Abstract
Background
This Phase II study evaluated the efficacy, safety and tolerability of the Aurora B kinase inhibitor barasertib, compared with low-dose cytosine arabinoside (LDAC), in patients aged ≥60 years with acute myeloid leukemia (AML).
Methods
Patients were randomized 2:1 to open-label barasertib 1200 mg (7-day iv infusion) or LDAC 20 mg (sc twice-daily for 10 days) in 28-day cycles. The primary endpoint was objective complete response rate (OCRR: CR + CRi [Cheson criteria, additionally requiring CRi reconfirmation ≥21 days after first appearance and associated with partial recovery of platelets and neutrophils]). Secondary endpoints included overall survival (OS) and safety.
Results
74 patients (barasertib, n=48; LDAC, n=26) completed ≥1 cycle. A significant improvement in OCRR was observed with barasertib (35.4% vs 11.5%; difference, 23.9% [95% CI, 2.7–39.9]; P<0.05). Although not formally sized to compare OS data, the median OS with barasertib was 8.2 months versus 4.5 months with LDAC. (HR=0.88, 95% CI, 0.49-1.58; P=0.663;). Stomatitis and febrile neutropenia were the most common adverse events with barasertib versus LDAC (71% vs 15%; 67% vs 19%, respectively).
Conclusions
Barasertib showed a significant improvement in OCRR versus LDAC, with a more toxic but manageable safety profile that was consistent with previous studies. Clinicaltrials.gov, NCT00952588.
Introduction
Acute myeloid leukemia (AML) presents more frequently with advancing age.1,2 With standard intensive induction chemotherapy, 5-year survival rates in patients younger than 60 years approach 50%; however in older patients, prognosis remains poor.3,4 In a recent study of 446 patients aged >70 years of age who were treated with intensive cytarabine chemotherapy between 1990 and 2008, median survival did not exceed 6 months and mortality rates of ≥30% were noted at 8 weeks.5 Patient- and drug-related factors, including age, contraindications/reduced tolerability to chemotherapy, and a poor cytogenetic risk profile, account for poor survival outcomes in elderly patients with AML.3,5 To date, low dose cytosine arabinoside (LDAC) is the only agent to have demonstrated clinical benefit in randomized studies in patients aged ≥60 years with AML who are not considered fit to receive intensive induction chemotherapy,6 and improvement in survival rates among elderly patients remains an elusive treatment goal.7
Aurora kinases are a family of proteins (Aurora A, B and C) that are known to play an integral role in the regulation of mitosis and chromosomal segregation.8,9 Observed over-expression in a variety of cancers, including AML, together with evidence of a potential for oncogenic transformation with increased activity,10-15 implicate Aurora B kinase as a rational target for small molecule anticancer therapy. Barasertib is a pro-drug that rapidly undergoes phosphatase-mediated cleavage in serum to release barasertib-hQPA, a highly potent and selective inhibitor of Aurora B kinase. Preclinical evidence of efficacy with barasertib (growth inhibition and survival in AML models)16-19 also extends to the clinical setting, where preliminary anti-AML activity has been demonstrated in early-phase clinical studies.20-23
This study was designed with two stages. Here, we report findings from Stage I, to compare the efficacy, safety and tolerability of barasertib and LDAC in elderly patients with newly diagnosed AML. This would then inform the decision to proceed to Stage II, to determine the relative efficacy of barasertib alone and in combination with LDAC compared with LDAC alone.
Methods
Patients
Eligible patients were aged ≥60 years with newly diagnosed de novo or secondary AML (excluding acute promyelocytic leukemia and blast crisis of chronic myeloid leukemia), considered unsuitable for intensive induction with anthracycline-based chemotherapy, and with a World Health Organization (WHO) performance status (PS) of 0–3 (PS 3 was acceptable if solely attributable to the underlying leukemia). Patients also had to be considered likely to complete three cycles of treatment. Unsuitability for intensive chemotherapy was determined by the treating physician in discussion with the patient, and also required at least one of the following: age ≥ 75 years; adverse cytogenetics; WHO performance status > 2; organ dysfunction arising from significant co-morbidities not directly related to leukemia. Exclusion criteria included serum bilirubin >1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × ULN; serum creatinine >1.5 × ULN or 24-hour creatinine clearance ≤50 mL/min (according to Cockcroft-Gault); CNS disease due to leukemic infiltration; selected uncontrolled intercurrent illness; QTc ≥470 ms; administration of anticancer agents within the 2 weeks prior to the start of study treatment; clinically significant toxicity (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] grade >1) related to treatment with anticancer agents. All patients provided written informed consent. Administration of hydroxyurea before and up to 3 days into Cycle 1 was allowed at the discretion of the investigator. This was limited to patients with WBC ≥ 25 × 109/L; the total duration of hydroxyurea could not exceed 7 days.
