PHASE III RANDOMIZED TRIAL OF VOLASERTIB PLUS LOW-DOSE CYTARABINE (LDAC) VERSUS PLACEBO PLUS LDAC IN PATIENTS AGED ?65 YEARS WITH PREVIOUSLY UNTREATED AML, INELIGIBLE FOR INTENSIVE THERAPY
Author(s): ,
Hartmut Döhner
Affiliations:
University of Ulm,Ulm,Germany
,
Anargyros Symeonidis
Affiliations:
University Hospital of Patras,Patras,Greece
,
Miguel A Sanz
Affiliations:
University Hospital La Fe,Valencia,Spain
,
Dries Deeren
Affiliations:
H.-Hartziekenhuis Roeselare-Menen,Roselare,Belgium
,
Judit Demeter
Affiliations:
Semmelweis University,Budapest,Hungary
,
Achilles Anagnostopoulos
Affiliations:
General Hospital G. Papanikolaou,Thessaloniki,Greece
,
Jordi Esteve
Affiliations:
Hospital Clinic de Barcelona,Barcelona,Spain
,
Walter Fiedler
Affiliations:
Universitätsklinikum Hamburg-Eppendorf,Hamburg,Germany
,
Kimmo Porkka
Affiliations:
Helsinki University Central Hospital,Helsinki,Finland
,
Hee-Je Kim
Affiliations:
The Catholic University of Korea, Seoul St. Mary's Hospital,Seoul,Korea, Republic Of
,
Je Hwan Lee
Affiliations:
Asan Medical Center,Seoul,Korea, Republic Of
,
Kensuke Usuki
Affiliations:
NTT Medical Center Tokyo,Tokyo,Japan
,
Chul Won Jung
Affiliations:
Samsung Medical Center,Seoul,Korea, Republic Of
,
Stefano D‘Ardia
Affiliations:
A.O. Citta della Salute e della Scienza,Torino,Italy
,
Olga Salamero
Affiliations:
Hospital Vall d' Hebron,Barcelona,Spain
,
Heinz-August Horst
Affiliations:
UKSH Campus Kiel,Kiel,Germany
,
Christian Recher
Affiliations:
Centre Hospitalier Universitaire de Toulouse, IUCT-Oncopole, Université Paul Sabatier Toulouse III,Toulouse,France
,
Philippe Rousselot
Affiliations:
Centre Hospitalier Andre Mignot,Le Chesnay cedex,France
,
Irwindeep Sandhu
Affiliations:
University of Alberta Hospital,Edmonton,Canada
,
Koen Theunissen
Affiliations:
Jessa Ziekenhuis,Hasselt,Belgium
,
Felicitas Thol
Affiliations:
Medizinische Hochschule Hannover,Hannover,Germany
,
Konstanze Döhner
Affiliations:
University of Ulm,Ulm,Germany
,
Veronica Teleanu
Affiliations:
University of Ulm,Ulm,Germany
,
Daniel J DeAngelo
Affiliations:
Dana-Farber Cancer Institute,Boston, Massachusetts,United States
,
Tomoki Naoe
Affiliations:
National Hospital Organization Nagoya Medical Center,Nagoya,Japan
,
Mikkael A Sekeres
Affiliations:
Cleveland Clinic Taussig Cancer Institute,Cleveland, Ohio,United States
,
Valerie Belsack
Affiliations:
SCS Boehringer Ingelheim Comm.V,Brussels,Belgium
,
Miaomiao Ge
Affiliations:
Boehringer Ingelheim Corporation,Ridgefield, Connecticut,United States
,
Tillmann Taube
Affiliations:
Boehringer Ingelheim Pharma GmbH & Co. KG,Biberach,Germany
Oliver G Ottmann
Affiliations:
Goethe University,Frankfurt/Main,Germany
EHA Learning Center. Döhner H. Jun 11, 2016; 135257
Prof. Dr. Hartmut Döhner
Prof. Dr. Hartmut Döhner
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Abstract
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Abstract: S501

Type: Oral Presentation

Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15

Location: Hall A3

Background
Volasertib (V) is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting polo-like kinase. In a randomized, open label, Phase II trial in patients (pts) with previously untreated AML, ineligible for intensive therapy, V+LDAC vs LDAC improved remission rate (31% vs 13%; p=0.052), event-free survival (EFS; HR 0.57 [95% CI 0.35–0.92]) and overall survival (OS; HR 0.63 [95% CI 0.40–1.00]; Döhner et al, Blood 2014).

Aims
A Phase III trial (NCT01721876) was conducted to confirm the Phase II results.

Methods
Pts were randomized 2:1 (stratified by ECOG [0/1 vs 2] and type of AML [de novo vs secondary]) to receive LDAC (20 mg s.c. BID Days 1–10 Q4W) and either V (350 mg; 1-hr iv infusion Days 1 and 15 Q4W) or placebo (P). The primary analysis was performed after completion of recruitment (Nov 2014) and focused on efficacy in pts randomized ≥5 months before clinical cut-off. Objective response (OR; complete response [CR] + CR with incomplete hematological recovery [CRi]; blinded central review) was the primary endpoint, and OS was the key secondary endpoint. An additional OS analysis was performed in all randomized pts (Nov 2015).

Results
666 pts were treated (444 V+LDAC; 222 P+LDAC). The primary analysis included 371 pts (246 V+LDAC; 125 P+LDAC); pt characteristics were balanced: median age, 75/75 yrs; secondary AML, 47%/49%; adverse genetics, 32%/32%, respectively. The percentage of pts with OR was not statistically significantly higher with V+LDAC vs P+LDAC (25.2% vs 16.8%; Odds ratio 1.66 [95% CI 0.95–2.89; p=0.071]), and thus the primary endpoint was not met. A negative OS trend was seen for V+LDAC vs P+LDAC (median OS: 4.8 vs 6.5 mos; HR 1.26 [95% CI 0.95–1.67; p=0.113]). Adverse event severity increased with V+LDAC vs P+LDAC, with fatal infection frequency of 16.6% vs 5.1%, considered to be the main reason for the negative OS trend. Consequently, the study was unblinded, and investigators/pts could stop/continue treatment based on individual benefit-risk evaluations.
Additional exploratory analyses were conducted. The protocol allowed doses to be missed or delayed for medical reasons; this dosing flexibility resulted in differences of overall treatment intensity, and a better outcome for pts treated in the V+LDAC arm at lower-dose density vs higher-dose density was shown. Competing risk modeling of survival endpoints (events resulting from lack of efficacy or non-tolerability) confirmed the antileukemic effect of V+LDAC.
An additional OS analysis was performed on all randomized pts from a Nov 2015 snapshot. The HR for OS was 1.06 (95% CI 0.88–1.28; p=0.552); these OS results may be affected by the communication of primary analysis results, unblinding and subsequent treatment decisions.

Conclusion
This Phase III trial did not meet the primary endpoint and did not confirm the promising efficacy results from the randomized Phase II study. Pts treated with V+LDAC had higher risk for fatal infections compared with P+LDAC, resulting in a negative OS trend at the primary analysis. Pt management/medical decision making (dose density) influenced the outcome and might have been affected by the blinded trial design. Updated results one year after unblinding show largely overlapping OS for both treatment arms. Competing risk modeling of survival endpoints confirmed the antileukemic effect of V+LDAC and supports investigation of modified V doses and schedules to improve tolerability. The trial is still ongoing; updated/final results will be presented at the meeting as available.

Session topic: New Compounds in AML Treatment

Keyword(s): AML, Cytarabine, Elderly, Phase III
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