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Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors
original article
Annals of Oncology 22: 431–437, 2011 doi:10.1093/annonc/mdq344 Published online 5 October 2010
Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors D. S. Boss1, P. O. Witteveen2, J. van der Sar1, M. P. Lolkema2, E. E. Voest2, P. K. Stockman3, O. Ataman3, D. Wilson3, S. Das3 & J. H. Schellens1* 1 Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam; 2Department of Medical Oncology, University Medical Centre, Utrecht, The Netherlands; 3AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK
Received 17 March 2010; revised 14 May 2010; accepted 17 May 2010
introduction The aurora kinase family comprises three highly conserved serine/threonine kinases (Aurora A, Aurora B and Aurora C) that have key regulatory roles at critical points of the cell cycle [1, 2]. Aurora A is commonly amplified in solid tumors and has been established as an oncogene, while Aurora B overexpression leads to defects in mitosis and increased tumor invasiveness. Aurora C has similar structural and localization properties to Aurora B and is implicated in mammalian spermatogenesis. While Aurora A has historically been most associated with tumorigenesis, several studies have highlighted a role for Aurora B in oncogenic transformation [3, 4]. The aurora kinases have been suggested as promising targets for cancer therapy due to their frequent overexpression in a variety of tumors [1]. Compared with more established inhibitors of cell division, such as anti-tubulins [5], aurora-selective small-molecule inhibitors have the potential to provide similar efficacy with fewer side-effects as they only target cells entering mitosis. Several small-molecule inhibitors of aurora kinases have been *Correspondence to: Prof. J. H. Schellens, Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. Tel: +31-20-512-2446; Fax: +31-20-512-2572; E-mail: [email protected]
developed as anticancer agents, a number of which are being evaluated clinically [6, 7]. One of these, AZD1152, an acetanilide-substituted pyrazole-aminoquinazoline phosphate pro-drug, is converted to the active moiety hydroxyquinazoline pyrazole anilide of AZD1152 (AZD1152-hQPA) in plasma [8]. AZD1152-hQPA is a highly potent and selective inhibitor of Aurora B compared with Aurora A [9]. Consistent with inhibition of Aurora B kinase, addition of AZD1152hQPA to tumor cells in vitro inhibits cytokinesis, but allows endoreduplication, such that large multinucleated giant cells are formed with >4N DNA content. The consequence of this phenomenon is to reduce cell viability and ultimately induce apoptosis [9]. In an in vivo panel, AZD1152 significantly inhibited the growth of human tumor xenografts [10]. This phase I study was undertaken to determine the maximumtolerated dose (MTD) of AZD1152 when given every 7 or 14 days and to evaluate the safety, efficacy and pharmacokinetic (PK) profile of AZD1152.
patients and methods patient selection Eligibility criteria included patients aged ‡18 years with histologically or cytologically confirmed solid malignancies refractory to standard therapy or
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
tolerated dose (MTD) of AZD1152, an Aurora B kinase inhibitor, and to evaluate its safety, biologic activity and pharmacokinetics (PK). Patients and methods: Patients with advanced solid malignancies were treated with escalating doses (100–650 mg) of AZD1152, administered as a 2-h infusion every 7 days (A) or 14 days (B). Adverse events (AEs), PK variables and tumor response were assessed. Results: Fifty-nine patients were treated; 19 in schedule A and 40 in schedule B. The MTDs were 200 and 450 mg, respectively. Neutropenia (with/without fever) was the most frequent AE and DLT in each schedule. Common Terminology Criteria of Adverse Events version 3.0 grade ‡3 neutropenia and leukopenia occurred in 58% and 11% of patients, respectively, in schedule A and 43% and 20%, respectively, in schedule B. No objective tumor responses were observed at any dose or schedule, although stable disease, as defined by RECIST, was achieved in 15 patients (25%) overall. Systemic exposure to AZD1152-hQPA (active drug) was observed by 1 h into the infusion and exhibited linear PK. Conclusions: AZD1152 was generally well tolerated with neutropenia being the most frequently reported AE and DLT. Exposure to AZD1152-hQPA, the active drug of AZD1152, was linear. Key words: aurora kinase inhibitor, AZD1152, pharmacokinetics, phase I, safety, solid tumors
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Background: To determine, for each of two dosing schedules, the dose-limiting toxicity (DLT) and maximum-
original article for whom no standard therapy existed; World Health Organization performance status of 0 to 2; at least one measurable or nonmeasurable site of disease as defined by modified RECIST [11] and previous chemotherapy >4 weeks before first dose. All patients provided written informed consent. The study was approved by the independent ethics committee for each trial center and was conducted in accordance with the Declaration of Helsinki.
trial design and procedures
toxicity criteria Adverse events (AEs) were monitored throughout the trial using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. An AZD1152-related DLT was defined as any grade 4 toxicity (grade 4 neutropenia for >3 days), grade ‡3 neutropenia with fever, grade 3 or 4 thrombocytopenia associated with bleeding (excluding patients receiving systemic anticoagulation) or any grade 3 or 4 non-hematologic toxicity. Any drug-related toxicity resulting in a dose interruption in cycle 1 of >7 days was also considered dose limiting. Patients could continue treatment with AZD1152 at the same dose for as long as they were considered by the investigator to be receiving benefit. All patients were monitored for at least 30 days following their final dose of AZD1152. Administration of granulocyte colony-stimulating factor was not allowed during AZD1152 treatment.