Study design
This was an open-label, randomized, two-stage, Phase II study of barasertib versus LDAC (ClinicalTrials.gov identifier: NCT00952588), conducted at 46 centers across Australia, Europe, Japan, and USA. Patients were randomized 2:1 to receive open-label barasertib 1200 mg, as a 7-day continuous intravenous infusion from Day 1 until 8, or LDAC 20 mg, by subcutaneous injection twice daily for 10 days, in 28-day cycles. Unless considered inappropriate by the investigator, patients were expected to complete at least three cycles (12 weeks) of treatment. Additional cycles could be administered, at the discretion of the investigator, if the patient was considered to be deriving clinical benefit. The trial was approved by the relevant institutional ethical committees or review bodies, and was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization/Good Clinical Practice, and the AstraZeneca policy on Bioethics.24
The primary endpoint for Stage I of this study was the objective complete response rate (OCRR), defined as the proportion of patients achieving complete response (CR) and confirmed CR with incomplete recovery of neutrophils or platelets (confirmed CRi; measured according to the criteria established by the International Working Group for AML trials,25 but also requiring partial recovery of neutrophils and platelets in the absence of transfusions and with confirmation of the CRi ≥21 days after the first appearance). Secondary endpoints included duration of response (DoR), time to response, overall survival (OS), disease-free survival (DFS) in responders, and safety.
Assessments
Blood samples and bone marrow aspirates were collected at baseline and at the end of each cycle; if an aspirate could not be obtained, an optional trephine biopsy was requested. Bone marrow aspirates/biopsies and peripheral blood samples were assessed by blinded independent central review. Patients who achieved CR or confirmed CRi were followed up every 4 weeks to assess DoR.
Safety assessments were conducted throughout the study and comprised the incidence of adverse events (AEs), graded according to NCI CTCAE version 3.0 and changes in vital signs, clinical laboratory parameters, and electrocardiograms (ECGs).
Statistical analysis
The sample size for Stage I was based on the assumption that, with 75 patients, there was 80% probability of observing at least a 10% difference in OCRR, assuming that the true LDAC and barasertib OCRR rates were 18%6 and 36%, respectively.
Efficacy analyses in Stage I were performed on the modified intention-to-treat set, which included all randomized patients who commenced study treatment. Treatment differences (and 95% confidence intervals) for the primary endpoint of OCRR were calculated according to the Newcombe-Wilson method.26 Estimates of OS were obtained using log-rank testing and Kaplan-Meier analysis. Additional response and OS analyses were conducted in patients grouped according to previously established profiles of cytogenetic risk.27 Safety data were summarized descriptively.
Results
Patients
Between August 2009 and July 2010, 77 patients (median age [range], 76 [61–85] years) were randomized to barasertib (n=51) or LDAC (n=26). Three patients who were randomized to the barasertib arm did not receive study treatment due to death (n=1) or no longer meeting the eligibility criteria (n=2). At data cut-off (DCO; 27 June 2011), 69 patients had actively discontinued treatment. The reasons for active discontinuation included disease progression/no improvement (barasertib, n=19 [37%]; LDAC, n=18 [69%]), improvement of their condition (barasertib, n=10 [20%]; LDAC, n=1 [4%]), voluntary discontinuation (barasertib, n=5 [10%]; LDAC, n=4 [15%]), and AEs (barasertib, n=4 [8%]; LDAC, n=2 [8%]). The remaining five patients died without actively discontinuing treatment. At DCO, no patients remained on treatment.
Baseline demographic and clinical characteristics were generally comparable between the treatment groups (Table 1). However, differences between the barasertib and LDAC groups were observed for the proportion of patients within the age category ≥75 years (65% vs 27%), those with ‘unknown’ cytogenetics (by central analysis; 29% vs 15%, respectively), and WHO PS 3 (6% vs 15%).
