 (0.6%)	2
Dry skin	7/355 (2%)	8	7/354 (2%)	7
Erythema multiforme	3/355 (0.8%)	3	3/354 (0.8%)	3
Hand-and-foot syndrome	2/355 (0.6%)	4	5/354 (1.4%)	5
Nail disorder	1/355 (0.3%)	1	0/354 (0%)	0
Pain of skin	1/355 (0.3%)	1	1/354 (0.3%)	1
Petechiae	35/355 (9.9%)	45	34/354 (9.6%)	52
Pruritus	11/355 (3.1%)	13	12/354 (3.4%)	13
Rash acneiform	1/355 (0.3%)	1	0/354 (0%)	0
Rash desquamating	59/355 (16.6%)	70	66/354 (18.6%)	71
Skin disorder	23/355 (6.5%)	28	23/354 (6.5%)	30
Skin hyperpigmentation	0/355 (0%)	0	1/354 (0.3%)	1
Skin ulceration	2/355 (0.6%)	2	2/354 (0.6%)	2
Sweating	14/355 (3.9%)	19	14/354 (4%)	15
Urticaria	3/355 (0.8%)	3	3/354 (0.8%)	4
Vascular disorders
Flushing	1/355 (0.3%)	1	0/354 (0%)	0
Hematoma	14/355 (3.9%)	17	13/354 (3.7%)	17
Hemorrhage	14/355 (3.9%)	19	12/354 (3.4%)	13
Hot flashes	1/355 (0.3%)	1	2/354 (0.6%)	2
Hypertension	13/355 (3.7%)	13	11/354 (3.1%)	11
Hypotension	25/355 (7%)	26	19/354 (5.4%)	22
Lymphangitic streak	0/355 (0%)	0	1/354 (0.3%)	1
Lymphedema	0/355 (0%)	0	1/354 (0.3%)	1
Phlebitis	6/355 (1.7%)	7	7/354 (2%)	7
Thrombosis	2/355 (0.6%)	2	0/354 (0%)	0
Vascular disorder	2/355 (0.6%)	2	2/354 (0.6%)	2
Vasculitis	1/355 (0.3%)	1	0/354 (0%)	0
Other (Not Including Serious) Adverse Events
	Induction and Consolidation Chemotherapy Plus Midostaurin		Induction and Consolidation Chemotherapy Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	321/355 (90.4%)		324/354 (91.5%)
Blood and lymphatic system disorders
Blood disorder	5/355 (1.4%)	11	4/354 (1.1%)	6
Disseminated intravascular coagulation	2/355 (0.6%)	2	1/354 (0.3%)	1
Febrile neutropenia	246/355 (69.3%)	422	238/354 (67.2%)	394
Hemoglobin decreased	312/355 (87.9%)	1059	311/354 (87.9%)	940
Lymph node pain	2/355 (0.6%)	2	0/354 (0%)	0
Lymphatic disorder	10/355 (2.8%)	13	9/354 (2.5%)	11
Cardiac disorders
Arrhythmia	1/355 (0.3%)	1	4/354 (1.1%)	4
Atrial fibrillation	3/355 (0.8%)	3	0/354 (0%)	0
Atrial flutter	0/355 (0%)	0	1/354 (0.3%)	1
Atrial tachycardia	1/355 (0.3%)	3	1/354 (0.3%)	1
Cardiac disorder	8/355 (2.3%)	12	13/354 (3.7%)	17
Cardiac pain	4/355 (1.1%)	6	1/354 (0.3%)	1
Cardiac valve disease	0/355 (0%)	0	1/354 (0.3%)	1
Conduction disorder	1/355 (0.3%)	1	2/354 (0.6%)	2
Left ventricular failure	6/355 (1.7%)	6	5/354 (1.4%)	9
Myocardial ischemia	1/355 (0.3%)	1	0/354 (0%)	0
Palpitations	3/355 (0.8%)	3	5/354 (1.4%)	13
Pericardial effusion	7/355 (2%)	8	1/354 (0.3%)	1
Pericarditis	2/355 (0.6%)	2	1/354 (0.3%)	1
Premature ventricular contractions	1/355 (0.3%)	3	0/354 (0%)	0
Sinus bradycardia	10/355 (2.8%)	10	5/354 (1.4%)	15
Sinus tachycardia	11/355 (3.1%)	13	23/354 (6.5%)	29
Supraventricular extrasystoles	1/355 (0.3%)	1	2/354 (0.6%)	7
Supraventricular tachycardia	1/355 (0.3%)	1	2/354 (0.6%)	2
