Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study

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Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study Farhad Ravandi, Ellen K Ritchie, Hamid Sayar, Jeffrey E Lancet, Michael D Craig, Norbert Vey, Stephen A Strickland, Gary J Schiller, Elias Jabbour, Harry P Erba, Arnaud Pigneux, Heinz-August Horst, Christian Recher, Virginia M Klimek, Jorge Cortes, Gail J Roboz, Olatoyosi Odenike, Xavier Thomas, Violaine Havelange, Johan Maertens, Hans-Günter Derigs, Michael Heuser, Lloyd Damon, Bayard L Powell, Gianluca Gaidano, Angelo-Michele Carella, Andrew Wei, Donna Hogge, Adam R Craig, Judith A Fox, Renee Ward, Jennifer A Smith, Gary Acton, Cyrus Mehta, Robert K Stuart, Hagop M Kantarjian

Summary Background Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia. Methods This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m² intravenously on days 1 and 4 in a first cycle; 70 mg/m² in subsequent cycles) plus cytarabine (1 g/m² intravenously on days 1–5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801. Findings Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4–8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2–7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73–1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p<0·0001). Early mortality was similar between treatment groups (30-day: 28 [8%] of 355 patients in the vosaroxin plus cytarabine group vs 23 [7%] of 350 in the placebo plus cytarabine group; 60-day: 70 [20%] vs 68 [19%]). Treatment-related deaths occurred at any time in 20 (6%) of 355 patients given vosaroxin plus cytarabine and in eight (2%) of 350 patients given placebo plus cytarabine. Treatment-related serious adverse events occurred in 116 (33%) and 58 (17%) patients in each group, respectively. Grade 3 or worse adverse events that were more frequent in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group included febrile neutropenia (167 [47%] vs 117 [33%]), neutropenia (66 [19%] vs 49 [14%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), bacteraemia (43 [12%] vs 16 [5%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%]). Interpretation Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia. Funding Sunesis Pharmaceuticals.

Introduction The prognosis for patients with relapsed or refractory acute myeloid leukaemia is poor; median survival is less than 1 year.1,2 High-dose cytarabine monotherapy or cytarabine-based combination regimens are often used as salvage therapy with limited efficacy; in a recent randomised trial, salvage chemotherapy with the

investigator’s choice of one of seven commonly used regimens (including high-dose cytarabine) produced complete remission in 12% of patients and a median survival of 3·3 months, with no significant difference between regimens.3 Toxicity is also a concern, particularly in patients older than 60 years, who constitute the majority of patients with acute myeloid leukaemia.1,4–6

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Lancet Oncol 2015 Published Online July 31, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)00201-6 See Online/Comment http://dx.doi.org/10.1016/ S1470-2045(15)00165-5 University of Texas MD Anderson Cancer Center, Houston, TX, USA (Prof F Ravandi MD, E Jabbour MD, Prof J Cortes MD, Prof H M Kantarjian MD); Weill Cornell Medical Center, New York, NY, USA (E K Ritchie MD, G J Roboz MD); Indiana University Cancer Center, Indianapolis, IN, USA (H Sayar MD); Moffitt Cancer Center, Tampa, FL, USA (J E Lancet MD); West Virginia University, Morgantown, WV, USA (M D Craig MD); Institut Paoli-Calmettes and Aix-Marseille University, Marseille, France (Prof N Vey MD); VanderbiltIngram Cancer Center, Nashville, TN, USA (S A Strickland MD); University of California, Los Angeles, CA, USA (Prof G J Schiller MD); Division of Hematology and Oncology, University of Alabama, Birmingham, AL, USA (Prof H P Erba MD); Université de Bordeaux, CHU de Bordeaux, Bordeaux, France (Prof A Pigneux MD); Medizinische Klinik und Poliklinik, University Hospital Schleswig-Holstein, Kiel, Germany (Prof H-A Horst MD); Institut Universitaire du Cancer de Toulouse Oncopole, Université de Toulouse III, CHU de Toulouse, Toulouse, France (Prof C Recher MD); Memorial Sloan-Kettering Cancer Center, New York, NY, USA (V M Klimek MD); University of

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Chicago, Chicago, IL, USA (O Odenike MD); Hôpital Edouard Herriot, Lyon, France (X Thomas MD); Cliniques Universitaires Saint-Luc, Brussels, Belgium (V Havelange MD); Universitair Ziekenhuis, Leuven, Belgium (Prof J Maertens MD); Klinikum Frankfurt Main, Frankfurt, Germany (Prof H-G Derigs MD); Hannover Medical School, Hannover, Germany (M Heuser MD); UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA (Prof L Damon MD); Wake Forest University Baptist Medical Center— Comprehensive Cancer Center, Winston-Salem, NC, USA (Prof B L Powell MD); Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy (Prof G Gaidano MD); Hematology Unit, IRCCS AOU San Martino-IST, Genova, Italy (A-M Carella MD); The Alfred Hospital and Monash University, Melbourne, VIC, Australia (A Wei MBBS); Vancouver General Hospital, Vancouver, BC, Canada (Prof D Hogge MD); Sunesis Pharmaceuticals, South San Francisco, CA, USA (A R Craig MD, J A Fox PhD, R Ward MD, J A Smith PhD, G Acton MD); Cytel, Cambridge, MA, USA (Prof C Mehta PhD); Harvard School of Public Health, Cambridge, MA, USA (Prof C Mehta); and Medical University of South Carolina, Charleston, SC, USA (R K Stuart MD) Correspondence to: Prof Farhad Ravandi, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA [email protected]

See Online for appendix

Panel: Research in context Evidence before this study There is no generally accepted standard of care for patients with relapsed or refractory acute myeloid leukaemia. The benefit of current treatment options is limited, and enrolment in a clinical trial is recommended when possible. We searched PubMed for randomised trials in patients with relapsed or refractory acute myeloid leukaemia in the decade before the initiation of the VALOR trial (Jan 1, 2000, until Dec 31, 2010) with the following search string: (“acute myeloid leukemia” or “acute myeloid leukaemia” or “AML”) AND (“relaps*” OR “refractory” OR “second-line” OR “salvage”) AND (“randomized” or “randomised”). Dose-finding trials, trials assessing transplant or maintenance therapy, and trials in populations other than patients with relapsed and/or refractory acute myeloid leukaemia were excluded. In the previous decade, none of the novel agents or regimens studied in a randomised trial in patients with relapsed or refractory acute myeloid leukaemia showed an overall survival benefit. Since the initiation of this study, three additional randomised

Vosaroxin is an anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II activity.7 By contrast with traditional topoisomerase inhibitors, vosaroxin is minimally metabolised because of its stable core quinolone structure and is not associated with substantial formation of free radicals, reactive oxygen species, or toxic metabolites.7–9 Vosaroxin is not a substrate of P-glycoprotein and can induce apoptosis independent of P53.7,10 Vosaroxin and cytarabine have non-overlapping primary mechanisms of action and showed synergistic antiproliferative activity in preclinical assays.10,11 In a phase 2 study, vosaroxin plus cytarabine showed clinical activity and was well tolerated in patients with relapsed or refractory acute myeloid leukaemia; 25% of patients in this study had a complete remission and 30-day all-cause mortality was low (2·5%).12 These results lent support to the initiation of a phase 3 trial. The cytarabine dose and schedule selected was based on several factors, including the phase 2 study results, regimens used in recent clinical registration studies,4 results from ex-vivo studies,13 and published clinical studies14–17 suggesting that intermediate-dose cytarabine might provide similar clinical benefit with lower toxicity than high-dose cytarabine. The phase 3 VALOR study was designed to assess whether the addition of vosaroxin to cytarabine confers a survival benefit in patients with relapsed or refractory acute myeloid leukaemia, compared with cytarabine alone.