Table 1. Patient demographics and baseline characteristics.
|
|
||
|---|---|---|
| Barasertib 1200 mg (n=51) | LDAC 400 mg (n=26) | |
| Median age (range), years | 76.0 (61–85) | 72.5 (62–84) |
| Age group, n (%) | ||
| ≥60–69 | 7 (14) | 9 (35) |
| ≥70–74 | 11 (22) | 10 (39) |
| ≥75 | 33 (65) | 7 (27) |
| Male/female, n | 27/24 | 18/8 |
| Race, n (%) | ||
| Caucasian | 39 (77) | 20 (77) |
| Asian | 12 (24) | 5 (19) |
| Black/African American | 0 | 1 (4) |
| WHO performance status, n (%) | ||
| 0 | 21 (41) | 8 (31) |
| 1 | 15 (29) | 10 (39) |
| 2 | 12 (24) | 4 (15) |
| 3 | 3 (6) | 4 (15) |
| AML type, n (%) | ||
| De novo | 24 (47) | 11 (42) |
| Secondary to myelodysplastic syndrome | 21 (41) | 14 (54) |
| Secondary to chemotherapy | 3 (6) | 1 (4) |
| Secondary to myeloproliferative disorder | 2 (4) | 0 |
| Secondary to chronic myelomonocytic leukemia | 1 (2) | 0 |
| Bone marrow chromosomal aberration(s)*, n (%) | ||
| Favorable | 3 (7) | 0 |
| Intermediate | 29 (71) | 15 (65) |
| Adverse | 9 (22) | 8 (35) |
| Sample not available† | 10 | 3 |
| Cytogenetics + FLT3/NPM1 mutation risk group‡, n (%) | ||
| Favorable | 4 (11) | 1 (5) |
| Intermediate | 23 (64) | 13 (59) |
| Adverse | 9 (25) | 8 (36) |
| Sample not available† | 15 | 4 |
Classified at each site
Missing samples are not included in the percentage calculations
Central analysis was performed to determine FLT3/NPM1 mutation status, and was combined with the bone marrow chromosomal aberration data classified at each site. Prognostic group stratification was based on the Medical Research Council criteria,27 but adapted to incorporate FLT3/NPM1 mutation status
Efficacy
Treatment with barasertib was associated with a significant improvement in OCRR when compared with LDAC treatment (35% [n=17/48] vs 12% [n=3/26]), which equated to a difference of 24% in favor of barasertib (95% CI, 2.7–39.9; P<0.05) (Table 2). Response to barasertib treatment was reported across all cytogenetic risk groups, including an OCRR of 33% in the nine patients with adverse cytogenetics (Table 2). In comparison, response to LDAC was confined to patients with either favorable or intermediate cytogenetic risk. Differences identified in baseline demographic and clinical characteristics between treatment arms were found to have a negligible impact on efficacy (data not shown).
Table 2. Response rates, overall and according to cytogenetic risk group.
| Overall | Cytogenetic + FLT3/NPM1 risk group* | |||||||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| Favorable/intermediate (n=41) | Adverse (n=17) | Unknown (n=16) | ||||||
|
|
||||||||
| Response, n (%) | Barasertib (n=48) | LDAC (n=26) | Barasertib (n=27) | LDAC (n=14) | Barasertib (n=9) | LDAC (n=8) | Barasertib (n=12) | LDAC (n=4) |
| OCRR | 17 (35) | 3 (12) | 10 (37) | 3 (21) | 3 (33) | 0 | 4 (33) | 0 |
| CR | 12 (25) | 1 (4) | 7 (26) | 1 (7) | 3 (33) | 0 | 2 (17) | 0 |
| Confirmed CRi | 5 (10) | 2 (8) | 3 (11) | 2 (14) | 0 | 0 | 2 (17) | 0 |
| RR [OCRR + Cheson CRi†] | 22 (46) | 4 (15) | 13 (48) | 4 (29) | 3 (33) | 0 | 6 (50) | 0 |
| No response | 26 (54)‡ | 22 (85)‡ | 14 (52) | 10 (71) | 6 (66) | 8 (100) | 6 (50) | 4 (100) |
Medical Research Council prognostic groups27
Established criteria by the International Working Group for AML trials25
Includes two patients who were not evaluable for response
CR, complete response; CRi, complete response with incomplete recovery of neutrophils or platelets; OCRR, objective complete response rate; LDAC, low dose cytosine arabinoside; RR, total response rate
Response with barasertib treatment was sustained for a median duration (range) of 82 (28–321) days. Median DoR with LDAC (three responses) could not be determined, but ranged between 30 and 85 days. Most responses were achieved within two treatment cycles (barasertib, 12 of 17; LDAC, 2 of 3), corresponding to a median time to response (range) of 59 (27–180) and 64 (63–96) days, respectively. Two patients randomized to barasertib, both with adverse cytogenetics, were ongoing in response at DCO (Figure 1).