Ventricular arrhythmia	1/355 (0.3%)	1	1/354 (0.3%)	1
Ventricular bigeminy	1/355 (0.3%)	2	0/354 (0%)	0
Ventricular fibrillation	1/355 (0.3%)	1	0/354 (0%)	0
Ventricular tachycardia	1/355 (0.3%)	1	1/354 (0.3%)	1
Ear and labyrinth disorders
Ear disorder	5/355 (1.4%)	5	3/354 (0.8%)	3
Ear pain	5/355 (1.4%)	6	6/354 (1.7%)	6
External ear inflammation	0/355 (0%)	0	2/354 (0.6%)	2
External ear pain	3/355 (0.8%)	3	2/354 (0.6%)	2
Hearing impaired	2/355 (0.6%)	4	2/354 (0.6%)	2
Middle ear inflammation	0/355 (0%)	0	1/354 (0.3%)	1
Tinnitus	3/355 (0.8%)	3	2/354 (0.6%)	2
Endocrine disorders
Endocrine disorder	1/355 (0.3%)	1	2/354 (0.6%)	2
Hyperthyroidism	2/355 (0.6%)	7	1/354 (0.3%)	3
Hypothyroidism	2/355 (0.6%)	2	2/354 (0.6%)	5
Eye disorders
Cataract	1/355 (0.3%)	9	0/354 (0%)	0
Conjunctivitis	7/355 (2%)	7	4/354 (1.1%)	5
Dry eye syndrome	5/355 (1.4%)	7	10/354 (2.8%)	12
Eye disorder	21/355 (5.9%)	28	16/354 (4.5%)	19
Eye pain	5/355 (1.4%)	5	5/354 (1.4%)	5
Eyelid function disorder	0/355 (0%)	0	1/354 (0.3%)	1
Flashing vision	1/355 (0.3%)	1	4/354 (1.1%)	5
Keratitis	14/355 (3.9%)	17	9/354 (2.5%)	14
Optic nerve disorder	0/355 (0%)	0	1/354 (0.3%)	1
Photophobia	2/355 (0.6%)	3	4/354 (1.1%)	4
Vision blurred	5/355 (1.4%)	8	4/354 (1.1%)	7
Vitreous hemorrhage	1/355 (0.3%)	1	2/354 (0.6%)	2
Watering eyes	4/355 (1.1%)	7	2/354 (0.6%)	2
Gastrointestinal disorders
Abdominal distension	6/355 (1.7%)	15	10/354 (2.8%)	11
Abdominal pain	57/355 (16.1%)	78	67/354 (18.9%)	84
Anal exam abnormal	0/355 (0%)	0	3/354 (0.8%)	3
Anal fistula	0/355 (0%)	0	1/354 (0.3%)	1
Anal hemorrhage	2/355 (0.6%)	2	3/354 (0.8%)	3
Anal mucositis	2/355 (0.6%)	2	2/354 (0.6%)	3
Anal pain	12/355 (3.4%)	15	6/354 (1.7%)	8
Anal ulcer	1/355 (0.3%)	1	3/354 (0.8%)	3
Ascites	1/355 (0.3%)	1	1/354 (0.3%)	1
Colitis	7/355 (2%)	9	12/354 (3.4%)	18
Colonic hemorrhage	0/355 (0%)	0	1/354 (0.3%)	1
Colonic perforation	0/355 (0%)	0	1/354 (0.3%)	2
Constipation	50/355 (14.1%)	86	60/354 (16.9%)	83
Dental prosthesis user	1/355 (0.3%)	1	0/354 (0%)	0
Diarrhea	228/355 (64.2%)	432	219/354 (61.9%)	310
Dry mouth	2/355 (0.6%)	2	2/354 (0.6%)	2
Dyspepsia	22/355 (6.2%)	36	16/354 (4.5%)	17
Dysphagia	6/355 (1.7%)	6	10/354 (2.8%)	10
Ear, nose and throat examination abnormal	112/355 (31.5%)	178	112/354 (31.6%)	169
Endoscopy large bowel abnormal	1/355 (0.3%)	1	0/354 (0%)	0
Enteritis	1/355 (0.3%)	1	3/354 (0.8%)	3
Esophageal mucositis	0/355 (0%)	0	1/354 (0.3%)	1
Esophageal pain	1/355 (0.3%)	1	3/354 (0.8%)	3
Esophageal perforation	1/355 (0.3%)	1	0/354 (0%)	0
Esophageal ulcer	1/355 (0.3%)	1	0/354 (0%)	0
Esophagitis	3/355 (0.8%)	3	4/354 (1.1%)	4
Flatulence	10/355 (2.8%)	20	7/354 (2%)	8
Gastric hemorrhage	2/355 (0.6%)	2	1/354 (0.3%)	1
Gastric mucositis	0/355 (0%)	0	1/354 (0.3%)	1