Methods Study design and participants This phase 3, randomised, double-blind, placebocontrolled trial was undertaken at 101 sites in North 2

studies in this population have shown no improvement in survival compared with controls. Added value of this study This is one of the largest studies to be done in the relapsed or refractory acute myeloid leukaemia setting. There is a suggestion of clinical benefit with the addition of vosaroxin to cytarabine in this population with some evidence of an effect in patients aged 60 years or older, a population with limited treatment options. Implications of all the available evidence Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients. Our data suggest that this combination could be a treatment option for salvage therapy in patients aged 60 years or older.

America, Europe, South Korea, Australia, and New Zealand (a complete list of study sites is provided in the appendix pp 1–2). The study protocol was approved by an ethics review board at each participating institution. The study was done in accordance with the Declaration of Helsinki. Written informed consent was provided by all patients. Eligible patients were at least 18 years of age with a diagnosis of acute myeloid leukaemia, as defined by WHO criteria,18 and were in first relapse or had refractory disease. Patients with acute promyelocytic leukaemia were excluded. Relapse was defined as re-emergence of at least 5% leukaemia blasts in bone marrow or at least 1% blasts in peripheral blood 90 days to 24 months after first complete remission or complete remission with incomplete platelet recovery. Refractory acute myeloid leukaemia was defined as persistent disease at least 28 days after initiation of induction therapy, or relapse less than 90 days after first complete remission or complete remission with incomplete platelet recovery. All patients must have received previous induction therapy with an anthracycline (or anthracenedione) plus cytarabine; no more than two previous induction cycles were allowed. All patients were eligible irrespective of cytogenetic or molecular status. Additional inclusion criteria were Eastern Cooperative Oncology Group performance status of 0–2 and adequate liver (total bilirubin ≤1·5 × the upper limit of normal [ULN], aspartate aminotransferase ≤2·5 × ULN, alanine aminotransferase ≤2·5 × ULN), renal (serum creatinine ≤177 μmol/L), and cardiac (left ventricular ejection fraction ≥40%) function. Patients were excluded if they had received cytarabinecontaining treatment at a total dose of 5 g/m² or more within 90 days of randomisation, because reinduction

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with cytarabine within 90 days was deemed unlikely to be successful. Other treatments for acute myeloid leukaemia were not allowed while the patient was receiving study drugs. Other exclusion criteria were: treatment with an investigational agent within 14 days prior to randomisation; hydroxyurea or medications to reduce blast count within 24 h prior to randomisation; allogeneic or autologous stem-cell transplant for acute myeloid leukaemia within 90 days prior to randomisation; active immunosuppressive therapy for graft-versus-host disease (GVHD) or GVHD prophylaxis within 2 weeks prior to randomisation; known or suspected central nervous system involvement of active acute myeloid leukaemia; any active or non-active cancers other than non-melanoma skin cancer or cervical intraepithelial neoplasia (including other haematological cancers) within 12 months before randomisation; any uncontrolled active infections or infestations; history of myocardial infarction, unstable angina, cerebrovascular accident, or transient ischaemic attack within 3 months before randomisation.

Randomisation and masking Patients were assigned to a treatment group in a 1:1 ratio through a central interactive voice system with a permuted block randomisation procedure. Randomisation was stratified by disease status (refractory, first relapse at ≥90 days and <12 months, or first relapse at ≥12 months and ≤24 months), age (<60 years or ≥60 years), and geographical location (US sites or nonUS sites). The study sponsor and all participants were masked to treatment group assignment; only the data and safety monitoring board and independent statistics provider had access to unblinded data in a controlled and restricted manner during the study. Placebo injection was identical to vosaroxin injection in colour and appearance. Treatment assignments remained blinded until follow-up was completed for the final analysis. The effectiveness of the blinding was not formally assessed.

Procedures Patients were randomly assigned to receive vosaroxin (90 mg/m² in cycle 1 and 70 mg/m² in subsequent cycles by short [within 10 min] intravenous infusion on days 1 and 4) or placebo in combination with cytarabine (1 g/m², 2-h infusion on days 1–5; see appendix p 5,6 for schedule of treatment and follow-up). A second induction cycle could be started between 14 days and 8 weeks after initiation of cycle 1, at the discretion of the investigator, in patients with residual leukaemia upon bone marrow assessment during initial induction, provided all drugrelated toxic effects had resolved to grade 1 or lower. Up to two additional cycles could be given as consolidation therapy in patients who achieved complete remission or complete remission with incomplete platelet recovery within 12 weeks after therapy initiation, at the discretion of the investigator. Growth factor support or transfusions, or both, were allowed according to institutional

guidelines. Dose reductions were not allowed. Criteria for treatment discontinuation were failure to achieve a complete remission, complete remission with incomplete platelet recovery, or complete remission with incomplete platelet or neutrophil recovery after two induction cycles; disease relapse after a complete remission, complete remission with incomplete platelet recovery, or complete response with incomplete platelet or neutrophil recovery; clinically significant neutropenia or thrombocytopenia, or treatment-related non-haematological adverse event in the absence of residual leukaemia that did not recover to grade 2 or lower within 12 weeks or 8 weeks, respectively, after the first dose of vosaroxin or placebo in any cycle; or any unacceptable or intolerable adverse event. Results of cytogenetic and molecular marker assessments were collected if available at screening, but were not required. Complete blood counts were obtained at least weekly to monitor haematological recovery. Bone marrow biopsy or aspirate was obtained at screening, at around day 15 during induction, and at haematological recovery (to absolute neutrophil count >1000 cells per μL) or by day 57 of induction cycles for response assessment. Safety, including documentation of adverse events, was assessed at every visit; severity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0).

Outcomes Primary endpoints were overall survival and all-cause mortality at 30 and 60 days. The secondary endpoint was the proportion of patients achieving a complete remission; tertiary endpoints were the combined proportion of patients achieving complete remission, complete remission with incomplete platelet recovery, and complete remission with incomplete platelet or neutrophil recovery, the proportion of patients achieving overall remission (including the combined proportion of patients achieving complete remission, complete remission with incomplete platelet recovery, and complete remission with incomplete platelet or neutrophil recovery as well as the proportion of patients achieving a partial response), event-free survival, leukaemia-free survival, proportion of patients who underwent posttreatment allogeneic stem-cell transplantation, and safety or tolerability of the treatment. Responses were categorised based on revised International Working Group response criteria19 and were reviewed by an independent review panel who were masked to treatment assignment.

