Volasertib in Combination With Low-dose Cytarabine in Patients Aged 65 Years and Above With Previously Untreated Acute Myeloid Leukaemia, Who Are Ineligible for Intensive Remission Induction Therapy (POLO-AML-2)

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01721876
• Collaborator: (none)
• Enrollment: 666
• Locations: 122
• Arms: 2
• Actual Duration (Months): 99.9
• Patients Per Site: 5.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To investigate the efficacy, safety, and pharmacokinetics of intravenous volasertib + subcutaneous low dose cytarabine in patients >= 65 years of age with previously untreated acute myeloid leukaemia, ineligible for intensive remission induction therapy

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myeloid, Acute	Drug: Placebo; Drug: Volasertib; Drug: Cytarabine	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 666 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Phase III Randomised, Double-blind, Controlled, Parallel Group Study of Intravenous Volasertib in Combination With Subcutaneous Low-dose Cytarabine vs. Placebo + Low-dose Cytarabine in Patients >=65 Years With Previously Untreated Acute Myeloid Leukaemia, Who Are Ineligible for Intensive Remission Induction Therapy
• Actual Study Start Date: Jan 29, 2013
• Actual Primary Completion Date: Aug 12, 2014
• Actual Study Completion Date: May 28, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Volasertib and Cytarabine	Drug: Volasertib; Volasertib; Drug: Cytarabine; Cytarabine
Placebo Comparator: Placebo and Cytarabine	Drug: Placebo; Placebo matching Volasertib; Drug: Cytarabine; Cytarabine

Outcome Measures

Primary Outcome Measures

1. Objective Response (OR) [Response assessment was performed at the end of every 2nd cycle, (i.e. at the end of Cycle 2, 4, 6, 8, etc., and at end of treatment), i.e. up to 52 months.]

   OR is the number of patients who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi), where OR was based on the best response attained during the treatment period.

Secondary Outcome Measures

1. Overall Survival (OS) [From randomization until death due to any cause, up to 1557 days.]

   OS is the key secondary endpoint and was measured from the date of randomization until death from any cause. Patients who were lost to follow-up were censored on the last date they were known to be alive.

2. Event-free Survival (EFS) [From randomization until disease progression or relapse or death from any cause, up to 1557 days.]

   EFS was measured from the date of randomisation to the date of progression or relapse, or death from any cause, whichever occurred first.

3. Relapse-free Survival (RFS) [From randomization until disease progression or relapse or death from any cause, up to 1557 days.]

   RFS was defined only for patients who achieved best overall response of CR or CRi; it was measured from the date of achievement of a remission until the date of relapse or death from any cause. Patients not known to have relapsed or died at last follow-up were censored on the date they were last examined.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. Age >= 65years.

2. Cytologically/histologically confirmed acute myeloid leukaemia (AML) according to WHO classification; (except for acute promyelocytic leukaemia (APL).

3. Previously untreated AML (except for hydroxyurea and/or corticosteroid therapy for no more than 28 days (cumulative)). Previous therapy for Myelodysplastic Syndrome (MDS) is allowed.

4. Investigator considers patient ineligible for intensive remission induction therapy based on documented medical reasons (e.g. disease characteristics like AML genetics, type of AML (de novo or secondary), and patient characteristics like performance score, concomitant diagnoses, organ dysfunctions).

5. Patient is eligible for Low-Dose Cytarabine (LDAC) treatment.

6. Eastern co-operative oncology group (ECOG) performance score <= 2 at screening.

7. Signed and dated written informed consent by start date of Screening visit in accordance with Good Clinical Practice (GCP) and local legislation.

Exclusion criteria:

1. Prior or concomitant chemotherapy for AML (with the exception of hydroxyurea and/or corticosteroid therapy for no more than 28 days (cumulative)). Please note that any prior therapy for MDS is allowed.

2. Treatment with any investigational drug within 2 weeks before first administration of present trial drug.

3. Acute promyelocytic leukaemia (French-American-British (FAB) classification subtype M3).

4. Current clinical central nervous system (CNS) symptoms deemed by the investigator to be related to leukaemic CNS involvement (no lumbar puncture required, clinical assessment per investigator´s judgement is sufficient).

5. Hypersensitivity to one of the trial drugs or the excipients.

6. Severe illness or organ dysfunction involving the heart, kidney, liver or other organ system (e.g. active infection, clinically relevant impairment of cardiac function, severe heart failure/cardiac insufficiency, unstable angina pectoris or history of recent myocardial infarction), which in the opinion of the investigator precludes treatment with LDAC.

7. Corrected QT interval according to Fridericia (QTcF) prolongation > 470 ms or QT prolongation deemed clinically relevant by the investigator (e.g., congenital long QT syndrome).The QTcF will be calculated as the mean of the 3 Electrocardiogram (ECGs) taken at screening.

8. Total bilirubin > 3 x upper limit of normal (ULN).

9. Creatinine clearance (CLcr) < 30 ml/min (estimated creatinine clearance by the Cockcroft-Gault (C-G) equation) .

10. Active hepatitis B or hepatitis C, or laboratory evidence for a chronic infection.

11. HIV infection.

12. Second malignancy currently requiring active therapy (except for hormonal/anti-hormonal treatment e.g. in prostate or breast cancer).

13. Any significant concurrent psychiatric disorder or social situation that according to the investigator´s judgement would compromise patient´s safety or compliance, interfere with consent, study participation, or interpretation of study results.