Gastric ulcer	0/355 (0%)	0	1/354 (0.3%)	1
Gastritis	3/355 (0.8%)	3	4/354 (1.1%)	4
Gastrointestinal disorder	28/355 (7.9%)	35	26/354 (7.3%)	29
Gastrointestinal pain	0/355 (0%)	0	1/354 (0.3%)	1
Gastroscopy abnormal	0/355 (0%)	0	3/354 (0.8%)	3
Gingival pain	3/355 (0.8%)	3	4/354 (1.1%)	4
Hemorrhoidal hemorrhage	1/355 (0.3%)	1	2/354 (0.6%)	3
Hemorrhoids	28/355 (7.9%)	36	21/354 (5.9%)	25
Ileal obstruction	0/355 (0%)	0	1/354 (0.3%)	1
Ileus	2/355 (0.6%)	3	3/354 (0.8%)	3
Large intestinal mucositis	1/355 (0.3%)	1	0/354 (0%)	0
Lower gastrointestinal hemorrhage	0/355 (0%)	0	2/354 (0.6%)	2
Mucositis oral	49/355 (13.8%)	59	31/354 (8.8%)	36
Nausea	258/355 (72.7%)	807	226/354 (63.8%)	449
Oesophagoscopy abnormal	2/355 (0.6%)	2	1/354 (0.3%)	1
Oral hemorrhage	12/355 (3.4%)	13	18/354 (5.1%)	27
Oral pain	8/355 (2.3%)	10	11/354 (3.1%)	11
Periodontal disease	4/355 (1.1%)	6	7/354 (2%)	7
Peritoneal pain	1/355 (0.3%)	1	0/354 (0%)	0
Proctitis	1/355 (0.3%)	1	0/354 (0%)	0
Proctoscopy abnormal	3/355 (0.8%)	3	0/354 (0%)	0
Rectal hemorrhage	7/355 (2%)	8	5/354 (1.4%)	7
Rectal obstruction	1/355 (0.3%)	1	0/354 (0%)	0
Rectal pain	5/355 (1.4%)	6	2/354 (0.6%)	2
Salivary gland disorder	0/355 (0%)	0	2/354 (0.6%)	2
Small intestinal mucositis	1/355 (0.3%)	1	2/354 (0.6%)	2
Stomach pain	34/355 (9.6%)	43	27/354 (7.6%)	32
Tooth development disorder	0/355 (0%)	0	1/354 (0.3%)	1
Tooth disorder	6/355 (1.7%)	6	2/354 (0.6%)	2
Toothache	9/355 (2.5%)	11	10/354 (2.8%)	10
Typhlitis	3/355 (0.8%)	3	4/354 (1.1%)	4
Upper gastrointestinal hemorrhage	2/355 (0.6%)	2	0/354 (0%)	0
Vomiting	188/355 (53%)	376	168/354 (47.5%)	259
General disorders
Chest pain	15/355 (4.2%)	17	20/354 (5.6%)	28
Chills	22/355 (6.2%)	26	17/354 (4.8%)	21
Disease progression	0/355 (0%)	0	1/354 (0.3%)	1
Edema limbs	33/355 (9.3%)	43	39/354 (11%)	56
Facial pain	2/355 (0.6%)	2	1/354 (0.3%)	1
Fatigue	221/355 (62.3%)	522	220/354 (62.1%)	474
Fever	72/355 (20.3%)	110	69/354 (19.5%)	107
Flu-like symptoms	5/355 (1.4%)	5	2/354 (0.6%)	2
Gait abnormal	1/355 (0.3%)	1	0/354 (0%)	0
General symptom	15/355 (4.2%)	18	17/354 (4.8%)	25
Hypothermia	1/355 (0.3%)	1	0/354 (0%)	0
Ill-defined disorder	3/355 (0.8%)	4	4/354 (1.1%)	4
Injection site reaction	20/355 (5.6%)	25	23/354 (6.5%)	34
Localized edema	16/355 (4.5%)	16	14/354 (4%)	19
Pain	40/355 (11.3%)	55	33/354 (9.3%)	44
Visceral edema	2/355 (0.6%)	2	2/354 (0.6%)	2
Hepatobiliary disorders
Cholecystitis	1/355 (0.3%)	1	1/354 (0.3%)	1
Gallbladder pain	1/355 (0.3%)	1	0/354 (0%)	0
Hepatic failure	1/355 (0.3%)	1	0/354 (0%)	0
Hepatobiliary disease	4/355 (1.1%)	16	4/354 (1.1%)	5
Immune system disorders
Cytokine release syndrome	1/355 (0.3%)	2	0/354 (0%)	0
Hypersensitivity	36/355 (10.1%)	41	30/354 (8.5%)	41