Figure 1. Duration of response.
The median follow-up for patients who were alive at DCO was 12.9 months in the barasertib group and 13.6 months in the LDAC group. Across both treatment arms, the minimum follow-up for patients who were alive at DCO was 11.2 months. There were 34 (71%) deaths in the barasertib group compared with 18 (69%) deaths in the LDAC group. Although Stage I was not formally sized to compare OS data, the median survival of barasertib-treated patients was 8.2 months, and of LDAC-treated patients 4.5 months. This difference was not statistically significant (HR=0.88, 95% CI, 0.49–1.58; P=0.663) (Figure 2A). The OS treatment effect was broadly similar within each of the cytogenetic risk groups, although the small numbers of patients in each subgroup preclude any definitive conclusions (Figure 2B).
Figure 2. Kaplan–Meier curves of overall survival for modified intent-to-treat population (A) and by cytogenetic risk group (B).
Additional exploration of the OS results revealed that the proportion of patients who received subsequent anticancer therapy following progression was comparable between treatment groups (barasertib, n=11 [23%]; LDAC, n=7 [27%]). However, these therapies were classified as intensive in a greater proportion of LDAC-treated patients (barasertib, n=4 [8%]; LDAC, n=7 [27%]). Moreover, the three patients with the longest survival duration in the LDAC group had subsequently begun intensive anticancer therapy within 3 months of randomization. In both groups, pyrimidine analogs were the most commonly administered subsequent anticancer therapies.
Median DFS among barasertib-treated patients who achieved a response of CR or CRi was 5.6 (range, 2.0–12.5) months. Median DFS with LDAC (based on three responses) could not be determined, but ranged between 2.3 and 5.9 months.
Safety
All patients who commenced therapy within this study received at least one cycle of treatment (Figure 3). Of the cycles completed, most patients received ≥80% of the planned dose (barasertib [n=45; 94%] or LDAC [n=24; 92%]).
Figure 3. Number of treatment cycles received.
AEs (any grade; any cause) that occurred most commonly, and with higher incidence in the barasertib group versus LDAC, were stomatitis (71% vs 15%), febrile neutropenia (67% vs 19%) and diarrhea (50% vs 12%) (Table 3). The overall incidence of grade ≥3 AEs was higher in the barasertib group (n=40; 83%) compared with LDAC (n=18; 69%), with grade ≥3 febrile neutropenia (50% vs 19%), stomatitis/mucositis (29% vs 0%) and pneumonia (23% vs 8%) being reported more frequently (≥15% higher incidence) with barasertib than LDAC (Table 3). Grade ≥3 infection events (grouped) also occurred at a higher incidence (>15%) in the barasertib group compared with LDAC (40% vs 23%, respectively), with pneumonia and lobar pneumonia the most commonly reported infection event in either treatment group (barasertib, 25%; LDAC, 8%).
Table 3. Adverse events (any grade; any cause) occurring in ≥20% of patients in either arm or grade ≥3 events (any cause) occurring in ≥3 patients.