Statistical analysis This study was event driven, incorporating an innovative adaptive trial design that permitted a prespecified, onetime increase in the target number of overall survival events, to ensure adequate statistical power to detect a clinically meaningful survival benefit over a range of potential outcomes and reject the one-sided null

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hypothesis that the hazard ratio (HR) was greater than or equal to 1. Initial target accrual was 375 overall survival events in 450 patients, providing 90% power (at two-sided level α=0·05) to detect an improvement in median survival from 5 months in the placebo plus cytarabine group to 7 months in the vosaroxin plus cytarabine group (HR 0·71). A formal interim survival analysis was done by the independent statistics provider after 173 events (roughly 50% of required events) according to predefined statistical procedures stipulated and evaluated by the data and safety monitoring board. On the basis of this interim analysis, the data and safety monitoring board could recommend: study termination based on efficacy or futility; continuation as planned; or a 50% increase in planned overall survival event accrual (to 562 events), with a corresponding increase in sample size (to 675 patients). After reviewing the interim results, the data and safety monitoring board recommended the latter option. Primary efficacy analyses were done after 562 deaths with an unstratified log-rank test. A stratified log-rank test using factors at randomisation was prespecified as supportive of efficacy. Because the adaptive trial design resulted in a data-dependent increase in the total number of events, a weighted log-rank statistic was used for both unstratified and stratified tests to control type I error.20,21 The independent statistic at stage 1 (before interim analysis) was combined with its independent increment at stage 2 (post-interim analysis) with prespecified weights of √(187/375) (ie, equal to the square root of the planned proportion of events expected if there were no adaptation in design). The use of the weighted statistic ensured that the type I error α of 0·05 would be preserved notwithstanding the adaptive increase in total events. 711 patients enrolled and randomised

356 assigned to vosaroxin plus cytarabine

355 assigned to placebo plus cytarabine

4 randomly assigned but not treated

2 randomly assigned but not treated

Primary reason for treatment discontinuation 176 treatment failure/relapse 48 patient or physician decision 45 other 40 completed maximum allowed treatments 32 death 9 adverse event 2 protocol violation

Primary reason for treatment discontinuation 258 treatment failure/relapse 28 patient or physician decision 27 other 18 completed maximum allowed treatments 10 death 8 adverse event 4 protocol violation

355 included in the safety population, as treated

350 included in the safety population, as treated

Figure 1: Trial profile Three patients assigned to receive placebo plus cytarabine received vosaroxin plus cytarabine. As a result, the safety analysis population includes 355 patients in the vosaroxin plus cytarabine group and 350 patients in the placebo plus cytarabine group.

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Additional log-rank tests were done within each stratum defined at randomisation. Kaplan-Meier methods and Cox proportional hazard modelling were used to analyse the time-to-event endpoints, both overall and within subsets of patients defined by randomisation strata. All reported p values are two sided. Although p values are provided for subgroup analyses and assessment of differences in treatment effect by subgroup, the study was not powered for these comparisons. All analyses were done with SAS version 9.3. Overall survival was defined as the time between randomisation and death; surviving patients were censored from the overall survival analysis at the cutoff date or the last date known to be alive, whichever occurred first. In the primary analysis of overall survival, patients were not censored for administration of subsequent non-protocol acute myeloid leukaemia therapy, including transplantation. A preplanned sensitivity analysis was done for overall survival in which patients were censored at the start of a transplant conditioning regimen; patients with subsequent non-transplant acute myeloid leukaemia therapy were not censored. Event-free survival was defined as the time from randomisation to treatment failure, relapse, or death from any cause. Leukaemia-free survival was defined as the time from complete remission to relapse or death from any cause. All-cause mortality and the proportion of patients who achieved remission were calculated for each treatment group and corresponding 95% CIs were calculated with the Clopper-Pearson method. All-cause mortality and the proportion of patients who achieved a remission were compared between treatment groups by use of a χ² test and by Cochran-Mantel-Haenszel tests stratified by factors used at randomisation, and corresponding 95% CIs were calculated with the normal approximation to the binomial distribution. The intention-to-treat population consisted of all randomised patients, and was used for the analysis of efficacy endpoints. The safety population consisted of all patients who received any amount of study drug. This study is registered with ClinicalTrials.gov, number NCT01191801.

Role of the funding source The study sponsor was involved in the trial design, was responsible for data management and analysis, and was involved in the interpretation of the data and the writing of the report. FR, NV, GJS, HPE, ARC, JAF, RW, JAS, GA, CM, and RKS had full access to the data. The corresponding author had final responsibility for the decision to submit for publication.

Results Between Dec 17, 2010, and Sept 25, 2013, 711 patients were enrolled and randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355; figure 1). All 711 randomised patients were included in

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the efficacy analysis. 705 patients received any study drug (vosaroxin plus cytarabine, n=355; placebo plus cytarabine, n=350) and were included in the safety Vosaroxin plus cytarabine (n=356)

Placebo plus cytarabine (n=355)

Sex Male

202 (57%)

192 (54%)

Female

154 (43%)

163 (46%)

Age (years)

64 (20–80)

63 (18–82)

Age subgroup (years)*

analysis. Table 1 shows baseline characteristics of enrolled participants, which were similar between both groups. Nearly all patients (705 [99%] of 711) received a first induction cycle; 148 (21%) of 705 patients received a second induction cycle (70 [20%] of 355 in the vosaroxin plus cytarabine group vs 78 [22%] of 350 in the placebo plus cytarabine group). 97 (27%) of 355 patients given vosaroxin plus cytarabine and 50 (14%) of 350 given placebo plus cytarabine received at least one consolidation cycle; 45 (13%) and 22 (6%) patients, respectively, received two consolidation cycles. Discontinuation before maximum allowed treatment was mainly attributed to treatment failure (n=434), patient or physician decision

<60

130 (37%)

130 (37%)

≥60

226 (63%)

225 (63%)

Early relapse†

127 (36%)

129 (36%)

Late relapse‡

77 (22%)

77 (22%)

A

152 (43%)

149 (42%)

100

Disease status*

Refractory

Patients censored (%) Median (95% Cl) Vosaroxin plus cytarabine Placebo plus cytarabine HR p=0·061 (unstratified log-rank) p=0·024 (stratified log-rank)

Region* 161 (45%)

159 (45%)

Outside USA

195 (55%)

196 (55%)

White

253 (71%)

242 (68%)

Black

21 (6%)

11 (3%)

Asian

20 (6%)

18 (5%)

Other

4 (1%)

7 (2%)

Multiple

0

3 (1%)

Race§

75 Overall survival (%)

USA

23·6 7·5 (6·4–8·5) 18·3 6·1 (5·2–7·1) 0·87 (95% CI 0·73–1·02) Vosaroxin plus cytarabine Censored Placebo plus cytarabine Censored

50

25

Type of AML¶ AML not otherwise specified

188 (53%)

180 (51%)

AML with myelodysplasia-related changes

103 (29%)

93 (26%)

AML with recurrent genetic abnormalities

54 (15%)

71 (20%)

Myeloid sarcoma

2 (1%)

1 (<1%)

Therapy-related myeloid neoplasm

9 (3%)

0 0 Number at risk Vosaroxin plus 356 cytarabine Placebo plus 355 cytarabine

10 (3%) 143 (41%)

1

158 (44%)

162 (46%)

2

40 (11%)

48 (14%)