Immune system disorder	12/355 (3.4%)	14	9/354 (2.5%)	14
Infections and infestations
Abdominal infection	0/355 (0%)	0	1/354 (0.3%)	1
Anal infection	8/355 (2.3%)	9	8/354 (2.3%)	12
Anorectal infection	2/355 (0.6%)	3	1/354 (0.3%)	1
Appendicitis	0/355 (0%)	0	2/354 (0.6%)	2
Bladder infection	8/355 (2.3%)	13	10/354 (2.8%)	11
Bone infection	0/355 (0%)	0	1/354 (0.3%)	1
Bronchitis	7/355 (2%)	9	6/354 (1.7%)	6
Catheter related infection	55/355 (15.5%)	74	43/354 (12.1%)	54
Cecal infection	1/355 (0.3%)	1	1/354 (0.3%)	2
Colitis, infectious (e.g., Clostridium difficile)	4/355 (1.1%)	4	4/354 (1.1%)	4
Conjunctivitis infective	8/355 (2.3%)	10	5/354 (1.4%)	7
Device related infection	1/355 (0.3%)	1	0/354 (0%)	0
Eye infection	2/355 (0.6%)	2	0/354 (0%)	0
Gastric infection	1/355 (0.3%)	1	2/354 (0.6%)	3
Gingival infection	5/355 (1.4%)	6	3/354 (0.8%)	3
Hepatic infection	3/355 (0.8%)	3	5/354 (1.4%)	14
Infection	57/355 (16.1%)	100	60/354 (16.9%)	99
Infectious colitis	5/355 (1.4%)	7	5/354 (1.4%)	5
Kidney infection	2/355 (0.6%)	2	1/354 (0.3%)	1
Lip infection	17/355 (4.8%)	22	21/354 (5.9%)	29
Lymph gland infection	1/355 (0.3%)	1	3/354 (0.8%)	4
Mediastinal infection	1/355 (0.3%)	1	0/354 (0%)	0
Mucosal infection	2/355 (0.6%)	2	0/354 (0%)	0
Nail infection	3/355 (0.8%)	4	2/354 (0.6%)	2
Opportunistic infection	4/355 (1.1%)	5	9/354 (2.5%)	14
Otitis media	2/355 (0.6%)	3	0/354 (0%)	0
Paranasal sinus infection	2/355 (0.6%)	2	1/354 (0.3%)	1
Penile infection	2/355 (0.6%)	2	0/354 (0%)	0
Pharyngitis	5/355 (1.4%)	5	7/354 (2%)	7
Phlebitis infective	3/355 (0.8%)	5	2/354 (0.6%)	2
Pneumonia	36/355 (10.1%)	53	36/354 (10.2%)	45
Rhinitis infective	6/355 (1.7%)	12	6/354 (1.7%)	7
Scrotal infection	0/355 (0%)	0	1/354 (0.3%)	1
Sepsis	26/355 (7.3%)	29	20/354 (5.6%)	23
Sinusitis	7/355 (2%)	7	5/354 (1.4%)	6
Skin infection	22/355 (6.2%)	24	15/354 (4.2%)	19
Soft tissue infection	2/355 (0.6%)	2	1/354 (0.3%)	1
Splenic infection	1/355 (0.3%)	1	2/354 (0.6%)	9
Tooth infection	4/355 (1.1%)	4	4/354 (1.1%)	5
Tracheitis	1/355 (0.3%)	1	0/354 (0%)	0
Upper aerodigestive tract infection	0/355 (0%)	0	4/354 (1.1%)	4
Upper respiratory infection	11/355 (3.1%)	17	8/354 (2.3%)	14
Ureteritis	4/355 (1.1%)	6	4/354 (1.1%)	6
Urinary tract infection	15/355 (4.2%)	17	15/354 (4.2%)	19
Vaginal infection	5/355 (1.4%)	6	8/354 (2.3%)	12
Viral hepatitis	1/355 (0.3%)	1	0/354 (0%)	0
Vulval infection	2/355 (0.6%)	2	0/354 (0%)	0
Vulvitis	0/355 (0%)	0	2/354 (0.6%)	2
Wound infection	3/355 (0.8%)	3	3/354 (0.8%)	3
Injury, poisoning and procedural complications
Bruising	3/355 (0.8%)	3	1/354 (0.3%)	1
Device complication	1/355 (0.3%)	1	0/354 (0%)	0
Fracture	1/355 (0.3%)	1	0/354 (0%)	0
Injury to inferior vena cava	0/355 (0%)	0	1/354 (0.3%)	1
Injury to jugular vein	0/355 (0%)	0	1/354 (0.3%)	1