PK analysis For each dosing schedule, plasma concentrations of AZD1152 and AZD1152-hQPA were determined following the first dose of AZD1152. Venous blood samples (4 ml) were taken at the following times: predose, 1 h after the start of the infusion, 5 min before the end of infusion (EOI) and at various timepoints from 0.25 to 22 h following the EOI. During the next three infusions (if given), blood samples were taken predose, 5 min before EOI and 1, 3 and 6 h after EOI. Plasma PK parameters of AZD1152 and AZD1152-hQPA were determined by non-compartmental methods, using WinNonlin Enterprise Version 4.1 (Pharsight Corporation, Mountain View, CA).
tumor measurement and response evaluation Tumor measurements were obtained at baseline by radiological techniques or, if appropriate, by physical examination. Tumor response was evaluated
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by RECIST every 6–8 weeks. If a response was observed, a confirmation scan was carried out after 4–8 weeks.
results patient characteristics In total, 59 patients received treatment, 19 in schedule A and 40 in schedule B (16 of these in the MTD expansion phase). Baseline patient characteristics are listed in Table 1 for each dosing schedule. In schedule A, 18/19 patients (95%) received at least one cycle of treatment across four dose levels (100, 200, 300 and 450 mg). Twelve patients (63%) received at least two cycles of treatment with one patient in the 300-mg group receiving 27 cycles. In schedule B, all 40 patients completed at least one cycle of treatment across five dose levels (200, 300, 450, 550 and 650 mg). Thirty-two of 40 patients (80%) received at least two cycles of treatment, with one patient in the 450-mg group receiving 10 cycles. Dose reductions or delays,
Table 1. Baseline patient characteristics
Sex Male Female Age, years Median Range Race Caucasian Oriental Prior therapya Chemotherapyb Hormonal Radiotherapy WHO performance status 0 1 2 Cancer types Colorectal Skin/soft tissue Head and neck Prostate Pancreas Esophagus Lung Stomach Otherc
Patients, n (%) Dosing schedule A (N = 19)
Dosing schedule B (N = 40)
14 (74) 5 (26)
30 (75) 10 (25)
59 40–71
59 25–73
19 (100) 0
38 (95) 2 (5)
19 (100) 4 (21) 10 (53)
32 (80) 2 (5) 19 (48)
1 (5) 16 (84) 2 (11)
9 (23) 28 (70) 3 (8)
8 3 2 2 1 1 0 0 2
(42) (16) (11) (11) (5) (5)
(11)
9 10 5 0 3 2 3 2 6
(23) (25) (13) (8) (5) (8) (5) (15)
a
Patients may have had more than one prior therapy. Patients may have had more than one kind of chemotherapy. c Schedule A: one patient each, pleura and renal; schedule B: one patient each, bladder, pleura, renal, ureter, ovary and adenocarcinoma of unknown primary origin. WHO, World Health Organization. b
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In this phase I, open-label, multicentre dose-escalation study, AZD1152 was administered as a 2-h i.v. infusion given every 7 days (schedule A) or 14 days (schedule B) (clinicaltrials.gov; NCT00497731) (Figure S1, available at Annals of Oncology online). For each schedule, a doseescalation phase was conducted to determine the dose-limiting toxicity (DLT) and MTD of AZD1152. For schedule A, a modified accelerated titration design [12] was used with a starting dose of 100 mg. AZD1152 was administered on days 1, 8 and 15 of a 21-day cycle with initial cohorts of one patient (until evidence of a grade ‡2 drug-related toxicity) and subsequent cohorts of three to six patients. When two or more patients from the same cohort experienced a DLT, this dose was defined as the non-tolerated dose and there were no further dose escalations. The dose level below the non-tolerated dose was defined as the MTD. The MTD established in schedule A was the starting dose for schedule B, and initial cohorts of three patients were given AZD1152 as a 2-h i.v. infusion every 14 days of a 28-day cycle. Doses were escalated until evidence of a DLT at which point the dose level was expanded to six patients. If two or more of the six patients experienced a DLT, the next lower dose (the MTD) was expanded to six patients. Once determined, the MTD dose level was expanded further.
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predominantly at higher doses, were observed in both phases and the majority were due to neutropenia.
MTDs and DLTs The MTD of AZD1152 was defined as 200 mg in schedule A and 450 mg in schedule B. In each schedule, the DLT was neutropenia. The 650 and 550 mg doses were confirmed as non-tolerated doses and the 450 mg dose expanded as the MTD. Sixteen subsequent patients were treated at this dose.
pharmacokinetics Plasma PK parameters of AZD1152 and AZD1152-hQPA for schedule B are shown in Table 4; these were similar for equivalent doses in schedule A. After the EOI, plasma concentrations of AZD1152 declined rapidly with mean half-lives of 3–9 h; by 24 h postdose, concentrations were at, or approaching, the limit of quantification (LoQ) of the assay (0.25 ng/ml), irrespective of dose level (Figure S2, available at Annals of Oncology online). Exposure [assessed by the area under plasma concentration– time curve (AUC)] to AZD1152-hQPA was higher than that for AZD1152 by twofold to sixfold across the doses studied. Systemic exposure to AZD1152-hQPA was observed by the time of the first sample taken at 1 h into the infusion with the maximum plasma concentration at the EOI. Plasma concentrations then declined in a biphasic manner with mean half-lives of 6.5–7.4 h. By 24 h postdose, they were still markedly higher than the LoQ with evidence of a third phase with very low but quantifiable plasma concentrations in the predose sample taken before the start of cycle 2. The terminal half-life of this phase was estimated to be 50 h. However, the majority of the exposure occurred up to 24 h postdose and no accumulation of AZD1152-hQPA was observed for either regimen as confirmed by similar mean AUCs for cycles 1 and
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antitumor activity No objective tumor response, as defined by RECIST, was observed at any dose in either dosing schedule. The best response observed was stable disease, in seven patients (37%) in schedule A (one patient in the 100-mg group and two in each of the 200-, 300- and 450-mg groups) and eight patients (20%) in schedule B (six patients in the 450-mg group and two in the 650-mg group). Most patients with stable disease as best response remained stable for 6–8 weeks and progressed at the next evaluation, 6–8 weeks later. However, some patients remained stable over longer periods of time, including a patient with adenoid cystic carcinoma who was treated in part A (450 mg; stable disease for 16 months). A patient with an adenocarcinoma of unknown primary origin who was treated in part B (450 mg dose) remained stable for 8 months. At week 6, progressive disease, as defined by RECIST, was observed in 7 patients (37%) in schedule A and 21 patients (53%) in schedule B. Five patients (26%) in schedule A and 11 patients (28%) in schedule B were inaccessible (Figure S3, available at Annals of Oncology online).