Cytogenetic risk** Favourable

7 (3%)

9 (4%)

Intermediate

175 (73%)

155 (65%)

Unfavourable

58 (24%)

75 (31%)

1

274 (77%)

259 (73%)

2

82 (23%)

95 (27%)

Number of previous induction cycles

>2

0

24

30

36

42

48

206

117

60

35

18

4

1

0

179

98

56

32

13

2

0

0

Patients censored (%) Median (95% Cl) Vosaroxin plus cytarabine Placebo plus cytarabine HR p=0·024 (unstratified log-rank) p=0·027 (stratified log-rank)

75

39·3 6·7 (5·4–8·1) 33·5 5·3 (4·4–6·3) 0·81 (95% CI 0·67–0·97)

50

25

1 (<1%)

Data are n (%) or median (range). AML=acute myeloid leukaemia. ECOG PS=Eastern Cooperative Oncology Group performance status. *Preplanned randomisation strata. †First complete remission duration of 90 days to 12 months. ‡First complete remission duration of 12 months to 24 months. §Race not reported in 132 patients. ¶Per WHO 2008 criteria.18 ||ECOG PS score only available for 354 patients in the vosaroxin plus cytarabine group and 353 patients in the placebo plus cytarabine group. **Per National Comprehensive Cancer Network Treatment Guidelines, AML, 2014; cytogenetic risk only available for 240 patients in the vosaroxin plus cytarabine group, and 239 patients in the placebo plus cytarabine group.

Table 1: Baseline characteristics

18

100

Overall survival (%)

156 (44%)

12

B

ECOG PS|| 0

6

0 0

6

12

18

24

30

36

42

48

Time (months) Number at risk Vosaroxin plus 356 cytarabine Placebo plus 355 cytarabine

121

52

18

8

3

1

0

0

95

37

17

6

2

0

0

0

Figure 2: Overall survival in the intention-to-treat population and censored for subsequent allogeneic stem-cell transplantation (A) All patients (n=711). (B) Censored for allogeneic stem-cell transplantation (n=711). HR=hazard ratio.

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(n=76), death (n=42), or adverse events (n=17; figure 1). At the time of this analysis, the median duration of follow-up was 24·4 months (IQR 16·2–30·4), as estimated by the reverse Kaplan-Meier method. Median overall survival was 7·5 months (95% CI 6·4–8·5) in the vosaroxin plus cytarabine group compared with 6·1 months (5·2–7·1) in the placebo plus cytarabine group (HR 0·87, 95% CI 0·73–1·02; unstratified log-rank p=0·061; figure 2). In a predefined secondary analysis that stratified by factors used in randomisation, overall survival was significantly longer in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (stratified log-rank p=0·024). Additionally, in a predefined analysis censoring for subsequent allogeneic stem-cell transplantation, A 100

Patients censored (%) Median (95% Cl) Vosaroxin plus cytarabine Placebo plus cytarabine HR p=0·0030 (log-rank)

Overall survival (%)

75

19·9 7·1 (5·8–8·1) 10·7 5·0 (3·8–6·4) 0·75 (95% CI 0·62–0·92) Vosaroxin plus cytarabine Censored Placebo plus cytarabine Censored

50

25

0 0 Number at risk Vosaroxin plus 226 cytarabine Placebo plus 225 cytarabine

6

12

18

24

30

36

42

48

127

69

33

18

9

2

0

0

99

47

24

11

5

1

0

0

B 100

Patients censored (%) Median (95% Cl) Vosaroxin plus cytarabine Placebo plus cytarabine HR p=0·60 (log-rank)

Overall survival (%)

75

30·0 9·1 (6·2–11·6) 31·5 7·9 (6·1–12·2) 1·08 (95% CI 0·81–1·44)

50

25

0 0

6

12

18

24

30

36

42

48

Time (months) Number at risk Vosaroxin plus 130 cytarabine Placebo plus 130 cytarabine

79

48

27

17

9

2

1

0

80

51

32

21

8

1

0

0

Figure 3: Overall survival by age (A) Patients aged 60 years or older (n=451). (B) Patients younger than 60 years (n=260). HR=hazard ratio.

6

overall survival was better in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (median 6·7 months vs 5·3 months; HR 0·81, 0·67–0·97; log-rank p=0·024; stratified log-rank p=0·027; figure 2); longer overall survival in the vosaroxin plus cytarabine group was also noted in a post-hoc analysis that treated transplant as a competing risk (Fine and Gray analysis; appendix p 5,7). Overall, 210 (30%) of 711 patients underwent allogeneic stem-cell transplantation after the study. Transplantations were similar between treatment groups (107 [30%] of 356 in the vosaroxin plus cytarabine group vs 103 [29%] of 355 in the placebo plus cytarabine group), but markedly higher in younger patients (119 [46%] of 260 aged <60 years vs 91 [20%] of 451 aged ≥60 years). Median time to transplantation was similar between treatment groups (3·3 months [95% CI 3·0–4·0] in the vosaroxin plus cytarabine group vs 3·1 months [2·8–3·5] in the placebo plus cytarabine group). Any subsequent non-protocol acute myeloid leukaemia therapy (including transplant) was given to 488 (69%) of 711 patients (208 [80%] of 260 aged <60 years vs 280 [62%] of 451 aged ≥60 years; appendix p 3). Prespecified subgroup analyses according to randomisation strata showed that the difference in overall survival between the vosaroxin plus cytarabine group and the placebo plus cytarabine group was greatest in patients aged 60 years or older (7·1 months vs 5·0 months; HR 0·75, 95% CI 0·62–0·92; log-rank p=0·0030; figure 3) and in those with early relapse (6·7 months vs 5·2 months; HR 0·77, 0·59–1·00; logrank p=0·039; figure 4). Overall survival was not significantly different between treatment groups in patients younger than 60 years (HR 1·08, 0·81–1·44; logrank p=0·60; figure 3), nor in patients with late relapse (HR 0·98, 0·66–1·46; p=0·96) or refractory disease (HR 0·87, 0·68–1·11; p=0·23; figure 4). Figure 5 shows HRs for overall survival by subgroup. The p value for the difference in treatment effect by age group (≥60 years vs <60 years) was pinteraction=0·050; however, the study was not powered to detect differences in treatment effect by subgroup. In post-hoc, exploratory analyses, overall survival benefit was seen in patients with unfavourable cytogenetic risk and FLT3 mutations (appendix p 3). Complete remission was achieved in 107 (30%) of 356 patients assigned to vosaroxin plus cytarabine compared with 58 (16%) of 355 patients assigned to placebo plus cytarabine (p<0·0001; table 2). Overall remission was achieved by 135 (38%) of 356 patients in the vosaroxin group compared with 67 (19%) of 355 in the placebo plus cytarabine group (a difference of 19·0%, 95% CI 12·6–25·5; p<0·0001). Prespecified subgroup analyses showed a significantly greater response rate in patients treated with vosaroxin plus cytarabine than in those treated with placebo plus cytarabine across all randomisation strata apart from in patients younger than 60 years (table 2), with the most pronounced difference

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Articles

A 100

Patients censored (%) Median (95% Cl) Vosaroxin plus cytarabine Placebo plus cytarabine HR p=0·039 (log-rank)