14. Known or suspected active alcohol or drug abuse.

15. Patient unable to comply with the protocol, in the opinion of the investigator.

16. Male patients with partners of childbearing potential who are unwilling to use condoms in combination with a second medically acceptable method of contraception during the trial and for a minimum of 6 months after study treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California	Los Angeles	California	United States	90095-1678
2	St. Luke's Hospital Association of Duluth, Inc.	Duluth	Minnesota	United States	55805
3	Henry-Joyce Cancer Clinic	Nashville	Tennessee	United States	37232
4	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
5	Fundacion COIR	Mendoza		Argentina	M5500AYB
6	Hospital Central de Salud Zenón Santillan	San Miguel de Tucumán		Argentina	T4000HXU
7	LKH-Univ. Hospital Graz	Graz		Austria	8036
8	LKH Leoben	Leoben		Austria	8700
9	Hospital Hietzing	Wien		Austria	1130
10	AZ Sint-Jan Brugge	Brugge		Belgium	8000
11	Brussels - UNIV Saint-Luc	Bruxelles		Belgium	1200
12	Haine-St-Paul - HOSP Jolimont	Haine-Saint-Paul		Belgium	7100
13	Jessa Ziekenhuis - Campus Virga Jesse	Hasselt		Belgium	3500
14	UZ Leuven	Leuven		Belgium	3000
15	Centre Hospitalier Universitaire de Liège	Liège		Belgium	4000
16	Roeselare - HOSP AZ Delta	Roeselare		Belgium	8800
17	Yvoir - UNIV UCL de Mont-Godinne	Yvoir		Belgium	5530
18	Hospital Doutor Amaral Carvalho	Jau		Brazil	17210-080
19	Hospital Mãe de Deus	Porto Alegre		Brazil	90470-340
20	H.C.da Fac. de Medicina de Ribeirao Preto	Ribeirao Preto		Brazil	14048-900
21	University of Alberta Hospital (University of Alberta)	Edmonton	Alberta	Canada	T6G 2G3
22	Vancouver General Hospital	Vancouver	British Columbia	Canada	V5Z 1M9
23	Maisonneuve-Rosemont Hospital	Montreal	Migration Data	Canada	H1T 2M4
24	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
25	Montreal General Hospital - McGill University Health Centre	Montreal	Quebec	Canada	H3G 1A4
26	Hospital Hradec Kralove	Hradec Kralove		Czechia	500 05
27	University Hospital Plzen, Plzen-Lochotin	Plzen - Lochotin		Czechia	304 60
28	Univ. Hospital Kralovske Vinohrady	Praha 10		Czechia	100 34
29	Meilahden sairaala	Helsinki		Finland	00290
30	TYKS, Sisätautien klinikka	Turku		Finland	20521
31	HOP Amiens-Picardie Sud	Amiens		France	80054
32	HOP Côte de Nacre	Caen		France	14000
33	HOP Michallon	La Tronche		France	38700
34	HOP André Mignot	Le Chesnay		France	78157
35	HOP Dupuytren 1	Limoges Cedex 1		France	87042
36	INS Paoli-Calmettes	Marseille		France	13273
37	HOP Nantes, Hémato, Nantes	Nantes		France	44000
38	HOP Saint-Antoine	Paris Cedex 12		France	75012
39	HOP Haut-Lévêque	Pessac		France	33604
40	HOP Lyon Sud	Pierre Bénite		France	69495
41	HOP Pontchaillou	Rennes Cedex 9		France	35033
42	INS Universitaire du Cancer	Toulouse		France	31059
43	Universitätsklinikum Augsburg	Augsburg		Germany	86156
44	Med. Klinik m.S. Hämatologie und Onkologie	Berlin		Germany	13353
45	Städtisches Klinikum Braunschweig gGmbH	Braunschweig		Germany	38114
46	Universitätsklinikum Erlangen	Erlangen		Germany	91054
47	Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitätsklinikum Essen gGmbH	Essen		Germany	45147
48	Universitätsklinikum Frankfurt	Frankfurt/Main		Germany	60590
49	Universitätsmedizin Göttingen, Georg-August-Universität	Göttingen		Germany	37075
50	Martin-Luther-Universität Halle-Wittenberg	Halle (Saale)		Germany	06120
51	Universitätsklinikum Hamburg-Eppendorf	Hamburg		Germany	20246
52	Medizinische Hochschule Hannover	Hannover		Germany	30625
53	Universitätsklinikum Heidelberg	Heidelberg		Germany	69120
54	Universitätsklinikum Schleswig-Holstein, Campus Kiel	Kiel		Germany	24105
55	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz		Germany	55131
56	Universitätsklinikum Gießen und Marburg GmbH	Marburg		Germany	35043
57	Klinikum rechts der Isar der Technischen Universität München	München		Germany	81675
58	Universitätsklinikum Münster	Münster		Germany	48149
59	Universitätsklinikum Regensburg	Regensburg		Germany	93053
60	Robert-Bosch-Krankenhaus GmbH	Stuttgart		Germany	70376
61	Universitätsklinikum Ulm	Ulm		Germany	89081
62	Schwarzwald-Baar Klinikum	Villingen-Schwenningen		Germany	78052
63	General Hospital of Athens "G. Gennimatas"	Athens		Greece	115 27
64	General Hospital of Athens "Laiko"	Athens		Greece	11526
65	Univ. Gen. Hosp. of Ioannina	Ioannina		Greece	45 500
66	University of Patras Medical School	Patras		Greece	26504
67	General Hospital of Thessaloniki "G. Papanikolaou"	Thessaloniki		Greece	57010
68	Semmelweis University	Budapest		Hungary	1083
69	Petz Aldar Hospital, 2nd Dept. of Internal Med., Haematology	Gyor		Hungary	9024
70	Univ. of Szeged, 2nd Dept. of Internal Med., Haematology	Szeged		Hungary	6725
71	St. John Medical College and hospital	Bangalore		India	560034
72	Tata Memorial Hospital	Mumbai		India	400012
73	A.O. Spedali Civili di Brescia	Brescia		Italy	25123
74	ASST Grande Ospedale Metropolitano Niguarda	Milano		Italy	20162
75	AO Città della Salute e della	Torino		Italy	10126
76	National Hospital Organization Nagoya Medical Center	Aichi, Nagoya		Japan	460-0001
77	Japanese Red Cross Nagoya Daini Hospital	Aichi, Nagoya		Japan	466-8650
78	Akita University Hospital	Akita, Akita		Japan	010-8543
79	University of Fukui Hospital	Fukui, Yoshida-gun		Japan	910-1193
80	Kyushu University Hospital	Fukuoka, Fukuoka		Japan	812-8582
81	Kobe University Hospital	Hyogo, Kobe		Japan	650-0017
82	Tokai University Hospital	Kanagawa, Isehara		Japan	259-1193
83	Yokohama City University Medical Center	Kanagawa, Yokohama		Japan	232-0024
84	Tohoku University Hospital	Miyagi, Sendai		Japan	980-8547
85	Nagasaki University Hospital	Nagasaki, Nagasaki		Japan	852-8523
86	Kurashiki Central Hospital	Okayama, Kurashiki		Japan	710-8602
87	Okayama University Hospital	Okayama, Okayama		Japan	700-8558
88	Osaka City University Hospital	Osaka, Osaka		Japan	545-8586
89	National Cancer Center Hospital	Tokyo, Chuo-ku		Japan	104-0045
90	NTT Medical Center Tokyo	Tokyo, Sinagawa-ku		Japan	141-8625
91	Chonnam National University Hwasun Hospital	Hwasun		Korea, Republic of	519-763
92	The Catholic University of Korea, Seoul St.Mary's Hospital	Seoul		Korea, Republic of	06591
93	Seoul National University Hospital	Seoul		Korea, Republic of	110-744
94	Severance Hospital	Seoul		Korea, Republic of	120-752
95	Samsung Medical Center	Seoul		Korea, Republic of	135-710
96	Asan Medical Center	Seoul		Korea, Republic of	138-736
97	Hospital Universitario Dr Jose Eleuterio Gonzalez	Monterrey		Mexico	64460
98	Amsterdam UMC Locatie VUMC	Amsterdam		Netherlands	1081 HV
99	Haukeland Universitetssykehus	Bergen		Norway	N-5021
100	Sykehuset Østfold Kalnes	Grålum		Norway	N-1714
101	Reg. Specialist Hospital of M. Kopernik, Dept. Haematology	Lodz		Poland	93-510
102	City Hospital Torun, Department of Hematology	Torun		Poland	87-100
103	CHULN, EPE - Hospital de Santa Maria	Lisboa		Portugal	1649-035
104	Centro Hospitalar Universitário do Porto, EPE - Hospital de Santo António	Porto		Portugal	4099-001
105	IPO Porto Francisco Gentil, EPE	Porto		Portugal	4200-072
106	Centro Hospitalar Universitário São João,EPE	Porto		Portugal	4202-451
107	Regional Clinical Hospital 'The Badge of Honor Order'	Irkutsk		Russian Federation	664079
108	FSBI "N.N Blokhin Med.Res.Cent.Onc."MoH of RF	Moscow		Russian Federation	115478
109	Nizhniy Novgorod Reg. Clinical Hospital, Dept. Haematology	Nizhniy Novgorod		Russian Federation	603126
110	Leningrad Reg. Clin. Hosp., Oncohematology Department No. 2	St. Petersburg		Russian Federation	194291
111	Netcare Pretoria East Hospital	Moreleta Park, Pretoria		South Africa	0044
112	Hospital Germans Trias i Pujol	Badalona		Spain	08916
113	Hospital Santa Creu i Sant Pau	Barcelona		Spain	08025
114	Hospital Vall d'Hebron	Barcelona		Spain	08035
115	Hospital Clínic de Barcelona	Barcelona		Spain	08036
116	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
117	Hospital La Paz	Madrid		Spain	28046
118	Hospital Universitario de Salamanca	Salamanca		Spain	37007
119	Hospital Politècnic La Fe	Valencia		Spain	46009
120	Chang-Hua Christian Hospital	ChangHua		Taiwan	500
121	National Taiwan University Hospital	Taipei		Taiwan	100
122	Mackay Memorial Hospital	Taipei		Taiwan	112