discussion AZD1152 was generally well tolerated. The most frequently reported CTCAE grade ‡3 events in this study were neutropenia and leukopenia, toxic effects that had been anticipated from preclinical experience with AZD1152 and have also been observed clinically with other aurora kinase inhibitors [13–15]. With the exception of neutropenia, there were no clinically relevant changes in laboratory variables. Very few patients permanently discontinued treatment due to a treatment-related AE, although some patients required a dose reduction or dose delay due to an AE. The best observed responses in this trial were prolonged disease stabilizations in some patients. These results are in accordance with other recently published studies in patients with solid tumors, with the aurora kinase inhibitors danusertib and MK-0457 [13–15]. Preliminary results have been presented for a number of other inhibitors of Aurora A or Aurora B, including MLN8237 [16], AT9283 [17], AS703569 (R763) [18], SNS-314 [19] and PF-03814735 [20]. Currently, it remains unclear which of the Aurora kinases, A or B, represents the best drug target. The lack of tumor responses in this study, in contrast to the impressive preclinical results, may reflect discrepancies between the growth rate of tumor cell lines in vitro versus tumor cells
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AEs and laboratory data In schedule A, all 19 patients had at least one AE (Table 2). Three patients (16%) experienced serious AEs (leukopenia, neutropenia, pyrexia and vomiting); one was considered to be drug related. Three patients (16%) had AEs resulting in drug withdrawal (lymphadenopathy, pulmonary embolism and pyrexia); none were considered to be drug related. In schedule B, 39 patients (98%) had at least one AE. Eleven patients (28%) had at least one serious AE. Of these, febrile neutropenia, leukopenia and sepsis were considered to be drug related. Four patients (10%) discontinued treatment due to AEs (femur fracture and pyrexia, lumbar vertebral fracture, malaise and osteomyelitis); none were considered to be AZD1152 related. The most frequently reported AEs, mainly hematologic or gastrointestinal, were of mild or moderate intensity for both dosing schedules (Table 2). Fifteen patients (79%) patients in schedule A and 24 patients (60%) in schedule B experienced CTCAE grade ‡3 events, the most commonly reported being neutropenia and leukopenia (Table 3). With the exception of neutropenia, there were no clinically relevant changes from baseline in any of the laboratory assessments.
3 (21780 and 19590 ngh/ml, respectively) for the MTD (schedule B). Based on maximum plasma concentration and AUC, the exposure to AZD1152-hQPA increased with increasing dose in an approximately dose-proportional manner. Both inter- and intrapatient variabilities in exposure were low, that for interpatient ranging from 1.1- to 2.3-fold and that for intrapatient up to a maximum of only 1.3-fold. The mean plasma clearance of AZD1152-hQPA ranged from 15 to 27 l/h and the mean volume of distribution at steady state ranged from 50 to 88 l.
Schedule A; patients with AE, n (%)a; AZD1152 dose (mg) 100 (N = 1) 200 (N = 6) 300 (N = 6) 450 (N = 6) 1 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0
(100)
(100)
(100)
(100)
6 1 4 2 3 2 3 3 2 1 1 1 1 2 1 1 1 0 0 0 2 2 1 2
(100) (17) (67) (33) (50) (33) (50) (50) (33) (17) (17) (17) (17) (33) (17) (17) (17)
(33) (33) (17) (33)
6 0 5 2 1 3 1 1 1 1 1 1 1 0 1 1 1 1 2 0 0 0 1 0
(100) (83) (33) (17) (50) (17) (17) (17) (17) (17) (17) (17) (17) (17) (17) (17) (33)
(17)
6 2 4 2 2 0 1 1 1 2 1 1 1 1 1 0 0 1 0 1 0 0 0 0
(100) (33) (67) (33) (33) (17) (17) (17) (33) (17) (17) (17) (17) (17)
(17) (17)
19 3 13 7 6 5 5 5 5 4 3 3 3 3 3 2 2 2 2 2 2 2 2 2
(100) (16) (68) (37) (32) (26) (26) (26) (26) (21) (16) (16) (16) (16) (16) (11) (11) (11) (11) (11) (11) (11) (11) (11)
Any AE Any SAE Neutropenia Nausea Leukopenia Fatigue Pyrexia Vomiting Alopecia Constipation Proteinuria Nasopharyngitis Anorexia Cough Diarrhea Abdominal pain Anemia Hematuria Dyspnea Flank pain
650 (N = 5)
Total (N = 40)
4 0 0 3 0 0 3 1 0 1 2 0 2 1 0 1 0 1 0 1
5 1 5 4 3 2 1 1 2 1 1 2 2 0 1 0 1 0 1 1
39 11 25 22 18 15 15 13 10 9 9 9 8 8 8 6 6 5 4 4
(100)
(75)
(75) (25) (25) (50) (50) (25)
(25) (25)
3 2 3 1 1 1 1 2 0 0 0 0 2 0 0 0 0 0 0 1
(100) (67) (100) (33) (33) (33) (33) (67)
(67)
(33)
22 7 12 11 10 11 9 6 7 5 4 7 2 7 5 4 4 3 2 1
(96) (30) (52) (48) (44) (48) (39) (26) (30) (22) (17) (30) (9) (30) (22) (17) (17) (13) (9) (4)
5 1 5 3 4 1 1 3 1 2 2 0 0 0 2 1 1 1 1 0
(100) (20) (100) (60) (80) (20) (20) (60) (20) (40) (40)
(40) (20) (20) (20) (20)
(100) (20) (100) (80) (60) (40) (20) (20) (40) (20) (20) (40) (40) (20) (20) (20) (20)
(98) (28) (63) (55) (45) (38) (38) (33) (25) (23) (23) (23) (20) (20) (20) (15) (15) (13) (10) (10)
a
Patients with multiple events in the same category are counted only once in that category; patients with events in more than one category are counted once in each of those categories. AE, adverse event; SAE, serious adverse event.