| Adverse event | Number of patients, n (%) | |||||||
|---|---|---|---|---|---|---|---|---|
| Barasertib 1200 mg(n=48) | LDAC 400 mg(n=26) | |||||||
| All grades | Grade 3 | Grade 4 | Grade 5 | All grades | Grade 3 | Grade 4 | Grade 5 | |
| Stomatitis/mucositis | 37 (77) | 14 (29) | – | – | 6 (23) | – | – | – |
| Febrile neutropenia | 32 (67) | 23 (48) | 1 (2) | – | 6 (23) | 5 (19) | – | – |
| Diarrhea | 24 (50) | 2 (4) | – | – | 3 (12) | – | – | – |
| Constipation | 22 (46) | – | – | – | 8 (31) | – | – | – |
| Nausea | 21 (44) | 1 (2) | – | – | 10 (39) | – | – | – |
| Vomiting | 16 (33) | – | – | – | 5 (19) | – | – | – |
| Pyrexia | 13 (27) | – | – | – | 8 (31) | – | – | – |
| Pneumonia/lobar pneumonia | 12 (25) | 7 (15)* | – | 4 (8) | 2 (8) | 1 (4)* | – | 1 (4) |
| Alopecia | 11 (23) | – | – | – | 0 | – | – | – |
| Epistaxis | 11 (23) | – | – | – | 6 (23) | – | – | – |
| Anemia | 10 (21) | 1 (2) | 6 (13) | – | 4 (15) | 4 (15) | – | – |
| Decreased appetite | 10 (21) | – | – | – | 5 (19) | – | – | – |
| Insomnia | 10 (21) | – | – | – | 3 (12) | – | – | – |
| Rash | 10 (21) | – | – | – | 2 (8) | – | – | – |
| Fatigue | 9 (19) | – | – | – | 6 (23) | – | – | – |
| Thrombocytopenia | 9 (19) | 1 (2) | 6 (13) | – | 5 (19) | – | 4 (15) | – |
| Back pain | 8 (17) | – | – | – | 2 (8) | – | – | – |
| Dyspnea | 8 (17) | 1 (2) | – | – | 5 (19) | 3 (12) | 1 (4) | – |
| Hypokalemia | 8 (17) | – | – | – | 2 (8) | – | – | – |
| Asthenia | 7 (15) | – | – | – | 8 (31) | – | – | – |
| Neutropenia | 7 (15) | 4 (8) | 3 (6) | – | 2 (8) | – | 2 (8) | – |
| Edema peripheral | 7 (15) | – | – | – | 7 (27) | – | – | – |
| Leukopenia | 6 (13) | 1 (2) | 5 (10) | – | – | – | – | – |
| Cellulitis | 4 (8) | 4 (8) | – | – | – | – | – | – |
| Lymphopenia | 4 (8) | 1 (2) | 3 (6) | – | – | – | – | – |
| Sepsis | 4 (8) | 3 (6) | 1 (2) | – | – | – | – | 1 (4) |
| Hyponatremia | 3 (6) | 3 (6) | – | – | 1 (4) | 1 (4) | – | – |
Classified as pneumonia only. Stomatitis/mucositis includes oral pain, oropharyngeal pain, mouth ulceration, tongue ulceration, gingivitis, and aphthous stomatitis. Febrile neutropenia includes neutropenic infection, febrile bone marrow aplasia, and neutropenic sepsis
Serious AEs (SAEs) were reported in 23 (48%) barasertib- and 10 (39%) LDAC-treated patients. In the barasertib group, SAEs observed in >1 patient were pneumonia (including lobar pneumonia; n=6; 13%), febrile neutropenia (n=5; 10%), pyrexia (n=4; 8%), stomatitis (n=3; 6%), and neutropenia (n=2; 4%); for the LDAC group, the only SAE to be reported in >1 patient was pneumonia (n=2; 8%). AEs led to dosing modifications in five patients overall (barasertib, n=3; LDAC, n=2). In two patients (both in the barasertib group), stomatitis (n=1) and stomatitis and febrile neutropenia (n=1) resolved with a reduction in dose. Interruption of dosing due to AEs was noted for one patient in the barasertib arm (grade 2 extravasation) and two patients in the LDAC arm (n=1, chills and hypoxia events; n=1, pharyngitis); effective resolution of the event was reported for the barasertib-treated patient only. Four (8.3%) patients discontinued barasertib treatment due to AEs of infective arthritis, febrile neutropenia, neutropenia, and renal failure; two (7.7%) patients treated with LDAC discontinued due to pneumonia. The events of febrile neutropenia, neutropenia and renal failure were considered by the investigator to be related to treatment.
Deaths that occurred as a consequence of AEs were reported for six (13%) patients in the barasertib arm (pneumonia and lobar pneumonia [previously reported as SAEs], n=4; pulmonary mycosis, n=1; acute renal failure, n=1) and three (12%) patients in the LDAC arm (pneumonia and lobar pneumonia [previously reported as a SAE]; Clostridium difficile sepsis; sepsis; all n=1); none of these events were judged treatment related, with the exception of sepsis which was deemed to be related to LDAC treatment. Further, mortality rates for each treatment group were evaluated by 30-day intervals (Table 4). At 30 days from the start of treatment, mortality rates were similar between treatment groups whereas, at 60 and 90 days, these were numerically lower in the barasertib group.