Overall survival (%)

75

19·7 6·7 (4·6–8·7) 12·4 5·2 (3·8–6·6) 0·77 (95% CI 0·59–1·00) Vosaroxin plus cytarabine Censored Placebo plus cytarabine Censored

50

25

0 0 Number at risk Vosaroxin plus 127 cytarabine Placebo plus 129 cytarabine

6

12

18

24

30

36

42

48

70

41

18

12

5

1

0

0

59

27

11

6

3

0

0

0

B 100

Patients censored (%) Median (95% Cl) Vosaroxin plus cytarabine Placebo plus cytarabine HR p=0·96 (log-rank)

Overall survival (%)

75

36·4 14·1 (7·9–22·6) 33·8 12·3 (9·1–18·4) 0·98 (95% CI 0·66–1·46)

50

25

0 0 Number at risk Vosaroxin plus 77 cytarabine Placebo plus 77 cytarabine

6

12

18

24

30

36

42

48

56

37

25

12

7

2

1

0

57

38

24

14

7

2

0

0

C 100

Patients censored (%) Median (95% Cl) Vosaroxin plus cytarabine Placebo plus cytarabine HR p=0·23 (log-rank)

75 Overall survival (%)

between treatment groups in patients aged 60 years or older (complete remission: 72 [32%] of 226 in the vosaroxin plus cytarabine group vs 31 [14%] of 225 in the placebo plus cytarabine group; p<0·0001). A higher proportion of patients in the vosaroxin plus cytarabine group achieved a complete remission before transplant compared with the placebo plus cytarabine group (51 [48%] of 107 in the vosaroxin plus cytarabine group vs 33 [32%] of 103 in the placebo plus cytarabine group). In patients who had a complete remission, median leukaemia-free survival was 11·0 months (95% CI 8·3–NE) in the vosaroxin plus cytarabine group compared with 8·7 months (6·5–18·0) in the placebo plus cytarabine group (HR 0·89, 95% CI 0·57–1·40; logrank p=0·63). Event-free survival was significantly longer for patients assigned to vosaroxin plus cytarabine than for those assigned to placebo plus cytarabine (1·9 months [95% CI 1·6–2·2] vs 1·3 months [1·2–1·4]; HR 0·67, 0·57–0·79; log-rank p<0.0001). Neither 30-day all-cause mortality (28 [8%] of 355 in the vosaroxin plus cytarabine group vs 23 [7%] of 350 in the placebo plus cytarabine group) nor 60-day all-cause mortality (70 [20%] in the vosaroxin plus cytarabine group vs 68 [19%] in the placebo plus cytarabine group) differed between treatment groups. Grade 3 and higher adverse events were mainly related to myelosuppression, infection, and gastrointestinal events (table 3). Use of granulocyte colony-stimulating factor was more frequent in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (145 [41%] vs 77 [22%]). Importantly, there was no increase in the frequency of organ-specific toxic effects (cardiac, renal, hepatic, or pulmonary) in the vosaroxin plus cytarabine group compared with the placebo plus cytarabine group. Serious adverse events attributed to study drug were more frequent in the vosaroxin plus cytarabine group (116 [33%]) than in the placebo plus cytarabine group (58 [17%]; appendix p 4), including febrile neutropenia, infections, and gastrointestinal mucosal toxicity. At the time of analysis, deaths were recorded for 273 (77%) of 355 patients given vosaroxin plus cytarabine and 288 (82%) of 350 patients given placebo plus cytarabine. Progressive disease was the primary cause of death (180 [66%] vs 229 [80%]). Deaths attributed to serious adverse events occurred in 50 (14%) and 26 (7%) patients (deemed related to therapy by the investigator in 20 [6%] and eight [2%]) in the vosaroxin plus cytarabine and placebo plus cytarabine groups, respectively. In both treatment groups, most deaths attributed to serious adverse events occurred within 60 days (48 [96%] of 50 vs 25 [96%] of 26).

20·4 6·7 (4·2–7·8) 15·4 5·0 (3·6–6·3) 0·87 (95% CI 0·68–1·11)

50

25

0 0

6

12

18

24

30

36

42

48

Time (months)

Figure 4: Overall survival by disease status (A) Patients with early relapse (within 12 months; n=256). (B) Patients with late relapse (12 months or later; n=154). (C) Patients with refractory disease (n=301). HR=hazard ratio.

Number at risk Vosaroxin plus 152 cytarabine Placebo plus 149 cytarabine

80

39

17

11

6

1

0

0

63

33

21

12

3

0

0

0

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Articles

Sample size

HR (95% Cl)

Heterogeneity p value

First relapse status Refractory

301 (42%)

0·87 (0·68–1·11)

90 days to 12 months

256 (36%)

0·77 (0·59–1·00)

12–24 months

154 (22%)

0·98 (0·66–1·46)

<60

260 (37%)

1·08 (0·81–1·44)

≥60

451 (63%)

0·75 (0·62–0·92)

USA

320 (45%)

0·91 (0·71–1·16)

Outside USA

391 (55%)

0·83 (0·67–1·05)

711

0·87 (0·73–1·02)

0·57

Age group (years) 0·050

Location

Overall

0·1

1·0 Favours vosaroxin plus cytarabine

0·55 NA

10·0 Favours placebo plus cytarabine

Figure 5: Subgroup analyses of overall survival The vertical dashed line indicates the hazard ratio (HR) in the overall population. NA=not applicable.

CR

Combined CR (CR/CRp/CRi)

Vosaroxin plus cytarabine, n/N (%, 95% CI)

Placebo plus cytarabine, n/N (%, 95% CI)

Difference, % (95% CI)

p value

Vosaroxin plus cytarabine, Placebo plus cytarabine, n/N (%, 95% CI) n/N (%, 95% CI)

Difference, % (95% CI)

p value

107/356 (30%, 25·3–35·1)

58/355 (16%, 12·6–20·6)

14% (7·6–19·8)

<0·0001

132/356 (37%, 32·0–42·3)

66/355 (19%, 14·7–23·0)

18% (12·0–24·9)

<0·0001

<60

35/130 (27%, 19·5–35·4)

27/130 (21%, 14·2–28·8)

6% (–4·2 to 16·5)

0·24

45/130 (35%, 26·5–43·5)

30/130 (23%, 16·1–31·3)

12% (0·6–22·5)

0·040

≥60

72/226 (32%, 25·8–38·4)

31/225 (14%, 9·6–19·0)

18% (10·5–25·6)

<0·0001

87/226 (38%, 32·1–45·2)

36/225 (16%, 11·5–21·5)

22% (14.5–30·4)

<0·0001

Early relapse*

35/127 (28%, 20·0–36·2)

16/129 (12%, 7·3–19·4)

15% (5·5–24·8)

0·0024

44/127 (35%, 26·4–43·6)

20/129 (16%, 9·7–22·9)

19% (8·8–29·5)

0·0004

Late relapse†

41/77 (53%, 41·5–64·7)

26/77 (34%, 23·4–45·4)

19% (4·1–34·8)

0·015

46/77 (60%, 47·9–70·8)

28/77 (36%, 25·7–48·1)

23% (8·0–38·7)