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Any AE Any SAE Neutropenia Constipation Fatigue Diarrhea Leukopenia Nausea Vomiting Pyrexia Alopecia Anemia Cough Dyspepsia Hemoglobin decrease Abdominal pain Abdominal pain upper Dry mouth Eczema Headache Hyperhidrosis Lymphadenopathy Paresthesia Stomatitis
Total (N = 19)
Schedule B; patients with AE, n (%)a; AZD1152 dose (mg) 200 (N = 4) 300 (N = 3) 450 (N = 23) 550 (N = 5)
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434 | Boss et al. Table 2. Most frequently reported AEs by AZD1152 dose and schedule in ‡10% of patients
Annals of Oncology
Schedule A; patients with AE, n (%)a; AZD1152 dose (mg) 100 (N = 1) 200 (N = 6) 300 (N = 6) 450 (N = 6) Total (N = 19) At least 1 CTCAE grade ‡3 Neutropenia Leukopenia ALT increased AST increased Back pain Blood ALP increased GGT increased Granulocytopenia Musculoskeletal pain Neutrophil count increased Pain in extremity Pulmonary embolism Spinal cord compression Vomiting
0
4 (67)
5 (83)
6 (100)
15 (79)
0 0 0 0 0 0 0 0 0 0 0 0 0
3 1 1 1 1 1 1 0 0 0 1 0 0
4 0 0 0 0 0 0 1 1 0 0 0 1
4 1 0 0 0 0 0 0 0 1 0 1 0
11 2 1 1 1 1 1 1 1 1 1 1 1
0
1 (17)
(50) (17) (17) (17) (17) (17) (17)
(17)
0
(67)
(17) (17)
(17)
0
(67) (17)
(17) (17)
(58) (11) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5)
1 (5)
Schedule B; patients with AE, n (%)a; AZD1152 dose (mg) 200 (N = 4) 300 (N = 3) 450 (N = 23) 550 (N = 5) 650 (N = 5) 1 (25)
2 (67)
0 0 0 0 0 0 0 0 0 1 (25) 0 0 0
2 (67) 0 0 0 0 1 (33) 0 0 0 0 1 (33) 0 0
5 1 1 1 1 0 1 1 0 0 0 1 0
0 0 0 0 0
1 (33) 0 0 0 0
0 0 0
0 0 0
a
11 (48)
Total (N = 40)
5 (100)
5 (100)
24 (60)
5 (100) 4 (80) 1 (20) 0 0 0 0 0 0 0 0 0 0
5 3 1 0 0 0 0 0 1 0 0 0 1
17 8 3 2 1 1 1 1 1 1 1 1 1
(43) (20) (8) (5) (3) (3) (3) (3) (3) (3) (3) (3) (3)
0 0 1 (4) 1 (4) 1 (4)
0 1 (20) 0 0 0
0 0 0 0 0
1 1 1 1 1
(3) (3) (3) (3) (3)
1 (4) 1 (4) 1 (4)
0 0 0
0 0 0
1 (3) 1 (3) 1 (3)
(22) (4) (4) (4) (4) (4) (4)
(4)
(100) (60) (20)
(20)
(20)
Patients with multiple events in the same category are counted only once in that category; patients with events in more than one category are counted once in each of those categories. AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma glutamyl transferase; INR, International Normalized Ratio.
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At least 1 CTCAE grade ‡3 Neutropenia Leukopenia Febrile neutropenia Fatigue Abdominal pain Anorexia AST increased Bacteremia Constipation Cough Drug toxicity Dyspnea Inferior vena caval occlusion INR increased Malaise Pain in extremity Pneumonia Post-op wound infection Pyrexia Sepsis Vomiting
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Table 3. Patients with at least one CTCAE grade ‡3 by AZD1152 dose and dosing schedule
11 830 19 280 7.080 33.72 15.61 (42.84) 11 230 (8.494) (47.79) 30 010 (1.879) (19.91) 6.738 (23.51) (71.59) 18.33 (1.859) (81.09) 53.26 (21.81) 6613 10 620 7.373 51.77 19.85 (22.72) (22.60) (18.74) (20.46) (22.55) (34.90) 9215 (7.06) 21 780 (16.08) 6.548 (46.60) 20.66 (63.15) 54.94 7037 10 460 6.629 43.01 19.62 (15.28) (11.68) (11.38) (11.64) (16.19) (50.03) 7696 (52.22) 19 990 (5.026) 6.727 (42.97) 15.01 (27.00) 50.12 2470 3572 9.292 83.98 35.95 (6.436) (4.518) (4.200) (4.404) (7.510) 2879 7470 7.001 26.77 88.42 (19.41) (14.96) (65.03) (16.32) (33.59) %) %) %) %) %) (CV, (CV, (CV, (CV, (CV, Gmean Gmean Gmean Gmean Gmean
Active moiety of the pro-drug AZD1152. Cmax, maximum plasma (peak) drug concentration; AUC, area under plasma concentration–time curve; t½, half-life; CL, total clearance; Vss, volume at steady state; Gmean, geometric mean; CV, coefficient of variation.