Intraoperative complications	1/355 (0.3%)	1	0/354 (0%)	0
Intraoperative gastrointestinal injury	0/355 (0%)	0	1/354 (0.3%)	1
Intraoperative gastrointestinal injury - Teeth	0/355 (0%)	0	1/354 (0.3%)	1
Intraoperative head and neck injury - Neck NOS	1/355 (0.3%)	1	0/354 (0%)	0
Intraoperative ocular injury - Lens	1/355 (0.3%)	2	0/354 (0%)	0
Postoperative hemorrhage	1/355 (0.3%)	1	0/354 (0%)	0
Radiation recall reaction (dermatologic)	0/355 (0%)	0	1/354 (0.3%)	1
Thermal burn	0/355 (0%)	0	3/354 (0.8%)	3
Tracheostomy site bleeding	0/355 (0%)	0	1/354 (0.3%)	1
Vaginal anastomotic leak	1/355 (0.3%)	1	0/354 (0%)	0
Vascular access complication	9/355 (2.5%)	15	6/354 (1.7%)	6
Venous injury - Extremity-lower	1/355 (0.3%)	1	0/354 (0%)	0
Wound dehiscence	2/355 (0.6%)	2	0/354 (0%)	0
Investigations
Activated partial thromboplastin time prolonged	26/355 (7.3%)	36	22/354 (6.2%)	27
Alanine aminotransferase increased	88/355 (24.8%)	312	83/354 (23.4%)	184
Alkaline phosphatase increased	30/355 (8.5%)	60	29/354 (8.2%)	55
Amylase increased	1/355 (0.3%)	1	1/354 (0.3%)	1
Aspartate aminotransferase increased	60/355 (16.9%)	201	56/354 (15.8%)	102
Blood bilirubin increased	49/355 (13.8%)	86	60/354 (16.9%)	104
Cardiac troponin T increased	1/355 (0.3%)	1	1/354 (0.3%)	1
Coagulopathy	7/355 (2%)	8	10/354 (2.8%)	14
Creatinine increased	13/355 (3.7%)	18	15/354 (4.2%)	25
Electrocardiogram QTc interval prolonged	45/355 (12.7%)	81	36/354 (10.2%)	48
Fibrinogen decreased	12/355 (3.4%)	14	8/354 (2.3%)	10
Forced expiratory volume decreased	1/355 (0.3%)	1	0/354 (0%)	0
Gamma-glutamyltransferase increased	25/355 (7%)	55	34/354 (9.6%)	57
INR increased	9/355 (2.5%)	11	12/354 (3.4%)	12
Laboratory test abnormal	31/355 (8.7%)	53	41/354 (11.6%)	81
Leukocyte count decreased	79/355 (22.3%)	240	92/354 (26%)	204
Lymphocyte count decreased	69/355 (19.4%)	195	71/354 (20.1%)	158
Neutrophil count decreased	308/355 (86.8%)	952	308/354 (87%)	879
Platelet count decreased	311/355 (87.6%)	1131	313/354 (88.4%)	1020
Serum cholesterol increased	0/355 (0%)	0	5/354 (1.4%)	10
Weight gain	15/355 (4.2%)	26	6/354 (1.7%)	11
Weight loss	9/355 (2.5%)	12	10/354 (2.8%)	12
Metabolism and nutrition disorders
Alkalosis	0/355 (0%)	0	3/354 (0.8%)	3
Anorexia	30/355 (8.5%)	40	40/354 (11.3%)	50
Blood glucose increased	72/355 (20.3%)	202	59/354 (16.7%)	134
Blood uric acid increased	21/355 (5.9%)	42	15/354 (4.2%)	23
Dehydration	1/355 (0.3%)	1	1/354 (0.3%)	1
Glucose intolerance	0/355 (0%)	0	2/354 (0.6%)	5
Iron overload	0/355 (0%)	0	2/354 (0.6%)	4
Serum albumin decreased	56/355 (15.8%)	101	56/354 (15.8%)	80
Serum calcium decreased	58/355 (16.3%)	88	56/354 (15.8%)	79
Serum calcium increased	6/355 (1.7%)	11	1/354 (0.3%)	2