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01721876
• Other Study ID Numbers: 1230.14; 2012-002487-27
• First Posted: Nov 6, 2012
• Last Update Posted: Nov 19, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Cytarabine

Study Results

Participant Flow

Recruitment Details	Patients aged 65 years or more with previously untreated acute myeloid leukaemia, who are ineligible for intensive remission induction therapy were recruited in the phase III randomised, double-blind, placebo-controlled, parallel group study.
Pre-assignment Detail	All patients were screened for eligibility to participate in the trial. Patients attended a specialist sites which ensured that they (the patients) met all strictly implemented inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any one of the specific entry criteria was violated.

Arm/Group Title	Placebo + Low-dose Cytarabine	Volasertib + Low-dose Cytarabine
Arm/Group Description	Patients received placebo matching to Volasertib 350 milligram (mg) intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.	Patients received Volasertib 350 mg intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, wherein no dose increase was allowed after a dose reduction, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.
Period Title: Overall Study
STARTED	222	444
Treated	221	440
COMPLETED	0	0
NOT COMPLETED	222	444

Baseline Characteristics

Arm/Group Title	Placebo + Low-dose Cytarabine	Volasertib + Low-dose Cytarabine	Total
Arm/Group Description	Patients received placebo matching to Volasertib 350 milligram (mg) intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.	Patients received Volasertib 350 mg intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, wherein no dose increase was allowed after a dose reduction, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.	Total of all reporting groups
Overall Participants	222	444	666
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	75.5 (4.9)	75.2 (5.4)	75.3 (5.2)
Sex: Female, Male (Count of Participants)
Female	87 39.2%	203 45.7%	290 43.5%
Male	135 60.8%	241 54.3%	376 56.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 4.5%	16 3.6%	26 3.9%
Not Hispanic or Latino	194 87.4%	399 89.9%	593 89%
Unknown or Not Reported	18 8.1%	29 6.5%	47 7.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	2 0.5%	2 0.3%
Asian	39 17.6%	74 16.7%	113 17%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	2 0.5%	2 0.3%
White	158 71.2%	328 73.9%	486 73%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	25 11.3%	38 8.6%	63 9.5%

Outcome Measures

1. Primary Outcome

Title	Objective Response (OR)
Description	OR is the number of patients who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi), where OR was based on the best response attained during the treatment period.
Time Frame	Response assessment was performed at the end of every 2nd cycle, (i.e. at the end of Cycle 2, 4, 6, 8, etc., and at end of treatment), i.e. up to 52 months.

Outcome Measure Data

Analysis Population Description

The randomised set (RS) included all patients who had been randomised at the database snapshot.

Arm/Group Title	Placebo + Low-dose Cytarabine	Volasertib + Low-dose Cytarabine
Arm/Group Description	Patients received placebo matching to Volasertib 350 milligram (mg) intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.	Patients received Volasertib 350 mg intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, wherein no dose increase was allowed after a dose reduction, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.
Measure Participants	222	444
Number [Participants]	38 17.1%	123 27.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Low-dose Cytarabine, Volasertib + Low-dose Cytarabine
	Comments	This analysis was exploratory and descriptive.
	Type of Statistical Test	Superiority
	Comments	The 2-sided test of the hypothesis was performed at a 0.05 level of significance. An odds ratio (OR) = 1 would indicate that the odds of achieving CR+CRi with Volasertib + Low-dose Cytarabine is equal to the odds of achieving CR+CRi with Placebo + Low-dose Cytarabine , whereas an OR ≠ 1 would indicate the opposite. H0, CR+CRi: OR = 1 vs. Ha, CR+CRi: OR ≠ 1.
Statistical Test of Hypothesis	p-Value	0.0024
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.8751
	Confidence Interval	(2-Sided) 95%; 1.2432 to 2.8281
	Parameter Dispersion	Type: Value:
	Estimation Comments	Common odds ratio is calculated by Mantel-Haenszel estimate adjusting for the two stratification factors (baseline Eastern Cooperative Oncology Group (ECOG) and type of AML). If odds ratio is above 1 then it favours Volasertib+Low-dose Cytarabine.

2. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is the key secondary endpoint and was measured from the date of randomization until death from any cause. Patients who were lost to follow-up were censored on the last date they were known to be alive.
Time Frame	From randomization until death due to any cause, up to 1557 days.

Outcome Measure Data

Analysis Population Description

RS

Arm/Group Title	Placebo + Low-dose Cytarabine	Volasertib + Low-dose Cytarabine
Arm/Group Description	Patients received placebo matching to Volasertib 350 milligram (mg) intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.	Patients received Volasertib 350 mg intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, wherein no dose increase was allowed after a dose reduction, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.
Measure Participants	222	444
Median (95% Confidence Interval) [Months]	6.5	5.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Low-dose Cytarabine, Volasertib + Low-dose Cytarabine
	Comments	This analysis was exploratory and descriptive.
	Type of Statistical Test	Superiority
	Comments	The hazard ratio (HR) between Volasertib + Low-dose Cytarabine and Placebo + Low-dose Cytarabine was tested against 1. The null hypothesis, H0,OS, was that the hazards are equal between Volasertib + Low-dose Cytarabine and Placebo + Low-dose Cytarabine, whereas the alternative hypothesis, Ha,OS, was that the hazards are not equal between the 2 treatment arms. H0, OS: HR = 1 vs. Ha, OS: HR ≠ 1.
Statistical Test of Hypothesis	p-Value	0.7571
	Comments	P-value is calculated from log-rank test stratified by baseline ECOG (0-1 vs. 2) and type of AML (denovo vs. secondary).
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.8 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is calculated from Cox proportional hazard model stratified by baseline ECOG and type of AML. If hazard ratio is below 1 then it favours volasertib.

3. Secondary Outcome

Title	Event-free Survival (EFS)
Description	EFS was measured from the date of randomisation to the date of progression or relapse, or death from any cause, whichever occurred first.
Time Frame	From randomization until disease progression or relapse or death from any cause, up to 1557 days.