a
1168 1807 4.785 110.7 53.31 Cmax (ng/ml) AUC (ngh/ml) t½ (h) CL (l/h) Vss (l)
(24.84) 13 010 (24.52) (26.69) 33 640 (23.36) (8.705) 6.915 (12.11) (34.16) 19.32 (23.68) (55.37) 57.61 (28.35)
200 mg (N = 4) 300 mg (N = 3) 450 mg (N = 23) 550 mg (N = 5) 650 mg (N = 5) AZD1152 AZD1152-hQPA AZD1152 AZD1152-hQPA AZD1152 AZD1152-hQPA AZD1152 AZD1152-hQPA AZD1152 AZD1152-hQPA Parameter (unit)
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in vivo. Based on the working mechanism of AZD1152, tumor cells may need to proliferate a few times before they kill themselves. In preclinical models, tumors have an extremely high proliferation rate, which perhaps makes them more susceptible to the actions of AZD1152. In humans, however, the growth rate is slower and perhaps we need to be more patient and even accept initial growth before a reduction is seen. With regards to the optimal treatment schedule for AZD1152, this study investigated a 2-h infusion. However, preclinical studies with AZD1152 have revealed prolonged drug administration to be more effective, and this has also been reported in a phase I study using AT9283 [21]. More research is needed to establish optimal treatment schedules for AZD1152 and other aurora kinase inhibitors. The use of validated biomarkers will be essential in future studies to assess the activity of these drugs. Assessing the phosphorylation of Histone H3 for instance is a useful tool for evaluating the degree of Aurora B inhibition [22]. Due to the absence of these data in the reported study, it remains difficult to draw conclusions on the most effective dose and schedule of AZD1152. The efficacy of AZD1152 in combination with other drug classes is also under investigation. Treatment with AZD1152 was found to be synergistic with a variety of chemotherapeutic agents in preclinical studies, including irinotecan, docetaxel (Taxotere), vinorelbine, gemcitabine, oxaliplatin and 5fluorouracil [23], and with vincristine and topoisomerase inhibitors in leukemia cell lines [24]. Combining AZD1152 with radiotherapy might also provide a promising strategy since the compound potentiates the radiation response in p53deficient cancer cells [25]. In summary, the MTD of AZD1152 was 200 mg for the 7-day dosing schedule and 450 mg for the 14-day dosing schedule. Neutropenia and leukopenia were the most frequently reported AEs and DLT of AZD1152 in this patient population. Overall, AZD1152 displayed a manageable tolerability profile on either dosing regimen, and there were no associated safety concerns. Further studies are assessing AZD1152 in patients with hematooncologic malignancies.
funding AstraZeneca (AstraZeneca study number D1531C00001).
acknowledgements MPL would like to acknowledge The Netherlands Organization for Scientific Research for funding his training with a personal grant (AGIKO). We thank Dr Colette O’Sullivan, from Scriva Medical Communications, who provided medical writing assistance funded by AstraZeneca.
disclosures PKS, OA, DW and SD, AstraZeneca. Consultant/advisory role: JHS, AstraZeneca. Stock ownership: OA and DW, AstraZeneca. Research funding: JHS.
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Table 4. Plasma pharmacokinetic parameters of AZD1152 and AZD1152-hQPAa, following a single 2-h infusion every 14 days (schedule B)
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granulocyte colony-stimulating factor in a 14-day cycle in patients with advanced solid tumors. Clin Cancer Res 2009; 15: 6694–6701. Traynor AM, Hewitt M, Liu G et al. Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors. Cancer Chemother Pharmacol 2010 Apr. 13 [epub ahead of print]. Infante J, Dees EC, Cohen RB et al. Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of MLN8237, a selective Aurora A kinase inhibitor, in the United States. Eur J Cancer Suppl 2008; 6(12): 90–91 (Abstr 280). Plummer ER, Calvert H, Arkenau H et al. A dose-escalation and pharmacodynamic study of AT9283 in patients with refractory solid tumours. J Clin Oncol 2008; 26(15S): 116s (Abstr 2519). Renshaw JS, Patnaik A, Gordon M et al. A phase I two arm trial of AS703569 (R763), an orally available aurora kinase inhibitor, in subjects with solid tumors: preliminary results. J Clin Oncol 2007; 25(18S): 622s (Abstr 14130). Robert F, Hurwitz H, Verschraegen CF et al. Phase 1 trial of SNS-314, a novel selective inhibitor of aurora kinases A, B, and C, in advanced solid tumor patients. J Clin Oncol 2008; 26(15S): 638s (Abstr 14642). Jones SF, Burris HA III, Dumez H et al. Phase I accelerated dose-escalation, pharmacokinetic (PK) and pharmacodynamic study of PF-03814735, an oral aurora kinase inhibitor, in patients with advanced solid tumors: preliminary results. J Clin Oncol 2008; 26(15S): 116s (Abstr 2517). Foran JM, Ravandi F, O’Brien SM et al. Phase I and pharmacodynamic trial of AT9283, an aurora kinase inhibitor, in patients with refractory leukemia. J Clin Oncol 2008; 26(15S): 116s (Abstr 2518). Carpinelli P, Moll J. Aurora kinase inhibitors: identification and preclinical validation of their biomarkers. Expert Opin Ther Targets 2008; 12: 69–80. Nair JS, Tse A, Keen N, Schwartz GK. A novel Aurora B kinase inhibitor with potent anticancer activity either as a single agent or in combination with chemotherapy. J Clin Oncol 2004; 22(14S): (Abstr 9568). Yang J, Ikezoe T, Nishioka C et al. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood 2007; 110: 2034–2040. Tao Y, Zhang P, Girdler F et al. Enhancement of radiation response in p53deficient cancer cells by the Aurora-B kinase inhibitor AZD1152. Oncogene 2007; 27: 3244–3255.