Serum glucose decreased	6/355 (1.7%)	8	9/354 (2.5%)	10
Serum magnesium decreased	30/355 (8.5%)	48	32/354 (9%)	65
Serum magnesium increased	7/355 (2%)	8	3/354 (0.8%)	3
Serum phosphate decreased	27/355 (7.6%)	31	27/354 (7.6%)	40
Serum potassium decreased	79/355 (22.3%)	117	74/354 (20.9%)	112
Serum potassium increased	5/355 (1.4%)	5	5/354 (1.4%)	6
Serum sodium decreased	48/355 (13.5%)	63	51/354 (14.4%)	64
Serum sodium increased	8/355 (2.3%)	8	8/354 (2.3%)	9
Serum triglycerides increased	1/355 (0.3%)	1	4/354 (1.1%)	5
Tumor lysis syndrome	2/355 (0.6%)	2	3/354 (0.8%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	30/355 (8.5%)	67	16/354 (4.5%)	25
Arthritis	0/355 (0%)	0	1/354 (0.3%)	1
Back pain	46/355 (13%)	74	34/354 (9.6%)	53
Bone pain	19/355 (5.4%)	32	21/354 (5.9%)	37
Buttock pain	3/355 (0.8%)	3	0/354 (0%)	0
Chest wall pain	6/355 (1.7%)	9	3/354 (0.8%)	4
Joint disorder	1/355 (0.3%)	1	0/354 (0%)	0
Joint effusion	0/355 (0%)	0	1/354 (0.3%)	1
Joint range of motion decreased lumbar spine	1/355 (0.3%)	2	0/354 (0%)	0
Muscle weakness	6/355 (1.7%)	6	4/354 (1.1%)	4
Muscle weakness lower limb	2/355 (0.6%)	2	1/354 (0.3%)	1
Musculoskeletal disorder	13/355 (3.7%)	19	6/354 (1.7%)	8
Myalgia	13/355 (3.7%)	24	16/354 (4.5%)	19
Myositis	0/355 (0%)	0	2/354 (0.6%)	2
Neck pain	16/355 (4.5%)	18	9/354 (2.5%)	9
Osteoporosis	0/355 (0%)	0	1/354 (0.3%)	1
Pain in extremity	30/355 (8.5%)	39	17/354 (4.8%)	23
Upper extremity dysfunction	1/355 (0.3%)	1	0/354 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myelodysplasia	0/355 (0%)	0	1/354 (0.3%)	1
Treatment related secondary malignancy	1/355 (0.3%)	1	1/354 (0.3%)	2
Tumor pain	1/355 (0.3%)	1	0/354 (0%)	0
Nervous system disorders
Ataxia	2/355 (0.6%)	2	10/354 (2.8%)	11
Cognitive disturbance	0/355 (0%)	0	1/354 (0.3%)	1
Depressed level of consciousness	2/355 (0.6%)	2	3/354 (0.8%)	3
Dizziness	44/355 (12.4%)	64	43/354 (12.1%)	55
Dysgeusia	5/355 (1.4%)	5	11/354 (3.1%)	14
Encephalopathy	0/355 (0%)	0	1/354 (0.3%)	5
Extrapyramidal disorder	0/355 (0%)	0	2/354 (0.6%)	5
Headache	105/355 (29.6%)	218	85/354 (24%)	143
Intracranial hemorrhage	1/355 (0.3%)	1	2/354 (0.6%)	2
Memory impairment	2/355 (0.6%)	4	1/354 (0.3%)	2
Neuralgia	2/355 (0.6%)	2	3/354 (0.8%)	6
Neurological disorder NOS	17/355 (4.8%)	22	7/354 (2%)	7
Olfactory nerve disorder	0/355 (0%)	0	1/354 (0.3%)	1
Peripheral motor neuropathy	2/355 (0.6%)	12	1/354 (0.3%)	1
Peripheral sensory neuropathy	6/355 (1.7%)	21	11/354 (3.1%)	26
Pyramidal tract syndrome	0/355 (0%)	0	1/354 (0.3%)	1
Seizure	0/355 (0%)	0	1/354 (0.3%)	1
Speech disorder	1/355 (0.3%)	16	1/354 (0.3%)	1
Syncope	8/355 (2.3%)	9	6/354 (1.7%)	6
Syncope vasovagal	2/355 (0.6%)	3	7/354 (2%)	9
Tremor	5/355 (1.4%)	8	4/354 (1.1%)	4
Psychiatric disorders