Outcome Measure Data

Analysis Population Description

RS

Arm/Group Title	Placebo + Low-dose Cytarabine	Volasertib + Low-dose Cytarabine
Arm/Group Description	Patients received placebo matching to Volasertib 350 milligram (mg) intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.	Patients received Volasertib 350 mg intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, wherein no dose increase was allowed after a dose reduction, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.
Measure Participants	222	444
Median (95% Confidence Interval) [Months]	2.8	3.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Low-dose Cytarabine, Volasertib + Low-dose Cytarabine
	Comments	This analysis was exploratory and descriptive.
	Type of Statistical Test	Superiority
	Comments	The hazard ratio (HR) between Volasertib + Low-dose Cytarabine and Placebo + Low-dose Cytarabine was tested against 1. The null hypothesis, H0,OS, was that the hazards are equal between Volasertib + Low-dose Cytarabine and Placebo + Low-dose Cytarabine, whereas the alternative hypothesis, Ha,OS, was that the hazards are not equal between the 2 treatment arms. H0, OS: HR = 1 vs. Ha, OS: HR ≠ 1.
Statistical Test of Hypothesis	p-Value	0.6718
	Comments	P-value is calculated from log-rank test stratified by baseline ECOG (0-1 vs. 2) and type of AML (denovo vs. secondary).
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.8 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is calculated from Cox proportional hazard model stratified by baseline ECOG and type of AML. If hazard ratio is below 1 then it favours volasertib.

4. Secondary Outcome

Title	Relapse-free Survival (RFS)
Description	RFS was defined only for patients who achieved best overall response of CR or CRi; it was measured from the date of achievement of a remission until the date of relapse or death from any cause. Patients not known to have relapsed or died at last follow-up were censored on the date they were last examined.
Time Frame	From randomization until disease progression or relapse or death from any cause, up to 1557 days.

Outcome Measure Data

Analysis Population Description

All patients in the RS who achieved best overall response of CR or CRi.

Arm/Group Title	Placebo + Low-dose Cytarabine	Volasertib + Low-dose Cytarabine
Arm/Group Description	Patients received placebo matching to Volasertib 350 milligram (mg) intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.	Patients received Volasertib 350 mg intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, wherein no dose increase was allowed after a dose reduction, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.
Measure Participants	38	123
Median (95% Confidence Interval) [Months]	18.7	13.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Low-dose Cytarabine, Volasertib + Low-dose Cytarabine
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; 0.7 to 2.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is calculated from Cox proportional hazard model stratified by baseline ECOG and type of AML. If hazard ratio is below 1 then it favours volasertib.