Annals of Oncology 22: 431–437, 2011 doi:10.1093/annonc/mdq344 Published online 5 October 2010
Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors D. S. Boss1, P. O. Witteveen2, J. van der Sar1, M. P. Lolkema2, E. E. Voest2, P. K. Stockman3, O. Ataman3, D. Wilson3, S. Das3 & J. H. Schellens1* 1 Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam; 2Department of Medical Oncology, University Medical Centre, Utrecht, The Netherlands; 3AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK
Received 17 March 2010; revised 14 May 2010; accepted 17 May 2010
introduction The aurora kinase family comprises three highly conserved serine/threonine kinases (Aurora A, Aurora B and Aurora C) that have key regulatory roles at critical points of the cell cycle [1, 2]. Aurora A is commonly amplified in solid tumors and has been established as an oncogene, while Aurora B overexpression leads to defects in mitosis and increased tumor invasiveness. Aurora C has similar structural and localization properties to Aurora B and is implicated in mammalian spermatogenesis. While Aurora A has historically been most associated with tumorigenesis, several studies have highlighted a role for Aurora B in oncogenic transformation [3, 4]. The aurora kinases have been suggested as promising targets for cancer therapy due to their frequent overexpression in a variety of tumors [1]. Compared with more established inhibitors of cell division, such as anti-tubulins [5], aurora-selective small-molecule inhibitors have the potential to provide similar efficacy with fewer side-effects as they only target cells entering mitosis. Several small-molecule inhibitors of aurora kinases have been *Correspondence to: Prof. J. H. Schellens, Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. Tel: +31-20-512-2446; Fax: +31-20-512-2572; E-mail: [email protected]
developed as anticancer agents, a number of which are being evaluated clinically [6, 7]. One of these, AZD1152, an acetanilide-substituted pyrazole-aminoquinazoline phosphate pro-drug, is converted to the active moiety hydroxyquinazoline pyrazole anilide of AZD1152 (AZD1152-hQPA) in plasma [8]. AZD1152-hQPA is a highly potent and selective inhibitor of Aurora B compared with Aurora A [9]. Consistent with inhibition of Aurora B kinase, addition of AZD1152hQPA to tumor cells in vitro inhibits cytokinesis, but allows endoreduplication, such that large multinucleated giant cells are formed with >4N DNA content. The consequence of this phenomenon is to reduce cell viability and ultimately induce apoptosis [9]. In an in vivo panel, AZD1152 significantly inhibited the growth of human tumor xenografts [10]. This phase I study was undertaken to determine the maximumtolerated dose (MTD) of AZD1152 when given every 7 or 14 days and to evaluate the safety, efficacy and pharmacokinetic (PK) profile of AZD1152.
patients and methods patient selection Eligibility criteria included patients aged ‡18 years with histologically or cytologically confirmed solid malignancies refractory to standard therapy or
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
tolerated dose (MTD) of AZD1152, an Aurora B kinase inhibitor, and to evaluate its safety, biologic activity and pharmacokinetics (PK). Patients and methods: Patients with advanced solid malignancies were treated with escalating doses (100–650 mg) of AZD1152, administered as a 2-h infusion every 7 days (A) or 14 days (B). Adverse events (AEs), PK variables and tumor response were assessed. Results: Fifty-nine patients were treated; 19 in schedule A and 40 in schedule B. The MTDs were 200 and 450 mg, respectively. Neutropenia (with/without fever) was the most frequent AE and DLT in each schedule. Common Terminology Criteria of Adverse Events version 3.0 grade ‡3 neutropenia and leukopenia occurred in 58% and 11% of patients, respectively, in schedule A and 43% and 20%, respectively, in schedule B. No objective tumor responses were observed at any dose or schedule, although stable disease, as defined by RECIST, was achieved in 15 patients (25%) overall. Systemic exposure to AZD1152-hQPA (active drug) was observed by 1 h into the infusion and exhibited linear PK. Conclusions: AZD1152 was generally well tolerated with neutropenia being the most frequently reported AE and DLT. Exposure to AZD1152-hQPA, the active drug of AZD1152, was linear. Key words: aurora kinase inhibitor, AZD1152, pharmacokinetics, phase I, safety, solid tumors
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Background: To determine, for each of two dosing schedules, the dose-limiting toxicity (DLT) and maximum-
original article for whom no standard therapy existed; World Health Organization performance status of 0 to 2; at least one measurable or nonmeasurable site of disease as defined by modified RECIST [11] and previous chemotherapy >4 weeks before first dose. All patients provided written informed consent. The study was approved by the independent ethics committee for each trial center and was conducted in accordance with the Declaration of Helsinki.
trial design and procedures
toxicity criteria Adverse events (AEs) were monitored throughout the trial using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. An AZD1152-related DLT was defined as any grade 4 toxicity (grade 4 neutropenia for >3 days), grade ‡3 neutropenia with fever, grade 3 or 4 thrombocytopenia associated with bleeding (excluding patients receiving systemic anticoagulation) or any grade 3 or 4 non-hematologic toxicity. Any drug-related toxicity resulting in a dose interruption in cycle 1 of >7 days was also considered dose limiting. Patients could continue treatment with AZD1152 at the same dose for as long as they were considered by the investigator to be receiving benefit. All patients were monitored for at least 30 days following their final dose of AZD1152. Administration of granulocyte colony-stimulating factor was not allowed during AZD1152 treatment.
PK analysis For each dosing schedule, plasma concentrations of AZD1152 and AZD1152-hQPA were determined following the first dose of AZD1152. Venous blood samples (4 ml) were taken at the following times: predose, 1 h after the start of the infusion, 5 min before the end of infusion (EOI) and at various timepoints from 0.25 to 22 h following the EOI. During the next three infusions (if given), blood samples were taken predose, 5 min before EOI and 1, 3 and 6 h after EOI. Plasma PK parameters of AZD1152 and AZD1152-hQPA were determined by non-compartmental methods, using WinNonlin Enterprise Version 4.1 (Pharsight Corporation, Mountain View, CA).
tumor measurement and response evaluation Tumor measurements were obtained at baseline by radiological techniques or, if appropriate, by physical examination. Tumor response was evaluated
432 | Boss et al.
by RECIST every 6–8 weeks. If a response was observed, a confirmation scan was carried out after 4–8 weeks.