Table 4. Summary of mortality rates.
| Patients, n (%) | ||
|---|---|---|
|
|
||
| Deaths by 30-day increments from start of treatment, n (%) | Barasertib 1200 mg (n=48) | LDAC 400 mg (n=26) |
| 30 | 6 (13) | 4 (15) |
| 60 | 9 (19) | 7 (27) |
| 90 | 13 (27) | 10 (39) |
There were no clinically significant changes in clinical laboratory parameters pertaining to liver or renal function or vital signs following treatment with either barasertib or LDAC.
Discussion
This is the first study to investigate barasertib versus a standard of care in AML. The first stage of this open-label, randomized study met its primary endpoint, demonstrating a significant and apparently durable improvement in OCRR with barasertib compared with LDAC in patients aged >60 years with newly diagnosed AML considered unfit for intensive chemotherapy. The magnitude of response observed in this study was up to two-fold higher than observed with preliminary signals in previously reported barasertib monotherapy studies,22,23 but is similar to that reported in a previous Phase I dose-escalation study of barasertib in combination with LDAC.21 Further, barasertib treatment demonstrated responses across all cytogenetic risk groups; a potential benefit was indicated for those patients with adverse cytogenetic profiles, although patient numbers were too small to make any definitive conclusions.
Survival analysis revealed a numerical trend in favor of barasertib in this population of elderly patients with AML. The failure to observe a more distinct result between treatment groups may reflect the lack of power in this study to detect a robust treatment effect on survival. However, previous studies with LDAC suggest that more death events may have been expected after 11 months post randomization than were observed in this study.6,28 On further analysis, an imbalance in subsequent intensive therapy received post discontinuation of randomized treatment (8% with barasertib compared with 27% with LDAC) may also have influenced these OS findings, although the small sample numbers preclude any robust conclusions.
Safety results were consistent with the known tolerability profile of barasertib in monotherapy studies.20,22,23 As expected, febrile neutropenia and stomatitis/mucositis occurred at a higher incidence in patients treated with barasertib compared with LDAC. Overall, observed AEs generally resolved and led to a dose modification in only a small proportion of patients. Despite the increased tolerability burden from barasertib treatment, cumulative toxicities were not observed with barasertib treatment and rates of drug discontinuation and mortality were similar for the barasertib group compared with LDAC. Although it was expected that patients enrolled in this study were to receive a minimum of three treatment cycles, in reality, only about 50% of patients received >1 cycle. The reasons for discontinuation following only one or two cycles were investigated and were considered justified, eg rising blast counts, no response. Early mortality rates with barasertib treatment observed here were superior to findings from a previous study of older patients with AML receiving intensive chemotherapy, which identified 8-week mortality rates in excess of 30%.5
Recent studies of other agents with activity versus Aurora kinases have also demonstrated preliminary evidence of anticancer activity. These include AMG900,29 a pan-Aurora kinase inhibitor, that is currently being investigated in a Phase I trial in adult patients with acute leukemias (NCT01380756). However, since AMG900 is not selective for Aurora B, it remains to be established whether the anti-leukemia activity observed with this agent is due to an effect on Aurora B and/or other target(s). The Aurora A kinase inhibitor MLN8237 has demonstrated preclinical anti-AML activity,30 and is currently in a Phase II trial in patients with AML or myelodysplastic syndrome (NCT00830518).
The significant favorable response to barasertib treatment versus LDAC seen in this study confirms and extends preliminary signals of efficacy observed in older patients with AML. On the basis of these results, AstraZeneca is considering further development options for this active compound in this area of high unmet medical need.
Key summary.
A significant improvement in objective complete response rates was observed with 1200 mg barasertib versus 400 mg LDAC in older AML patients
The safety profile of barasertib, although more toxic than that of LDAC, was manageable and consistent with previous studies
Acknowledgments
This research is supported in part by the National Institutes of Health through MD Anderson's Cancer Center Support Grant CA016672.”
Writing assistance was provided by Zoë van Helmond PhD, from Mudskipper Bioscience, funded by AstraZeneca.