Adverse Events

Time Frame	From first drug administration until 21 days after last drug administration, i.e., up to 91.4 months.
Adverse Event Reporting Description	The treated set (TS) included all patients who were dispensed study medication and were documented to have taken at least one dose of Volasertib, placebo, or Low-dose Cytarabine. One patient was randomised to the Volasertib + Low-dose Cytarabine arm but only took Low-dose Cytarabine and was therefore allocated to the Placebo + Low-dose Cytarabine arm in the treated set.
Arm/Group Title	Subjects Assigned to Placebo + Low-dose Cytarabine		Subjects Assigned to Volasertib + Low-dose Cytarabine
Arm/Group Description	Patients received placebo matching to Volasertib 350 milligram (mg) intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.		Patients received Volasertib 350 mg intravenous infusion for 1 hour on day 1 and day 15 of each 28-day cycle, wherein no dose increase was allowed after a dose reduction, in combination with Cytarabine 20 mg subcutaneous injection given twice daily at 12 hours interval from day 1 to 10 of each 28-day cycle.
All Cause Mortality
	Subjects Assigned to Placebo + Low-dose Cytarabine		Subjects Assigned to Volasertib + Low-dose Cytarabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/222 (18%)		138/439 (31.4%)
Serious Adverse Events
	Subjects Assigned to Placebo + Low-dose Cytarabine		Subjects Assigned to Volasertib + Low-dose Cytarabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	163/222 (73.4%)		380/439 (86.6%)
Blood and lymphatic system disorders
Anaemia	10/222 (4.5%)		20/439 (4.6%)
Bone marrow failure	0/222 (0%)		1/439 (0.2%)
Disseminated intravascular coagulation	1/222 (0.5%)		3/439 (0.7%)
Febrile bone marrow aplasia	1/222 (0.5%)		5/439 (1.1%)
Febrile neutropenia	42/222 (18.9%)		203/439 (46.2%)
Haemolytic anaemia	0/222 (0%)		1/439 (0.2%)
Haemorrhagic diathesis	0/222 (0%)		1/439 (0.2%)
Haemorrhagic disorder	1/222 (0.5%)		0/439 (0%)
Hypofibrinogenaemia	0/222 (0%)		1/439 (0.2%)
Leukocytosis	4/222 (1.8%)		0/439 (0%)
Leukopenia	0/222 (0%)		1/439 (0.2%)
Lymphadenitis	1/222 (0.5%)		0/439 (0%)
Lymphadenopathy	1/222 (0.5%)		0/439 (0%)
Neutropenia	2/222 (0.9%)		13/439 (3%)
Splenic infarction	1/222 (0.5%)		0/439 (0%)
Thrombocytopenia	9/222 (4.1%)		23/439 (5.2%)
Blood loss anaemia	0/222 (0%)		1/439 (0.2%)
Cardiac disorders
Acute coronary syndrome	1/222 (0.5%)		1/439 (0.2%)
Acute myocardial infarction	0/222 (0%)		4/439 (0.9%)
Angina unstable	0/222 (0%)		1/439 (0.2%)
Arrhythmia	2/222 (0.9%)		1/439 (0.2%)
Arrhythmia supraventricular	0/222 (0%)		1/439 (0.2%)
Atrial fibrillation	4/222 (1.8%)		6/439 (1.4%)
Atrial flutter	2/222 (0.9%)		1/439 (0.2%)
Bradyarrhythmia	1/222 (0.5%)		0/439 (0%)
Cardiac arrest	1/222 (0.5%)		4/439 (0.9%)
Cardiac disorder	0/222 (0%)		1/439 (0.2%)
Cardiac failure	8/222 (3.6%)		10/439 (2.3%)
Cardiac failure acute	0/222 (0%)		2/439 (0.5%)
Cardiac failure congestive	0/222 (0%)		2/439 (0.5%)
Cardio-respiratory arrest	1/222 (0.5%)		2/439 (0.5%)
Cardiogenic shock	1/222 (0.5%)		1/439 (0.2%)
Cardiopulmonary failure	0/222 (0%)		1/439 (0.2%)
Coronary artery disease	0/222 (0%)		1/439 (0.2%)
Left ventricular dysfunction	0/222 (0%)		1/439 (0.2%)
Myocardial infarction	0/222 (0%)		1/439 (0.2%)
Myocardial ischaemia	0/222 (0%)		2/439 (0.5%)
Right ventricular failure	1/222 (0.5%)		1/439 (0.2%)
Supraventricular tachycardia	0/222 (0%)		2/439 (0.5%)
Tachyarrhythmia	0/222 (0%)		1/439 (0.2%)
Ventricular fibrillation	0/222 (0%)		1/439 (0.2%)
Ventricular tachycardia	0/222 (0%)		1/439 (0.2%)
Atrioventricular block	0/222 (0%)		1/439 (0.2%)
Congenital, familial and genetic disorders
Aplasia	1/222 (0.5%)		1/439 (0.2%)
Endocrine disorders
Hyperthyroidism	0/222 (0%)		1/439 (0.2%)
Eye disorders
Blindness transient	0/222 (0%)		1/439 (0.2%)
Retinal haemorrhage	0/222 (0%)		1/439 (0.2%)
Gastrointestinal disorders
Abdominal pain	0/222 (0%)		2/439 (0.5%)
Abdominal pain upper	1/222 (0.5%)		0/439 (0%)
Anal haemorrhage	0/222 (0%)		1/439 (0.2%)
Anal ulcer	0/222 (0%)		1/439 (0.2%)
Ascites	1/222 (0.5%)		0/439 (0%)
Colitis	3/222 (1.4%)		4/439 (0.9%)
Diarrhoea	2/222 (0.9%)		8/439 (1.8%)
Enteritis	0/222 (0%)		3/439 (0.7%)
Enterocolitis	0/222 (0%)		1/439 (0.2%)
Gastric haemorrhage	1/222 (0.5%)		0/439 (0%)
Gastritis	1/222 (0.5%)		0/439 (0%)
Gastrointestinal haemorrhage	1/222 (0.5%)		4/439 (0.9%)
Gastrointestinal inflammation	0/222 (0%)		1/439 (0.2%)
Gingival bleeding	0/222 (0%)		1/439 (0.2%)
Haematochezia	0/222 (0%)		1/439 (0.2%)
Haemorrhoidal haemorrhage	0/222 (0%)		1/439 (0.2%)
Haemorrhoids	0/222 (0%)		1/439 (0.2%)
Ileus	1/222 (0.5%)		2/439 (0.5%)
Ileus paralytic	2/222 (0.9%)		1/439 (0.2%)
Inguinal hernia strangulated	1/222 (0.5%)		0/439 (0%)
Intestinal perforation	0/222 (0%)		1/439 (0.2%)
Large intestinal haemorrhage	1/222 (0.5%)		0/439 (0%)
Large intestine perforation	1/222 (0.5%)		0/439 (0%)
Melaena	0/222 (0%)		1/439 (0.2%)
Mesenteric panniculitis	0/222 (0%)		1/439 (0.2%)
Mouth haemorrhage	0/222 (0%)		1/439 (0.2%)
Mouth ulceration	0/222 (0%)		2/439 (0.5%)
Neutropenic colitis	0/222 (0%)		5/439 (1.1%)
Odynophagia	1/222 (0.5%)		0/439 (0%)
Oesophagitis	1/222 (0.5%)		0/439 (0%)
Oral pain	0/222 (0%)		1/439 (0.2%)
Pancreatitis	0/222 (0%)		1/439 (0.2%)
Rectal haemorrhage	1/222 (0.5%)		2/439 (0.5%)
Rectal ulcer	0/222 (0%)		1/439 (0.2%)
Small intestinal obstruction	0/222 (0%)		1/439 (0.2%)
Stomatitis	4/222 (1.8%)		6/439 (1.4%)
Upper gastrointestinal haemorrhage	0/222 (0%)		1/439 (0.2%)
Vomiting	1/222 (0.5%)		1/439 (0.2%)