0·0037

Refractory

31/152 (20%, 14·3–27·7)

16/149 (11%, 6·3–16·9)

10% (1·5–17·8)

0·021

42/152 (28%, 20·7–35·5)

18/149 (12%, 7·3–18·4)

16% (6·7–24·4)

0·0007

USA

45/161 (28%, 21·2–35·6)

23/159 (14%, 9·4–20·9)

13% (4·7–22·3)

0·0032

57/161 (35%, 28·0–43·3)

27/159 (17%, 11·5–23·7)

18% (9·0–27·8)

0·0002

Outside USA

62/195 (32%, 25·3–38·8)

35/196 (18%, 12·8–23·9)

14% (5·5–22·4)

0·0014

75/195 (38%, 31·6–45·7)

39/196 (20%, 14·5–26·2)

19% (9·7–27·4)

<0·0001

Overall By age (years)

By disease status

By region

CR=complete remission. CRi=CR with incomplete recovery of platelets or neutrophils. CRp=CR with incomplete recovery of platelets. *First complete remission duration of 90 days to 12 months. †First complete remission duration of 12 months to 24 months.

Table 2: Response in all patients and predefined subgroups

Discussion Although in the primary analysis of this trial, the addition of vosaroxin to cytarabine did not significantly prolong overall survival in patients with relapsed or refractory acute myeloid leukaemia, additional preplanned analyses (stratified by randomisation factors and a sensitivity analysis censored for subsequent allogeneic stem-cell transplantation) suggest that vosaroxin plus cytarabine might provide a clinical benefit in these patients. Additionally, an effect on survival was noted for the subgroup of patients aged 60 years or older, one of the most treatment-resistant groups. 8

Several factors could underlie the difference in the treatment effect between younger and older patients, including differences in disease biology and chemosensitivity.22 In patients younger than 60 years, a survival benefit with vosaroxin might not have been detected because more of these patients had a transplantation than did older patients and the ability to effectively salvage younger patients with more aggressive subsequent therapies. In the past 40 years, little progress has been achieved in prolonging survival in patients with relapsed or refractory acute myeloid leukaemia. Median survival with current

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Articles

Vosaroxin plus cytarabine (n=355) Grades 1 or 2

Placebo plus cytarabine (n=350)

Grade 3

Grade 4

Grade 5

20 (6%)

133 (37%)

151 (43%)

50 (14%)

Grades 1 or 2

Grade 3

Grade 4

Grade 5

54 (15%)

140 (40%)

129 (37%)

26 (7%)

Any adverse event Number of patients Haematological events Febrile neutropenia

3 (1%)

163 (46%)

4 (1%)

0

3 (1%)

115 (33%)

2 (1%)

0

17 (5%)

72 (20%)

6 (2%)

0

24 (7%)

76 (22%)

5 (1%)

0

Thrombocytopenia

5 (1%)

6 (2%)

78 (22%)

0

4 (1%)

8 (2%)

79 (23%)

0

Neutropenia

4 (1%)

9 (3%)

57 (16%)

0

2 (1%)

5 (1%)

44 (13%)

0

Leucopenia

0

0

10 (3%)

0

2 (1%)

1 (<1%)

7 (2%)

0

Anaemia

Non-haematological events Gastrointestinal disorders Nausea

207 (58%)

11 (3%)

0

0

165 (47%)

2 (1%)

0

0

Diarrhoea

224 (63%)

19 (5%)

1 (<1%)

0

114 (33%)

7 (2%)

0

0

Constipation

136 (38%)

0

0

140 (40%)

Stomatitis

120 (34%)

6 (2%)

0

56 (16%)

Vomiting

0 48 (14%)

0 10 (3%)

1 (<1%)

0

0

0

129 (36%)

6 (2%)

0

0

72 (21%)

1 (<1%)

0

0

Abdominal pain

68 (19%)

11 (3%)

0

0

43 (12%)

3 (1%)

0

0

Dyspepsia

46 (13%)

17 (5%)

0

0

0

0

0

0

Colitis

1 (<1%)

8 (2%)

1 (<1%)

1 (<1%)

3 (1%)

1 (<1%)

0

0

Caecitis

0

1 (<1%)

0

1 (<1%)

1 (<1%)

1 (<1%)

0

0

General disorders and administration site disorders Pyrexia

104 (29%)

15 (4%)

0

0

96 (27%)

11 (3%)

0

0

Fatigue

92 (26%)

15 (4%)

0

0

87 (25%)

7 (2%)

0

0

Peripheral oedema

92 (26%)

4 (1%)

0

0

67 (19%)

2 (<1%)

0

0

Chills

58 (16%)

3 (1%)

0

0

46 (13%)

0

0

0

Asthenia

49 (14%)

11 (3%)

40 (11%)

0

0

3 (1%)

0

0

Multiorgan failure

0

1 (<1%)

1 (<1%)

1 (<1%)

0

0

0

0

Sudden death

0

0

0

1 (<1%)

0

0

0

0

Infections and infestations Pneumonia

7 (2%)

23 (6%)

3 (1%)

13 (4%)

9 (3%)

16 (5%)

1 (<1%)

9 (3%)

Sepsis

2 (1%)

8 (2%)

20 (6%)

14 (4%)

1 (<1%)

5 (1%)

7 (2%)

6 (2%)

Bacteraemia

3 (1%)

39 (11%)

4 (1%)

0

0

Device-related infection

6 (2%)

8 (2%)

0

0

6 (2%)

Cellulitis

5 (1%)

8 (2%)

1 (<1%)

1 (<1%)

Urinary tract infection

6 (2%)

1 (<1%)

0

0

14 (4%)

1 (<1%)

1 (<1%)

8 (2%)

0

0

3 (1%)

5 (1%)

0

0

6 (2%)

9 (3%)

0

0

Neutropenic sepsis

0

10 (3%)

0

0

1 (<1%)

2 (1%)

4 (1%)

1 (<1%)

Fungal pneumonia

1 (<1%)

10 (3%)

0

1 (<1%)

1 (<1%)

4 (1%)

0

0

Septic shock

0

1 (<1%)

6 (2%)

2 (1%)

0

0

3 (1%)

3 (1%)

Staphylococcal sepsis

3 (1%)

4 (1%)

0

0

1 (<1%)

7 (2%)

0

0

Bronchopulmonary aspergillosis

2 (1%)

5 (1%)

0

1 (<1%)

0

4 (1%)

1 (<1%)

0

Fungal infection

2 (1%)

3 (1%)

0

1 (<1%)

3 (1%)

4 (1%)

0

0

Escherichia bacteraemia

0

9 (3%)

0

0

0

3 (1%)

0

0

Aspergillosis

3 (1%)

2 (1%)

0

2 (1%)

1 (<1%)

1 (<1%)

0

0

Klebsiella sepsis

0

3 (1%)

0

1 (<1%)

0

0

1 (<1%)

0

Pseudomonal sepsis

0

1 (<1%)

1 (<1%)

0

0

1 (<1%)

0

1 (<1%)

Infection

0

0

0

1 (<1%)

0

2 (1%)

0

0

Pseudomonas infection

0

1 (<1%)

0

0

0

1 (<1%)

0

1 (<1%)