results patient characteristics In total, 59 patients received treatment, 19 in schedule A and 40 in schedule B (16 of these in the MTD expansion phase). Baseline patient characteristics are listed in Table 1 for each dosing schedule. In schedule A, 18/19 patients (95%) received at least one cycle of treatment across four dose levels (100, 200, 300 and 450 mg). Twelve patients (63%) received at least two cycles of treatment with one patient in the 300-mg group receiving 27 cycles. In schedule B, all 40 patients completed at least one cycle of treatment across five dose levels (200, 300, 450, 550 and 650 mg). Thirty-two of 40 patients (80%) received at least two cycles of treatment, with one patient in the 450-mg group receiving 10 cycles. Dose reductions or delays,
Table 1. Baseline patient characteristics
Sex Male Female Age, years Median Range Race Caucasian Oriental Prior therapya Chemotherapyb Hormonal Radiotherapy WHO performance status 0 1 2 Cancer types Colorectal Skin/soft tissue Head and neck Prostate Pancreas Esophagus Lung Stomach Otherc
Patients, n (%) Dosing schedule A (N = 19)
Dosing schedule B (N = 40)
14 (74) 5 (26)
30 (75) 10 (25)
59 40–71
59 25–73
19 (100) 0
38 (95) 2 (5)
19 (100) 4 (21) 10 (53)
32 (80) 2 (5) 19 (48)
1 (5) 16 (84) 2 (11)
9 (23) 28 (70) 3 (8)
8 3 2 2 1 1 0 0 2
(42) (16) (11) (11) (5) (5)
(11)
9 10 5 0 3 2 3 2 6
(23) (25) (13) (8) (5) (8) (5) (15)
a
Patients may have had more than one prior therapy. Patients may have had more than one kind of chemotherapy. c Schedule A: one patient each, pleura and renal; schedule B: one patient each, bladder, pleura, renal, ureter, ovary and adenocarcinoma of unknown primary origin. WHO, World Health Organization. b
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In this phase I, open-label, multicentre dose-escalation study, AZD1152 was administered as a 2-h i.v. infusion given every 7 days (schedule A) or 14 days (schedule B) (clinicaltrials.gov; NCT00497731) (Figure S1, available at Annals of Oncology online). For each schedule, a doseescalation phase was conducted to determine the dose-limiting toxicity (DLT) and MTD of AZD1152. For schedule A, a modified accelerated titration design [12] was used with a starting dose of 100 mg. AZD1152 was administered on days 1, 8 and 15 of a 21-day cycle with initial cohorts of one patient (until evidence of a grade ‡2 drug-related toxicity) and subsequent cohorts of three to six patients. When two or more patients from the same cohort experienced a DLT, this dose was defined as the non-tolerated dose and there were no further dose escalations. The dose level below the non-tolerated dose was defined as the MTD. The MTD established in schedule A was the starting dose for schedule B, and initial cohorts of three patients were given AZD1152 as a 2-h i.v. infusion every 14 days of a 28-day cycle. Doses were escalated until evidence of a DLT at which point the dose level was expanded to six patients. If two or more of the six patients experienced a DLT, the next lower dose (the MTD) was expanded to six patients. Once determined, the MTD dose level was expanded further.
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predominantly at higher doses, were observed in both phases and the majority were due to neutropenia.
MTDs and DLTs The MTD of AZD1152 was defined as 200 mg in schedule A and 450 mg in schedule B. In each schedule, the DLT was neutropenia. The 650 and 550 mg doses were confirmed as non-tolerated doses and the 450 mg dose expanded as the MTD. Sixteen subsequent patients were treated at this dose.
pharmacokinetics Plasma PK parameters of AZD1152 and AZD1152-hQPA for schedule B are shown in Table 4; these were similar for equivalent doses in schedule A. After the EOI, plasma concentrations of AZD1152 declined rapidly with mean half-lives of 3–9 h; by 24 h postdose, concentrations were at, or approaching, the limit of quantification (LoQ) of the assay (0.25 ng/ml), irrespective of dose level (Figure S2, available at Annals of Oncology online). Exposure [assessed by the area under plasma concentration– time curve (AUC)] to AZD1152-hQPA was higher than that for AZD1152 by twofold to sixfold across the doses studied. Systemic exposure to AZD1152-hQPA was observed by the time of the first sample taken at 1 h into the infusion with the maximum plasma concentration at the EOI. Plasma concentrations then declined in a biphasic manner with mean half-lives of 6.5–7.4 h. By 24 h postdose, they were still markedly higher than the LoQ with evidence of a third phase with very low but quantifiable plasma concentrations in the predose sample taken before the start of cycle 2. The terminal half-life of this phase was estimated to be 50 h. However, the majority of the exposure occurred up to 24 h postdose and no accumulation of AZD1152-hQPA was observed for either regimen as confirmed by similar mean AUCs for cycles 1 and
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antitumor activity No objective tumor response, as defined by RECIST, was observed at any dose in either dosing schedule. The best response observed was stable disease, in seven patients (37%) in schedule A (one patient in the 100-mg group and two in each of the 200-, 300- and 450-mg groups) and eight patients (20%) in schedule B (six patients in the 450-mg group and two in the 650-mg group). Most patients with stable disease as best response remained stable for 6–8 weeks and progressed at the next evaluation, 6–8 weeks later. However, some patients remained stable over longer periods of time, including a patient with adenoid cystic carcinoma who was treated in part A (450 mg; stable disease for 16 months). A patient with an adenocarcinoma of unknown primary origin who was treated in part B (450 mg dose) remained stable for 8 months. At week 6, progressive disease, as defined by RECIST, was observed in 7 patients (37%) in schedule A and 21 patients (53%) in schedule B. Five patients (26%) in schedule A and 11 patients (28%) in schedule B were inaccessible (Figure S3, available at Annals of Oncology online).