Diverticulum	0/222 (0%)		1/439 (0.2%)
General disorders
Asthenia	2/222 (0.9%)		6/439 (1.4%)
Catheter site phlebitis	0/222 (0%)		1/439 (0.2%)
Chest pain	1/222 (0.5%)		0/439 (0%)
Death	0/222 (0%)		2/439 (0.5%)
Device related thrombosis	0/222 (0%)		1/439 (0.2%)
Fatigue	5/222 (2.3%)		2/439 (0.5%)
General physical health deterioration	3/222 (1.4%)		15/439 (3.4%)
Induration	1/222 (0.5%)		0/439 (0%)
Malaise	0/222 (0%)		1/439 (0.2%)
Mucosal haemorrhage	0/222 (0%)		1/439 (0.2%)
Mucosal inflammation	0/222 (0%)		5/439 (1.1%)
Multiple organ dysfunction syndrome	0/222 (0%)		3/439 (0.7%)
Oedema peripheral	0/222 (0%)		1/439 (0.2%)
Performance status decreased	0/222 (0%)		1/439 (0.2%)
Pyrexia	19/222 (8.6%)		33/439 (7.5%)
Sudden death	0/222 (0%)		1/439 (0.2%)
Hepatobiliary disorders
Bile duct stone	1/222 (0.5%)		0/439 (0%)
Cholecystitis	0/222 (0%)		1/439 (0.2%)
Cholelithiasis	1/222 (0.5%)		0/439 (0%)
Hepatic failure	1/222 (0.5%)		2/439 (0.5%)
Hepatic function abnormal	1/222 (0.5%)		0/439 (0%)
Hyperbilirubinaemia	0/222 (0%)		1/439 (0.2%)
Liver injury	1/222 (0.5%)		2/439 (0.5%)
Hepatic cytolysis	1/222 (0.5%)		0/439 (0%)
Immune system disorders
Allergy to vaccine	0/222 (0%)		1/439 (0.2%)
Anaphylactic reaction	0/222 (0%)		1/439 (0.2%)
Hypersensitivity	1/222 (0.5%)		1/439 (0.2%)
Infections and infestations
Anal abscess	1/222 (0.5%)		3/439 (0.7%)
Anal infection	0/222 (0%)		1/439 (0.2%)
Appendicitis	1/222 (0.5%)		1/439 (0.2%)
Aspergillus infection	1/222 (0.5%)		1/439 (0.2%)
Atypical pneumonia	0/222 (0%)		1/439 (0.2%)
Bacillus infection	0/222 (0%)		1/439 (0.2%)
Bacteraemia	3/222 (1.4%)		5/439 (1.1%)
Bacterial infection	0/222 (0%)		1/439 (0.2%)
Bacterial sepsis	0/222 (0%)		4/439 (0.9%)
Bronchitis	1/222 (0.5%)		3/439 (0.7%)
Bronchopulmonary aspergillosis	3/222 (1.4%)		12/439 (2.7%)
Campylobacter sepsis	0/222 (0%)		1/439 (0.2%)
Catheter site infection	0/222 (0%)		1/439 (0.2%)
Cellulitis	6/222 (2.7%)		3/439 (0.7%)
Cellulitis of male external genital organ	0/222 (0%)		1/439 (0.2%)
Clostridium colitis	0/222 (0%)		2/439 (0.5%)
Clostridium difficile infection	0/222 (0%)		1/439 (0.2%)
Colonic abscess	1/222 (0.5%)		0/439 (0%)
Conjunctivitis	0/222 (0%)		1/439 (0.2%)
Cystitis	2/222 (0.9%)		0/439 (0%)
Device related infection	3/222 (1.4%)		5/439 (1.1%)
Diverticulitis	2/222 (0.9%)		1/439 (0.2%)
Enteritis infectious	1/222 (0.5%)		0/439 (0%)
Enterobacter infection	0/222 (0%)		1/439 (0.2%)
Enterobacter sepsis	0/222 (0%)		1/439 (0.2%)
Enterococcal bacteraemia	1/222 (0.5%)		1/439 (0.2%)
Enterococcal sepsis	0/222 (0%)		2/439 (0.5%)
Enterocolitis infectious	0/222 (0%)		3/439 (0.7%)
Epididymitis	0/222 (0%)		1/439 (0.2%)
Erysipelas	0/222 (0%)		2/439 (0.5%)
Escherichia bacteraemia	0/222 (0%)		1/439 (0.2%)
Escherichia infection	2/222 (0.9%)		1/439 (0.2%)
Escherichia sepsis	0/222 (0%)		4/439 (0.9%)
Escherichia urinary tract infection	0/222 (0%)		1/439 (0.2%)
Fungal infection	0/222 (0%)		1/439 (0.2%)
Fungal sepsis	0/222 (0%)		3/439 (0.7%)
Fungal skin infection	1/222 (0.5%)		0/439 (0%)
Gastroenteritis	1/222 (0.5%)		1/439 (0.2%)
Genital herpes	1/222 (0.5%)		0/439 (0%)
Infection	1/222 (0.5%)		3/439 (0.7%)
Influenza	1/222 (0.5%)		2/439 (0.5%)
Klebsiella infection	0/222 (0%)		1/439 (0.2%)
Klebsiella sepsis	0/222 (0%)		2/439 (0.5%)
Laryngitis	0/222 (0%)		1/439 (0.2%)
Liver abscess	0/222 (0%)		1/439 (0.2%)
Localised infection	1/222 (0.5%)		0/439 (0%)
Lower respiratory tract infection	1/222 (0.5%)		2/439 (0.5%)
Lymphadenitis bacterial	0/222 (0%)		1/439 (0.2%)
Myocarditis septic	0/222 (0%)		1/439 (0.2%)
Neutropenic infection	1/222 (0.5%)		7/439 (1.6%)
Neutropenic sepsis	1/222 (0.5%)		2/439 (0.5%)
Oral candidiasis	1/222 (0.5%)		1/439 (0.2%)
Oral herpes	0/222 (0%)		1/439 (0.2%)
Oropharyngeal candidiasis	0/222 (0%)		1/439 (0.2%)
Osteomyelitis fungal	0/222 (0%)		1/439 (0.2%)
Parotitis	1/222 (0.5%)		0/439 (0%)
Perichondritis	0/222 (0%)		1/439 (0.2%)
Pharyngitis	0/222 (0%)		2/439 (0.5%)
Pharyngotonsillitis	0/222 (0%)		1/439 (0.2%)
Pneumonia	44/222 (19.8%)		113/439 (25.7%)
Pneumonia fungal	1/222 (0.5%)		7/439 (1.6%)
Pneumonia klebsiella	0/222 (0%)		1/439 (0.2%)
Pneumonia staphylococcal	1/222 (0.5%)		1/439 (0.2%)
Prostatitis Escherichia coli	0/222 (0%)		1/439 (0.2%)
Pseudomembranous colitis	1/222 (0.5%)		2/439 (0.5%)
Pseudomonal sepsis	1/222 (0.5%)		4/439 (0.9%)
Pseudomonas infection	0/222 (0%)		1/439 (0.2%)
Pulmonary sepsis	1/222 (0.5%)		1/439 (0.2%)
Pulmonary tuberculosis	0/222 (0%)		1/439 (0.2%)
Rash pustular	0/222 (0%)		1/439 (0.2%)
Respiratory syncytial virus infection	0/222 (0%)		1/439 (0.2%)
Respiratory tract infection	3/222 (1.4%)		7/439 (1.6%)
Respiratory tract infection fungal	1/222 (0.5%)		0/439 (0%)
Respiratory tract infection viral	0/222 (0%)		1/439 (0.2%)
Sepsis	9/222 (4.1%)		44/439 (10%)
Septic shock	10/222 (4.5%)		28/439 (6.4%)
Sinusitis	3/222 (1.4%)		1/439 (0.2%)
Sinusitis aspergillus	1/222 (0.5%)		0/439 (0%)
Sinusitis fungal	1/222 (0.5%)		1/439 (0.2%)
Skin infection	0/222 (0%)		4/439 (0.9%)
Soft tissue infection	1/222 (0.5%)		2/439 (0.5%)
Staphylococcal infection	1/222 (0.5%)		2/439 (0.5%)
Staphylococcal sepsis	0/222 (0%)		3/439 (0.7%)
Stenotrophomonas sepsis	0/222 (0%)		1/439 (0.2%)
Streptococcal sepsis	0/222 (0%)		1/439 (0.2%)
Subcutaneous abscess	0/222 (0%)		1/439 (0.2%)
Testicular abscess	0/222 (0%)		1/439 (0.2%)
Tonsillitis	1/222 (0.5%)		1/439 (0.2%)
Tonsillitis bacterial	0/222 (0%)		1/439 (0.2%)
Tooth infection	0/222 (0%)		2/439 (0.5%)
Tuberculosis	1/222 (0.5%)		0/439 (0%)
Upper respiratory tract infection	3/222 (1.4%)		5/439 (1.1%)