Footnotes
Contribution: HK contributed towards the conception and design, acquisition and interpretation of data and drafting of the manuscript. PS contributed towards the conception, design and drafting of the manuscript. NS was involved in the study design. EJ, AQ-C, KA, J-OB, AW, SG, CP, AG and KO contributed towards the acquisition of data. GM contributed towards data analysis; KO, LP, NS, EJ, and PS contributed towards the data analysis and interpretation. All authors critically reviewed and commented on the manuscript and all authors approved the final manuscript.
Conflict of interest disclosure: HK has received research grants from AstraZeneca; GM is a Consultant for Novartis, BMS, Pfizer and Roche, and on speaker bureaus for Novartis, BMS and Pfizer; NS is an AZ employee; KO, LP and PS are AZ employees and shareholders. The remaining authors declare no competing financial interests.
All authors have read and approved the manuscript.
This manuscript is not under consideration elsewhere.
Informed consents were obtained from the subjects and/or guardian(s).
References
- 1.Löwenberg B, Downing JR, Burnett A. Acute myeloid leukemia. N Engl J Med. 1999;341(14):1051–1062. doi: 10.1056/NEJM199909303411407. [DOI] [PubMed] [Google Scholar]
- 2.Stone RM, O'Donnell MR, Sekeres MA. Acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2004:98–117. doi: 10.1182/asheducation-2004.1.98. [DOI] [PubMed] [Google Scholar]
- 3.Krug U, Buchner T, Berdel WE, Muller-Tidow C. The treatment of elderly patients with acute myeloid leukemia. Dtsch Arztebl Int. 2011;108(51-52):863–870. doi: 10.3238/arztebl.2011.0863. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Overcash J, Extermann M, Parr J, Perry J, Balducci L. Validity and reliability of the FACT-G scale for use in the older person with cancer. Am J Clin Oncol. 2001;24(6):591–596. doi: 10.1097/00000421-200112000-00013. [DOI] [PubMed] [Google Scholar]
- 5.Kantarjian H, Ravandi F, O'Brien S, et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010;116(22):4422–4429. doi: 10.1182/blood-2010-03-276485. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109(6):1114–1124. doi: 10.1002/cncr.22496. [DOI] [PubMed] [Google Scholar]
- 7.Erba HP. Prognostic factors in elderly patients with AML and the implications for treatment. Hematology Am Soc Hematol Educ Program. 2007:420–428. doi: 10.1182/asheducation-2007.1.420. [DOI] [PubMed] [Google Scholar]
- 8.Meraldi P, Honda R, Nigg EA. Aurora kinases link chromosome segregation and cell division to cancer susceptibility. Curr Opin Genet Dev. 2004;14(1):29–36. doi: 10.1016/j.gde.2003.11.006. [DOI] [PubMed] [Google Scholar]
- 9.Mistry HB, MacCallum DE, Jackson RC, Chaplain MA, Davidson FA. Modeling the temporal evolution of the spindle assembly checkpoint and role of Aurora B kinase. Proc Natl Acad Sci USA. 2008;105(51):20215–20220. doi: 10.1073/pnas.0810706106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Araki K, Nozaki K, Ueba T, Tatsuka M, Hashimoto N. High expression of Aurora-B/Aurora and Ipll-like midbody-associated protein (AIM-1) in astrocytomas. J Neurooncol. 2004;67(1-2):53–64. doi: 10.1023/b:neon.0000021784.33421.05. [DOI] [PubMed] [Google Scholar]
- 11.Bischoff JR, Anderson L, Zhu Y, et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 1998;17(11):3052–3065. doi: 10.1093/emboj/17.11.3052. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Kanda A, Kawai H, Suto S, et al. Aurora-B/AIM-1 kinase activity is involved in Ras-mediated cell transformation. Oncogene. 2005;24(49):7266–7272. doi: 10.1038/sj.onc.1208884. [DOI] [PubMed] [Google Scholar]
- 13.Ota T, Suto S, Katayama H, et al. Increased mitotic phosphorylation of histone H3 attributable to AIM-1/Aurora-B overexpression contributes to chromosome number instability. Cancer Res. 2002;62(18):5168–5177. [PubMed] [Google Scholar]