Agitation	4/355 (1.1%)	4	3/354 (0.8%)	3
Anxiety	16/355 (4.5%)	21	18/354 (5.1%)	32
Confusion	4/355 (1.1%)	5	4/354 (1.1%)	4
Depression	14/355 (3.9%)	26	24/354 (6.8%)	50
Euphoria	1/355 (0.3%)	1	0/354 (0%)	0
Insomnia	30/355 (8.5%)	47	20/354 (5.6%)	35
Personality change	0/355 (0%)	0	1/354 (0.3%)	1
Psychosis	1/355 (0.3%)	1	1/354 (0.3%)	1
Renal and urinary disorders
Bladder hemorrhage	0/355 (0%)	0	1/354 (0.3%)	1
Bladder pain	3/355 (0.8%)	5	1/354 (0.3%)	1
Bladder spasm	2/355 (0.6%)	2	0/354 (0%)	0
Cystitis	5/355 (1.4%)	6	7/354 (2%)	8
Hemoglobin urine positive	0/355 (0%)	0	1/354 (0.3%)	1
Hemorrhage urinary tract	2/355 (0.6%)	2	4/354 (1.1%)	4
Kidney pain	1/355 (0.3%)	2	0/354 (0%)	0
Proteinuria	1/355 (0.3%)	3	1/354 (0.3%)	1
Renal failure	3/355 (0.8%)	3	1/354 (0.3%)	1
Urethral obstruction	1/355 (0.3%)	1	0/354 (0%)	0
Urethral pain	0/355 (0%)	0	2/354 (0.6%)	2
Urinary frequency	1/355 (0.3%)	1	4/354 (1.1%)	9
Urinary incontinence	1/355 (0.3%)	1	2/354 (0.6%)	2
Urinary retention	1/355 (0.3%)	1	2/354 (0.6%)	3
Urine discoloration	0/355 (0%)	0	1/354 (0.3%)	1
Urogenital disorder	11/355 (3.1%)	12	10/354 (2.8%)	11
Reproductive system and breast disorders
Breast pain	2/355 (0.6%)	2	0/354 (0%)	0
Gynecomastia	1/355 (0.3%)	1	1/354 (0.3%)	3
Pelvic pain	1/355 (0.3%)	1	2/354 (0.6%)	2
Perineal pain	1/355 (0.3%)	1	1/354 (0.3%)	1
Reproductive tract disorder	1/355 (0.3%)	1	0/354 (0%)	0
Uterine hemorrhage	8/355 (2.3%)	12	6/354 (1.7%)	7
Uterine pain	1/355 (0.3%)	1	3/354 (0.8%)	3
Vaginal discharge	1/355 (0.3%)	1	1/354 (0.3%)	2
Vaginal hemorrhage	16/355 (4.5%)	17	17/354 (4.8%)	24
Vaginal inflammation	1/355 (0.3%)	1	1/354 (0.3%)	1
Vaginal mucositis	2/355 (0.6%)	2	2/354 (0.6%)	2
Vaginal pain	1/355 (0.3%)	1	2/354 (0.6%)	2
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/355 (0.3%)	1	1/354 (0.3%)	1
Allergic rhinitis	3/355 (0.8%)	3	8/354 (2.3%)	14
Atelectasis	1/355 (0.3%)	1	2/354 (0.6%)	2
Bronchopulmonary hemorrhage	0/355 (0%)	0	1/354 (0.3%)	1
Bronchospasm	2/355 (0.6%)	2	2/354 (0.6%)	2
Cough	38/355 (10.7%)	57	41/354 (11.6%)	51
Dyspnea	28/355 (7.9%)	33	29/354 (8.2%)	30
Epistaxis	55/355 (15.5%)	63	46/354 (13%)	62
Hypoxia	9/355 (2.5%)	9	11/354 (3.1%)	11
Laryngeal edema	1/355 (0.3%)	1	0/354 (0%)	0
Laryngeal mucositis	1/355 (0.3%)	1	2/354 (0.6%)	3
Laryngeal pain	2/355 (0.6%)	2	1/354 (0.3%)	1
Laryngoscopy abnormal	2/355 (0.6%)	2	1/354 (0.3%)	2
Nasal congestion	4/355 (1.1%)	4	4/354 (1.1%)	6
Pharyngeal examination abnormal	2/355 (0.6%)	2	6/354 (1.7%)	6
Pharyngeal mucositis	4/355 (1.1%)	4	1/354 (0.3%)	1
Pharyngeal stenosis	1/355 (0.3%)	1	0/354 (0%)	0
Pharyngolaryngeal pain	28/355 (7.9%)	35	25/354 (7.1%)	30
Pleural effusion	9/355 (2.5%)	9	6/354 (1.7%)	6
Pneumonitis	23/355 (6.5%)	33	33/354 (9.3%)	40