Systemic candida

0

0

0

1 (<1%)

0

1 (<1%)

1 (<1%)

0

Septic embolus

0

1 (<1%)

0

1 (<1%)

0

0

0

0

Appendicitis perforated

0

0

0

0

0

0

0

1 (<1%)

(Table 3 continues on next page)

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Articles

Vosaroxin plus cytarabine (n=355) Grades 1 or 2

Grade 3

Placebo plus cytarabine (n=350) Grade 4

Grade 5

Grades 1 or 2

Grade 3

Grade 4

Grade 5

(Continued fom previous page) Enterobacter sepsis

0

0

0

1 (<1%)

0

0

0

0

Fungal sepsis

0

0

0

1 (<1%)

0

0

0

0

Gastrointestinal infection

0

0

0

1 (<1%)

0

0

0

0

7 (2%)

1 (<1%)

0

12 (3%)

4 (1%)

0

0

0

81 (23%)

19 (5%)

0

52 (15%)

7 (2%)

0

0

58 (17%)

0

0

3 (1%)

0

15 (4%)

11 (3%)

0

0

Laboratory investigations Increased AST

16 (5%)

Metabolism and nutrition disorders Hypokalaemia

118 (33%)

41 (12%)

Decreased appetite

106 (30%)

20 (6%)

Hypomagnesaemia

94 (26%)

Hypophosphataemia

28 (8%)

25 (7%)

1 (<1%)

11 (3%) 0

0

2 (1%)

0

0

0

Hyperglycaemia

24 (7%)

18 (5%)

1 (<1%)

0

18 (5%)

15 (4%)

0

0

Hypocalcaemia

36 (10%)

11 (3%)

2 (1%)

0

19 (5%)

5 (1%)

1 (<1%)

0

Hyponatraemia

23 (6%)

8 (2%)

0

0

13 (4%)

8 (2%)

0

0

Musculoskeletal and connective tissue disorders Pain in extremity

33 (9%)

1 (<1%)

0

0

41 (12%)

3 (1%)

0

0

Back pain

33 (9%)

2 (1%)

0

0

36 (10%)

2 (1%)

0

0 0

Nervous system disorders Headache

101 (28%)

Dizziness

32 (9%)

Syncope

1 (<1%)

2 (1%)

0

0

90 (26%)

3 (1%)

0

0

0

0

35 (10%)

0

0

0

7 (2%)

0

0

1 (<1%)

8 (2%)

0

0

Ischaemic stroke

0

0

0

0

0

1 (<1%)

0

1 (<1%)

Coma

0

0

0

1 (<1%)

0

0

0

0

Intracranial haemorrhage

0

0

0

0

0

0

0

1 (<1%)

Psychiatric disorders Insomnia

76 (21%)

2 (1%)

0

0

68 (19%)

2 (1%)

0

0

Anxiety

41 (12%)

2 (1%)

0

0

54 (15%)

2 (1%)

0

0

Cough

68 (19%)

3 (1%)

0

0

44 (13%)

0

0

0

Epistaxis

55 (15%)

1 (<1%)

0

0

52 (15%)

6 (2%)

0

0

Respiratory, thoracic, and mediastinal disorders

Dyspnoea

51 (14%)

11 (3%)

Oropharyngeal pain

44 (12%)

2 (1%)

Hypoxia

1 (<1%)

0

36 (10%)

8 (2%)

0

0

0

0

39 (11%)

2 (1%)

0

0

11 (3%)

4 (1%)

2 (1%)

0

3 (1%)

7 (2%)

0

0

Respiratory failure

3 (1%)

3 (1%)

2 (1%)

1 (<1%)

2 (1%)

0

1 (<1%)

0

Acute respiratory distress syndrome

0

2 (1%)

1 (<1%)

0

0

0

0

1 (<1%)

Pulmonary haemorrhage

0

1 (<1%)

1 (<1%)

1 (<1%)

0

0

0

0

Skin and subcutaneous tissue disorders Rash

51 (14%)

2 (1%)

0

0

37 (11%)

0

0

0

Pruritus

41 (12%)

0

0

0

28 (8%)

0

0

0

Vascular disorders Hypotension

51 (14%)

11 (3%)

4 (1%)

0

41 (12%)

6 (2%)

Hypertension

19 (5%)

21 (6%)

0

0

20 (6%)

12 (3%)

3 (1%)

0

0

0

Shock

0

1 (<1%)

0

2 (1%)

0

0

0

0

Hypovolaemic shock

0

0

0

1 (<1%)

0

0

0

0

6 (2%)

2 (1%)

0

9 (3%)

6 (2%)

1 (<1%)

0

0

0

1 (<1%)

0

0

0

0

Cardiac disorders Atrial fibrillation Myocardial infarction

15 (4%) 0

Data are n (%). Events that occurred as any grade in at least 10% of patients in either treatment group, as grade 3–4 or worse in at least 2% of patients in either treatment group, and any grade 5 event. AST=aspartate aminotransferase.

Table 3: Treatment-emergent adverse events

10

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salvage options, including high-dose cytarabine or anthracycline-based or anthracenedione-based combination regimens, is less than 1 year, ranging from 3·3 months to 9·0 months in recent phase 2 and 3 clinical trial reports.3,4,23–27 Many investigational agents have failed to improve survival in randomised trials in this setting, despite promising early clinical data.3,4,23–26,28,29 Two of these drugs, laromustine and clofarabine, improved the proportion of patients achieving a complete remission, with complete remission of 20% and 35%, for each drug respectively, vs 16% and 18% in the control groups. However, these improvements did not translate into improved survival, in part because of the increased toxicity and subsequent higher early mortality associated with these treatments compared with the control treatment groups.4,23,24 By contrast, the efficacy results with vosaroxin and cytarabine were noted without an appreciable increase in 30-day or 60-day mortality. The proportion of patients achieving a complete remission was nearly doubled in the vosaroxin plus cytarabine group compared with the placebo plus cytarabine group, and was notably higher in the vosaroxin plus cytarabine group in all subgroups analysed apart from in patients younger than 60 years. Similar to survival, the improvement in response was most compelling in patients aged 60 years or older. Responses in both treatment groups were durable, as shown by the leukaemia-free survival data. Our finding that the addition of another cytotoxic agent to the treatment regimen did not increase early mortality lends support to the conclusion that the addition of vosaroxin to cytarabine does not increase toxicity to a point where it outweighs any effect on efficacy. Adverse events reported in this study are consistent with those in previous studies of vosaroxin, including myelosuppression and gastrointestinal toxic effects. Neutropenia, neutropenic fever, and infection were more common in the vosaroxin group, as would be expected with the addition of a second cytotoxic agent. More frequent use of growth factors in patients given vosaroxin plus cytarabine was in line with the higher frequency of neutropenia in this group, and is not expected to affect efficacy outcomes.30 Although the number of deaths within 60 days was not increased, the number of deaths within 60 days because of adverse events, mainly infection, was higher in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group. Careful management of infections is crucial. Stomatitis was also more common in the vosaroxin group, as expected from phase 1 and 2 trials. Oral mucositis typically resolves within a few weeks of therapy and is thus unlikely to delay transplantation; however, it should also be managed attentively. Significantly increased cardiac, renal, neurological, and hepatic adverse events in the vosaroxin plus cytarabine group were not reported. Despite a significantly higher proportion of patients achieving a complete remission in patients assigned to