- 14.Ross ME, Mahfouz R, Onciu M, et al. Gene expression profiling of pediatric acute myelogenous leukemia. Blood. 2004;104(12):3679–3687. doi: 10.1182/blood-2004-03-1154. [DOI] [PubMed] [Google Scholar]
- 15.Sen S, Zhou H, White RA. A putative serine/threonine kinase encoding gene BTAK on chromosome 20q13 is amplified and overexpressed in human breast cancer cell lines. Oncogene. 1997;14(18):2195–2200. doi: 10.1038/sj.onc.1201065. [DOI] [PubMed] [Google Scholar]
- 16.Joel SP, Oke A, Foot N, et al. The activity of the novel Aurora Kinase B inhibitor AZD1152 in acute myeloid leukaemia cells. Blood. 2005;106(11):3374. [Google Scholar]
- 17.Oke A, Pearce D, Wilkinson RW, et al. AZD1152 rapidly and negatively affects the growth and survival of human acute myeloid leukemia cells in vitro and in vivo. Cancer Res. 2009;69(10):4150–4158. doi: 10.1158/0008-5472.CAN-08-3203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Walsby E, Walsh V, Pepper C, Burnett A, Mills K. Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts. Haematologica. 2008;93(5):662–669. doi: 10.3324/haematol.12148. [DOI] [PubMed] [Google Scholar]
- 19.Wilkinson RW, Odedra R, Heaton SP, et al. AZD1152, a selective inhibitor of aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res. 2007;13(12):3682–3688. doi: 10.1158/1078-0432.CCR-06-2979. [DOI] [PubMed] [Google Scholar]
- 20.Boss DS, Witteveen PO, van der Sar J, et al. Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors. Ann Oncol. 2011;22(2):431–437. doi: 10.1093/annonc/mdq344. [DOI] [PubMed] [Google Scholar]
- 21.Kantarjian HM, Sekeres MA, Ribrag V, et al. Phase I study to assess the safety and tolerability of AZD1152 in combination with low dose cytosine arabinoside in patients with acute myeloid leukemia (AML) Blood. 2010;116(21) abst 656. [Google Scholar]
- 22.Löwenberg B, Rousselot P, Martinelli G, et al. Phase I/II study to assess the safety and efficacy of the Aurora B kinase inhibitor, AZD1152, in patients with advanced acute myeloid leukemia. Blood. 2009;11422 doi: 10.1182/blood-2011-07-366930. abst 2080. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Tsuboi K, Yokozawa T, Sakura T, et al. A Phase I study to assess the safety, pharmacokinetics and efficacy of barasertib (AZD1152), an Aurora B kinase inhibitor, in Japanese patients with advanced acute myeloid leukemia. Leuk Res. 2011;35(10):1384–1349. doi: 10.1016/j.leukres.2011.04.008. [DOI] [PubMed] [Google Scholar]
- 24.AstraZeneca. Global Policy: Bioethics. 2011 Available at: http://www.astrazeneca.com/Responsibility/Code-policies-standards/Policiesstandards.
- 25.Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21(24):4642–4649. doi: 10.1200/JCO.2003.04.036. [DOI] [PubMed] [Google Scholar]
- 26.Newcombe RG. Interval estimation for the difference between independent proportions: comparison of eleven methods. Stat Med. 1998;17(8):873–890. doi: 10.1002/(sici)1097-0258(19980430)17:8<873::aid-sim779>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
- 27.Grimwade D, Hills RK. Independent prognostic factors for AML outcome. Hematology Am Soc Hematol Educ Program. 2009:385–395. doi: 10.1182/asheducation-2009.1.385. [DOI] [PubMed] [Google Scholar]
- 28.Thomas XG, Dmoszynska A, Wierzbowska A, et al. Results from a randomized phase III trial of decitabine versus supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed AML. J Clin Oncol. 2011;29(15S) doi: 10.1200/JCO.2011.38.9429. abst 6504. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Payton M, Bush TL, Chung G, et al. Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines. Cancer Res. 2010;70(23):9846–9854. doi: 10.1158/0008-5472.CAN-10-3001. [DOI] [PubMed] [Google Scholar]
- 30.Kelly KR, Nawrocki ST, Espitia CM, et al. Targeting Aurora A kinase activity with the investigational agent alisertib increases the efficacy of cytarabine through a FOXO-dependent mechanism. Int J Cancer. 2012;131:2693–2703. doi: 10.1002/ijc.27579. [DOI] [PMC free article] [PubMed] [Google Scholar]