Upper respiratory tract infection bacterial	0/222 (0%)		1/439 (0.2%)
Urinary tract infection	3/222 (1.4%)		12/439 (2.7%)
Urosepsis	1/222 (0.5%)		0/439 (0%)
Vulvitis	0/222 (0%)		1/439 (0.2%)
Clostridium bacteraemia	0/222 (0%)		1/439 (0.2%)
Clostridium difficile colitis	0/222 (0%)		1/439 (0.2%)
Haematoma infection	0/222 (0%)		1/439 (0.2%)
Large intestine infection	0/222 (0%)		1/439 (0.2%)
Nasopharyngitis	1/222 (0.5%)		0/439 (0%)
Pneumonia influenzal	0/222 (0%)		1/439 (0.2%)
Pneumonia pseudomonal	0/222 (0%)		1/439 (0.2%)
Vascular device infection	1/222 (0.5%)		0/439 (0%)
Injury, poisoning and procedural complications
Allergic transfusion reaction	0/222 (0%)		1/439 (0.2%)
Concussion	0/222 (0%)		1/439 (0.2%)
Craniocerebral injury	1/222 (0.5%)		0/439 (0%)
Extradural haematoma	0/222 (0%)		1/439 (0.2%)
Fall	3/222 (1.4%)		0/439 (0%)
Femoral neck fracture	0/222 (0%)		2/439 (0.5%)
Humerus fracture	1/222 (0.5%)		0/439 (0%)
Infusion related reaction	1/222 (0.5%)		0/439 (0%)
Pelvic fracture	1/222 (0.5%)		0/439 (0%)
Spinal compression fracture	0/222 (0%)		2/439 (0.5%)
Spinal fracture	0/222 (0%)		1/439 (0.2%)
Subdural haematoma	1/222 (0.5%)		4/439 (0.9%)
Subdural haemorrhage	0/222 (0%)		1/439 (0.2%)
Tracheal obstruction	0/222 (0%)		1/439 (0.2%)
Transfusion reaction	0/222 (0%)		2/439 (0.5%)
Transfusion-related acute lung injury	0/222 (0%)		2/439 (0.5%)
Transfusion-related circulatory overload	1/222 (0.5%)		0/439 (0%)
Upper limb fracture	0/222 (0%)		1/439 (0.2%)
Wound haemorrhage	0/222 (0%)		1/439 (0.2%)
Investigations
Alanine aminotransferase increased	0/222 (0%)		1/439 (0.2%)
Blood bilirubin increased	1/222 (0.5%)		2/439 (0.5%)
Blood creatinine increased	1/222 (0.5%)		2/439 (0.5%)
Blood pressure orthostatic decreased	1/222 (0.5%)		0/439 (0%)
C-reactive protein increased	1/222 (0.5%)		2/439 (0.5%)
Electrocardiogram QT prolonged	2/222 (0.9%)		2/439 (0.5%)
Haematocrit decreased	0/222 (0%)		1/439 (0.2%)
Haemoglobin decreased	0/222 (0%)		1/439 (0.2%)
Liver function test abnormal	0/222 (0%)		1/439 (0.2%)
Platelet count decreased	0/222 (0%)		3/439 (0.7%)
Troponin increased	2/222 (0.9%)		1/439 (0.2%)
White blood cell count increased	0/222 (0%)		1/439 (0.2%)
Metabolism and nutrition disorders
Acidosis	0/222 (0%)		1/439 (0.2%)
Cachexia	0/222 (0%)		1/439 (0.2%)
Decreased appetite	2/222 (0.9%)		0/439 (0%)
Dehydration	0/222 (0%)		2/439 (0.5%)
Diabetic ketoacidosis	0/222 (0%)		1/439 (0.2%)
Fluid overload	0/222 (0%)		2/439 (0.5%)
Hypercreatininaemia	0/222 (0%)		1/439 (0.2%)
Hyperglycaemia	1/222 (0.5%)		1/439 (0.2%)
Hyperkalaemia	1/222 (0.5%)		0/439 (0%)
Hypernatraemia	0/222 (0%)		2/439 (0.5%)
Hypoglycaemia	1/222 (0.5%)		0/439 (0%)
Hypokalaemia	1/222 (0.5%)		1/439 (0.2%)
Metabolic acidosis	2/222 (0.9%)		2/439 (0.5%)
Tumour lysis syndrome	0/222 (0%)		2/439 (0.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/222 (0.5%)		0/439 (0%)
Arthritis	1/222 (0.5%)		0/439 (0%)
Back pain	0/222 (0%)		1/439 (0.2%)
Bone pain	0/222 (0%)		1/439 (0.2%)
Gouty arthritis	1/222 (0.5%)		0/439 (0%)
Groin pain	0/222 (0%)		2/439 (0.5%)
Haemarthrosis	0/222 (0%)		1/439 (0.2%)
Musculoskeletal pain	0/222 (0%)		1/439 (0.2%)
Neck pain	1/222 (0.5%)		1/439 (0.2%)
Osteoporosis	0/222 (0%)		1/439 (0.2%)
Pain in extremity	1/222 (0.5%)		0/439 (0%)
Rhabdomyolysis	1/222 (0.5%)		0/439 (0%)
Synovitis	0/222 (0%)		1/439 (0.2%)
Osteitis	0/222 (0%)		1/439 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/222 (0.5%)		0/439 (0%)
Chronic lymphocytic leukaemia	1/222 (0.5%)		0/439 (0%)
Malignant neoplasm of thorax	1/222 (0.5%)		0/439 (0%)
Malignant neoplasm progression	17/222 (7.7%)		22/439 (5%)
Metastases to peritoneum	1/222 (0.5%)		0/439 (0%)
Neoplasm skin	0/222 (0%)		1/439 (0.2%)
Rectal cancer	1/222 (0.5%)		0/439 (0%)
Squamous cell carcinoma	0/222 (0%)		1/439 (0.2%)
Tumour associated fever	1/222 (0.5%)		0/439 (0%)
Breast cancer	0/222 (0%)		1/439 (0.2%)
Myeloproliferative neoplasm	0/222 (0%)		1/439 (0.2%)
Nervous system disorders
Brain stem haemorrhage	0/222 (0%)		1/439 (0.2%)
Cerebellar haemorrhage	1/222 (0.5%)		0/439 (0%)
Cerebral haemorrhage	2/222 (0.9%)		3/439 (0.7%)
Cerebral infarction	2/222 (0.9%)		3/439 (0.7%)
Cerebral ischaemia	1/222 (0.5%)		0/439 (0%)
Cerebrovascular accident	1/222 (0.5%)		2/439 (0.5%)
Dizziness	1/222 (0.5%)		1/439 (0.2%)
Embolic cerebral infarction	0/222 (0%)		1/439 (0.2%)
Epilepsy	1/222 (0.5%)		1/439 (0.2%)
Haemorrhage intracranial	1/222 (0.5%)		1/439 (0.2%)
Haemorrhagic stroke	0/222 (0%)		2/439 (0.5%)
Hemiparesis	0/222 (0%)		1/439 (0.2%)
Hypotonia	0/222 (0%)		2/439 (0.5%)
Seizure	1/222 (0.5%)		2/439 (0.5%)
Sneddon's syndrome	1/222 (0.5%)		0/439 (0%)
Spinal cord compression	0/222 (0%)		1/439 (0.2%)
Stupor	1/222 (0.5%)		0/439 (0%)
Syncope	1/222 (0.5%)		3/439 (0.7%)
Transient ischaemic attack	0/222 (0%)		2/439 (0.5%)
Subarachnoid haemorrhage	0/222 (0%)		3/439 (0.7%)
Psychiatric disorders
Confusional state	1/222 (0.5%)		4/439 (0.9%)
Disorientation	0/222 (0%)		1/439 (0.2%)
Mental disorder	1/222 (0.5%)		0/439 (0%)
Renal and urinary disorders
Acute kidney injury	7/222 (3.2%)		19/439 (4.3%)
Bladder obstruction	0/222 (0%)		1/439 (0.2%)
Haematuria	1/222 (0.5%)		4/439 (0.9%)
Renal failure	0/222 (0%)		6/439 (1.4%)
Renal impairment	0/222 (0%)		1/439 (0.2%)
Ureterolithiasis	1/222 (0.5%)		0/439 (0%)
Urinary retention	0/222 (0%)		2/439 (0.5%)
Reproductive system and breast disorders
Vaginal haemorrhage	0/222 (0%)		1/439 (0.2%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/222 (0%)		1/439 (0.2%)