Pneumothorax	1/355 (0.3%)	1	0/354 (0%)	0
Pulmonary fibrosis	0/355 (0%)	0	1/354 (0.3%)	1
Respiratory disorder	17/355 (4.8%)	23	21/354 (5.9%)	31
Voice alteration	3/355 (0.8%)	4	1/354 (0.3%)	1
Skin and subcutaneous tissue disorders
Alopecia	8/355 (2.3%)	10	6/354 (1.7%)	9
Decubitus ulcer	0/355 (0%)	0	1/354 (0.3%)	1
Dry skin	11/355 (3.1%)	13	9/354 (2.5%)	12
Erythema multiforme	0/355 (0%)	0	1/354 (0.3%)	1
Hand-and-foot syndrome	8/355 (2.3%)	9	9/354 (2.5%)	11
Nail disorder	1/355 (0.3%)	3	0/354 (0%)	0
Pain of skin	3/355 (0.8%)	3	2/354 (0.6%)	2
Petechiae	67/355 (18.9%)	89	51/354 (14.4%)	68
Photosensitivity	3/355 (0.8%)	5	0/354 (0%)	0
Pruritus	25/355 (7%)	31	31/354 (8.8%)	41
Rash acneiform	2/355 (0.6%)	2	2/354 (0.6%)	2
Rash desquamating	201/355 (56.6%)	358	200/354 (56.5%)	317
Skin disorder	44/355 (12.4%)	67	42/354 (11.9%)	58
Skin hyperpigmentation	1/355 (0.3%)	3	3/354 (0.8%)	4
Skin induration	0/355 (0%)	0	1/354 (0.3%)	2
Skin striae	1/355 (0.3%)	1	0/354 (0%)	0
Skin ulceration	5/355 (1.4%)	6	6/354 (1.7%)	8
Sweating	30/355 (8.5%)	50	19/354 (5.4%)	32
Urticaria	6/355 (1.7%)	7	5/354 (1.4%)	5
Vascular disorders
Flushing	0/355 (0%)	0	2/354 (0.6%)	3
Hematoma	32/355 (9%)	40	34/354 (9.6%)	39
Hemorrhage	15/355 (4.2%)	22	31/354 (8.8%)	33
Hot flashes	2/355 (0.6%)	4	4/354 (1.1%)	4
Hypertension	15/355 (4.2%)	21	13/354 (3.7%)	25
Hypotension	32/355 (9%)	37	32/354 (9%)	36
Lymphedema	0/355 (0%)	0	1/354 (0.3%)	1
Lymphocele	0/355 (0%)	0	1/354 (0.3%)	1
Phlebitis	13/355 (3.7%)	19	15/354 (4.2%)	17
Thrombosis	6/355 (1.7%)	6	3/354 (0.8%)	3
Vascular disorder	0/355 (0%)	0	4/354 (1.1%)	4
Vasculitis	2/355 (0.6%)	2	0/354 (0%)	0
Visceral arterial ischemia	0/355 (0%)	0	1/354 (0.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

Results Point of Contact

Name/Title	Richard Stone, MD
Organization	Dana Farber Cancer Institute
Phone
Email	rstone@partners.org

Responsible Party:

Alliance for Clinical Trials in Oncology

ClinicalTrials.gov Identifier:

NCT00651261

Other Study ID Numbers:

CALGB-10603
CALGB-10603
EUDRACT-2006-006852-37
CDR0000590404

First Posted:

Apr 2, 2008

Last Update Posted:

Aug 18, 2021

Last Verified:

Aug 1, 2021

Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

Study Details

Study Description

Brief Summary

Detailed Description

Remission Induction Therapy:

Remission Consolidation (Four Remission Consolidation Cycles):

Midostaurin/Placebo Continuation Therapy:

The primary and secondary objectives of this study are:

Primary objective:

Secondary objectives:

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

More Information

Publications

Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

More Information

Certain Agreements

Results Point of Contact