vosaroxin plus cytarabine than in those assigned to placebo plus cytarabine, the proportion of patients who had transplantations was similar in each treatment group. This finding probably reflects a shift in treatment practice during the past decade. Because of several factors, such as increased donor availability and improved conditioning regimens, transplant is being recommended to a higher proportion of patients with relapsed or refractory acute myeloid leukaemia, including patients who have not achieved a conventional complete remission. Among transplanted patients in our study, a higher proportion achieved a complete remission with vosaroxin plus cytarabine before transplant than did those assigned to placebo plus cytarabine; however, a substantial number of patients were transplanted either without remission, or after achieving remission with subsequent non-protocol therapy. Our study represents one of the largest datasets available in the relapsed or refractory acute myeloid leukaemia setting. Although there was no significant difference in the primary endpoint between groups, a prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia. The toxicity reported with the addition of vosaroxin is acceptable in view of the benefit conferred. Our findings suggest that this combination could be a treatment option for salvage therapy in patients aged 60 years or older. Contributors FR, NV, GJS, HPE, ARC, JAF, RW, JAS, GA, CM, RKS, and HMK contributed to the study design. FR, EKR, HS, JEL, MDC, NV, SAS, GJS, EJ, HPE, AP, H-AH, CR, VMK, JC, GJR, OO, XT, VH, JM, H-GD, MH, LD, BLP, GG, A-MC, AW, DH, RKS, and HMK contributed to data collection. ARC, JAF, RW, JAS, GA, and CM contributed to data analysis. All authors contributed to the interpretation of the data and all authors critically reviewed the manuscript and approved the final version for submission. Declaration of interests FR reports grants and personal fees from Sunesis during the conduct of the study; grants from Sunesis outside the submitted work. NV reports personal fees from Sunesis during the conduct of the study. SAS and AW report personal fees from Sunesis Pharmaceuticals outside the submitted work. HPE reports grants and personal fees from Sunesis during the conduct of the study; personal fees from Novartis, personal fees from Incyte, personal fees from Celgene, grants from Millennium, grants and personal fees from Seattle Genetics, grants from Celator, grants from Amgen, grants from Astellas, personal fees from Ariad, outside the submitted work. H-AH reports reports grants from Sunesis during the conduct of the study; grants from Amgen, grants from Boehringer, outside the submitted work. CR reports other support from Sunesis during the conduct of the study; grants from Amgen, grants from Chugai, grants and other support from Celgene, outside the submitted work. VMK and GJR report other support from Sunesis during the conduct of the study; other support from Sunesis outside the submitted work. JC reports grants from Celator, grants and personal fees from Novartis, grants from Arog, grants from Ambit, grants and personal fees from Astellas, outside the submitted work. OO reports grants from Sunesis Pharmaceuticals during the conduct of the study; personal fees from Sunesis Pharmaceuticals, personal fees from Algeta Pharamceuticals, personal fees from Spectrum Pharamceuticals, grants from Astex, grants from MEI Pharma, grants from Topotarget, grants

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from Lily, grants from Celgene, outside the submitted work. MH and RKS report grants and personal fees from Sunesis during the conduct of the study. LD reports other support from Sunesis during the conduct of the study; other support from Celator, other support from Maxygen, outside the submitted work. GG reports personal fees from Novartis, personal fees from GlaxoSmithKline, personal fees from Janssen, personal fees from Roche, personal fees from Celgene, personal fees from Amgen, outside the submitted work. ARC reports personal fees from Sunesis Pharmaceuticals during the conduct of the study; personal fees and other support from Sunesis Pharmaceuticals, outside the submitted work. CM is an employee of Cytel Inc and receives no remuneration other than his Cytel salary; he declares no other competing interests. JAF, RW, JAS, and GA report personal fees from Sunesis, during the conduct of the study; personal fees from Sunesis, outside the submitted work. EKR, HS, JEL, MDC, GJS, EJ, AP, XT, VH, JM, H-GD, BLP, A-MC, DH, and HMK declare no competing interests. Acknowledgments This study was funded by Sunesis Pharmaceuticals. We acknowledge Shuling Hwang and Feng Zhou, contracted by Sunesis Pharmaceuticals (South San Francisco, CA USA), for statistical programming. Medical writing assistance was provided by Janis Leonoudakis, of Powered 4 Significance, and was funded by Sunesis Pharmaceuticals. References 1 Breems DA, Van Putten WL, Huijgens PC, et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol 2005; 23: 1969–78. 2 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: acute myeloid leukemia. Version 1. 2015. http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf (accessed April 6, 2015). 3 Roboz GJ, Rosenblat T, Arellano M, et al. International randomized phase III study of elacytarabine versus investigator choice in patients with relapsed/refractory acute myeloid leukemia. J Clin Oncol 2014; 32: 1919–26. 4 Faderl S, Wetzler M, Rizzieri D, et al. Clofarabine plus cytarabine compared with cytarabine alone in older patients with relapsed or refractory acute myelogenous leukemia: results from the CLASSIC I Trial. J Clin Oncol 2012; 30: 2492–99. 5 Ferrara F, Palmieri S, Mele G. Prognostic factors and therapeutic options for relapsed or refractory acute myeloid leukemia. Haematologica 2004; 89: 998–1008. 6 Juliusson G, Antunovic P, Derolf A, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 2009; 113: 4179–87. 7 Hawtin RE, Stockett DE, Byl JA, et al. Voreloxin is an anticancer quinolone derivative that intercalates DNA and poisons topoisomerase II. PLoS One 2010; 5: e10186. 8 Evanchik MJ, Allen D, Yoburn JC, et al. Metabolism of (+)-1,4-dihydro-7-(trans-3-methoxy-4-methylamino-1-pyrrolidinyl)-4oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid (voreloxin; formerly SNS-595), a novel replication-dependent DNA-damaging agent. Drug Metab Dispos 2009; 37: 594–601. 9 Mjos KD, Cawthray JF, Jamieson G, et al. Iron(III)-binding of the anticancer agents doxorubicin and vosaroxin. Dalton Trans 2015; 44: 2348–58. 10 Walsby EJ, Coles SJ, Knapper S, et al. The topoisomerase II inhibitor voreloxin causes cell cycle arrest and apoptosis in myeloid leukemia cells and acts in synergy with cytarabine. Haematologica 2011; 96: 393–99. 11 Scatena CD, Kumer JL, Arbitrario JP, et al. Voreloxin, a first-in-class anticancer quinolone derivative, acts synergistically with cytarabine in vitro and induces bone marrow aplasia in vivo. Cancer Chemother Pharmacol 2010; 66: 881–88. 12 Lancet JE, Roboz GJ, Cripe LD, et al. A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia. Haematologica 2015; 100: 231–37. 13 Plunkett W, Liliemark JO, Adams TM, et al. Saturation of 1-beta-Darabinofuranosylcytosine 5’-triphosphate accumulation in leukemia cells during high-dose 1-beta-D-arabinofuranosylcytosine therapy. Cancer Res 1987; 47: 3005–11.

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