Acute respiratory distress syndrome	0/222 (0%)		2/439 (0.5%)
Acute respiratory failure	3/222 (1.4%)		3/439 (0.7%)
Bronchospasm	0/222 (0%)		1/439 (0.2%)
Dyspnoea	3/222 (1.4%)		3/439 (0.7%)
Dyspnoea at rest	0/222 (0%)		1/439 (0.2%)
Dyspnoea exertional	1/222 (0.5%)		0/439 (0%)
Epistaxis	0/222 (0%)		6/439 (1.4%)
Haemothorax	1/222 (0.5%)		0/439 (0%)
Hypoxia	0/222 (0%)		1/439 (0.2%)
Interstitial lung disease	0/222 (0%)		2/439 (0.5%)
Lung disorder	1/222 (0.5%)		2/439 (0.5%)
Lung infiltration	0/222 (0%)		1/439 (0.2%)
Orthopnoea	0/222 (0%)		1/439 (0.2%)
Pleural effusion	1/222 (0.5%)		2/439 (0.5%)
Pneumonitis	0/222 (0%)		2/439 (0.5%)
Pulmonary embolism	0/222 (0%)		1/439 (0.2%)
Pulmonary haemorrhage	0/222 (0%)		3/439 (0.7%)
Pulmonary hypertension	2/222 (0.9%)		1/439 (0.2%)
Pulmonary oedema	0/222 (0%)		4/439 (0.9%)
Respiratory distress	0/222 (0%)		2/439 (0.5%)
Respiratory failure	6/222 (2.7%)		11/439 (2.5%)
Respiratory tract haemorrhage	0/222 (0%)		1/439 (0.2%)
Aspiration	0/222 (0%)		1/439 (0.2%)
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis	0/222 (0%)		1/439 (0.2%)
Drug eruption	0/222 (0%)		1/439 (0.2%)
Erythema nodosum	0/222 (0%)		1/439 (0.2%)
Skin haemorrhage	0/222 (0%)		1/439 (0.2%)
Skin lesion	0/222 (0%)		1/439 (0.2%)
Toxic skin eruption	1/222 (0.5%)		0/439 (0%)
Rash	0/222 (0%)		2/439 (0.5%)
Surgical and medical procedures
Angioplasty	0/222 (0%)		1/439 (0.2%)
Vascular disorders
Deep vein thrombosis	3/222 (1.4%)		5/439 (1.1%)
Embolism	0/222 (0%)		1/439 (0.2%)
Haematoma	0/222 (0%)		1/439 (0.2%)
Haemorrhage	0/222 (0%)		1/439 (0.2%)
Hypertension	0/222 (0%)		1/439 (0.2%)
Hypertensive emergency	0/222 (0%)		1/439 (0.2%)
Hypotension	2/222 (0.9%)		1/439 (0.2%)
Hypovolaemic shock	0/222 (0%)		1/439 (0.2%)
Orthostatic hypotension	0/222 (0%)		1/439 (0.2%)
Peripheral artery thrombosis	1/222 (0.5%)		0/439 (0%)
Phlebitis	0/222 (0%)		1/439 (0.2%)
Thrombophlebitis	1/222 (0.5%)		1/439 (0.2%)
Venous thrombosis limb	0/222 (0%)		1/439 (0.2%)
Aortitis	0/222 (0%)		1/439 (0.2%)
Peripheral arterial occlusive disease	0/222 (0%)		1/439 (0.2%)
Other (Not Including Serious) Adverse Events
	Subjects Assigned to Placebo + Low-dose Cytarabine		Subjects Assigned to Volasertib + Low-dose Cytarabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	203/222 (91.4%)		404/439 (92%)
Blood and lymphatic system disorders
Anaemia	53/222 (23.9%)		137/439 (31.2%)
Febrile neutropenia	28/222 (12.6%)		101/439 (23%)
Leukopenia	23/222 (10.4%)		45/439 (10.3%)
Neutropenia	34/222 (15.3%)		124/439 (28.2%)
Thrombocytopenia	59/222 (26.6%)		163/439 (37.1%)
Gastrointestinal disorders
Abdominal pain	26/222 (11.7%)		47/439 (10.7%)
Abdominal pain upper	14/222 (6.3%)		30/439 (6.8%)
Constipation	55/222 (24.8%)		122/439 (27.8%)
Diarrhoea	49/222 (22.1%)		116/439 (26.4%)
Nausea	79/222 (35.6%)		123/439 (28%)
Stomatitis	13/222 (5.9%)		75/439 (17.1%)
Vomiting	27/222 (12.2%)		71/439 (16.2%)
Dyspepsia	9/222 (4.1%)		22/439 (5%)
General disorders
Asthenia	42/222 (18.9%)		64/439 (14.6%)
Chest pain	8/222 (3.6%)		22/439 (5%)
Chills	12/222 (5.4%)		26/439 (5.9%)
Fatigue	29/222 (13.1%)		62/439 (14.1%)
Mucosal inflammation	11/222 (5%)		63/439 (14.4%)
Oedema	13/222 (5.9%)		36/439 (8.2%)
Oedema peripheral	42/222 (18.9%)		75/439 (17.1%)
Pain	10/222 (4.5%)		31/439 (7.1%)
Pyrexia	58/222 (26.1%)		85/439 (19.4%)
Infections and infestations
Oral candidiasis	5/222 (2.3%)		25/439 (5.7%)
Oral herpes	10/222 (4.5%)		31/439 (7.1%)
Pneumonia	9/222 (4.1%)		38/439 (8.7%)
Urinary tract infection	4/222 (1.8%)		24/439 (5.5%)
Nasopharyngitis	13/222 (5.9%)		18/439 (4.1%)
Injury, poisoning and procedural complications
Fall	9/222 (4.1%)		26/439 (5.9%)
Investigations
Alanine aminotransferase increased	16/222 (7.2%)		26/439 (5.9%)
Aspartate aminotransferase increased	14/222 (6.3%)		19/439 (4.3%)
Electrocardiogram QT prolonged	8/222 (3.6%)		32/439 (7.3%)
Weight decreased	20/222 (9%)		39/439 (8.9%)
Metabolism and nutrition disorders
Decreased appetite	43/222 (19.4%)		82/439 (18.7%)
Hyperuricaemia	13/222 (5.9%)		13/439 (3%)
Hypoalbuminaemia	14/222 (6.3%)		24/439 (5.5%)
Hypokalaemia	37/222 (16.7%)		120/439 (27.3%)
Hypomagnesaemia	13/222 (5.9%)		23/439 (5.2%)
Hypophosphataemia	6/222 (2.7%)		22/439 (5%)
Musculoskeletal and connective tissue disorders
Arthralgia	30/222 (13.5%)		45/439 (10.3%)
Back pain	18/222 (8.1%)		50/439 (11.4%)
Pain in extremity	12/222 (5.4%)		30/439 (6.8%)
Nervous system disorders
Dizziness	18/222 (8.1%)		43/439 (9.8%)
Headache	23/222 (10.4%)		48/439 (10.9%)
Psychiatric disorders
Insomnia	21/222 (9.5%)		38/439 (8.7%)
Confusional state	7/222 (3.2%)		22/439 (5%)
Respiratory, thoracic and mediastinal disorders
Cough	21/222 (9.5%)		95/439 (21.6%)
Dyspnoea	30/222 (13.5%)		76/439 (17.3%)
Epistaxis	28/222 (12.6%)		71/439 (16.2%)
Oropharyngeal pain	4/222 (1.8%)		28/439 (6.4%)
Pleural effusion	17/222 (7.7%)		17/439 (3.9%)
Skin and subcutaneous tissue disorders
Alopecia	4/222 (1.8%)		30/439 (6.8%)
Petechiae	24/222 (10.8%)		73/439 (16.6%)
Pruritus	17/222 (7.7%)		27/439 (6.2%)
Rash	30/222 (13.5%)		72/439 (16.4%)
Vascular disorders
Haematoma	20/222 (9%)		55/439 (12.5%)
Hypertension	7/222 (3.2%)		31/439 (7.1%)
Hypotension	9/222 (4.1%)		23/439 (5.2%)

Limitations/Caveats

The final analysis presented in this report was conducted after 574 Overall Survival events had occurred. The final analysis was exploratory and descriptive.

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Certain Agreements

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

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.