discussion AZD1152 was generally well tolerated. The most frequently reported CTCAE grade ‡3 events in this study were neutropenia and leukopenia, toxic effects that had been anticipated from preclinical experience with AZD1152 and have also been observed clinically with other aurora kinase inhibitors [13–15]. With the exception of neutropenia, there were no clinically relevant changes in laboratory variables. Very few patients permanently discontinued treatment due to a treatment-related AE, although some patients required a dose reduction or dose delay due to an AE. The best observed responses in this trial were prolonged disease stabilizations in some patients. These results are in accordance with other recently published studies in patients with solid tumors, with the aurora kinase inhibitors danusertib and MK-0457 [13–15]. Preliminary results have been presented for a number of other inhibitors of Aurora A or Aurora B, including MLN8237 [16], AT9283 [17], AS703569 (R763) [18], SNS-314 [19] and PF-03814735 [20]. Currently, it remains unclear which of the Aurora kinases, A or B, represents the best drug target. The lack of tumor responses in this study, in contrast to the impressive preclinical results, may reflect discrepancies between the growth rate of tumor cell lines in vitro versus tumor cells
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AEs and laboratory data In schedule A, all 19 patients had at least one AE (Table 2). Three patients (16%) experienced serious AEs (leukopenia, neutropenia, pyrexia and vomiting); one was considered to be drug related. Three patients (16%) had AEs resulting in drug withdrawal (lymphadenopathy, pulmonary embolism and pyrexia); none were considered to be drug related. In schedule B, 39 patients (98%) had at least one AE. Eleven patients (28%) had at least one serious AE. Of these, febrile neutropenia, leukopenia and sepsis were considered to be drug related. Four patients (10%) discontinued treatment due to AEs (femur fracture and pyrexia, lumbar vertebral fracture, malaise and osteomyelitis); none were considered to be AZD1152 related. The most frequently reported AEs, mainly hematologic or gastrointestinal, were of mild or moderate intensity for both dosing schedules (Table 2). Fifteen patients (79%) patients in schedule A and 24 patients (60%) in schedule B experienced CTCAE grade ‡3 events, the most commonly reported being neutropenia and leukopenia (Table 3). With the exception of neutropenia, there were no clinically relevant changes from baseline in any of the laboratory assessments.
3 (21780 and 19590 ngh/ml, respectively) for the MTD (schedule B). Based on maximum plasma concentration and AUC, the exposure to AZD1152-hQPA increased with increasing dose in an approximately dose-proportional manner. Both inter- and intrapatient variabilities in exposure were low, that for interpatient ranging from 1.1- to 2.3-fold and that for intrapatient up to a maximum of only 1.3-fold. The mean plasma clearance of AZD1152-hQPA ranged from 15 to 27 l/h and the mean volume of distribution at steady state ranged from 50 to 88 l.
Schedule A; patients with AE, n (%)a; AZD1152 dose (mg) 100 (N = 1) 200 (N = 6) 300 (N = 6) 450 (N = 6) 1 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0
(100)
(100)
(100)
(100)
6 1 4 2 3 2 3 3 2 1 1 1 1 2 1 1 1 0 0 0 2 2 1 2
(100) (17) (67) (33) (50) (33) (50) (50) (33) (17) (17) (17) (17) (33) (17) (17) (17)
(33) (33) (17) (33)
6 0 5 2 1 3 1 1 1 1 1 1 1 0 1 1 1 1 2 0 0 0 1 0
(100) (83) (33) (17) (50) (17) (17) (17) (17) (17) (17) (17) (17) (17) (17) (17) (33)
(17)
6 2 4 2 2 0 1 1 1 2 1 1 1 1 1 0 0 1 0 1 0 0 0 0
(100) (33) (67) (33) (33) (17) (17) (17) (33) (17) (17) (17) (17) (17)
(17) (17)
19 3 13 7 6 5 5 5 5 4 3 3 3 3 3 2 2 2 2 2 2 2 2 2
(100) (16) (68) (37) (32) (26) (26) (26) (26) (21) (16) (16) (16) (16) (16) (11) (11) (11) (11) (11) (11) (11) (11) (11)
Any AE Any SAE Neutropenia Nausea Leukopenia Fatigue Pyrexia Vomiting Alopecia Constipation Proteinuria Nasopharyngitis Anorexia Cough Diarrhea Abdominal pain Anemia Hematuria Dyspnea Flank pain
650 (N = 5)
Total (N = 40)
4 0 0 3 0 0 3 1 0 1 2 0 2 1 0 1 0 1 0 1
5 1 5 4 3 2 1 1 2 1 1 2 2 0 1 0 1 0 1 1
39 11 25 22 18 15 15 13 10 9 9 9 8 8 8 6 6 5 4 4
(100)
(75)
(75) (25) (25) (50) (50) (25)
(25) (25)
3 2 3 1 1 1 1 2 0 0 0 0 2 0 0 0 0 0 0 1
(100) (67) (100) (33) (33) (33) (33) (67)
(67)
(33)
22 7 12 11 10 11 9 6 7 5 4 7 2 7 5 4 4 3 2 1
(96) (30) (52) (48) (44) (48) (39) (26) (30) (22) (17) (30) (9) (30) (22) (17) (17) (13) (9) (4)
5 1 5 3 4 1 1 3 1 2 2 0 0 0 2 1 1 1 1 0
(100) (20) (100) (60) (80) (20) (20) (60) (20) (40) (40)
(40) (20) (20) (20) (20)
(100) (20) (100) (80) (60) (40) (20) (20) (40) (20) (20) (40) (40) (20) (20) (20) (20)
(98) (28) (63) (55) (45) (38) (38) (33) (25) (23) (23) (23) (20) (20) (20) (15) (15) (13) (10) (10)
a
Patients with multiple events in the same category are counted only once in that category; patients with events in more than one category are counted once in each of those categories. AE, adverse event; SAE, serious adverse event.
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Any AE Any SAE Neutropenia Constipation Fatigue Diarrhea Leukopenia Nausea Vomiting Pyrexia Alopecia Anemia Cough Dyspepsia Hemoglobin decrease Abdominal pain Abdominal pain upper Dry mouth Eczema Headache Hyperhidrosis Lymphadenopathy Paresthesia Stomatitis
Total (N = 19)
Schedule B; patients with AE, n (%)a; AZD1152 dose (mg) 200 (N = 4) 300 (N = 3) 450 (N = 23) 550 (N = 5)
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Schedule A; patients with AE, n (%)a; AZD1152 dose (mg) 100 (N = 1) 200 (N = 6) 300 (N = 6) 450 (N = 6) Total (N = 19) At least 1 CTCAE grade ‡3 Neutropenia Leukopenia ALT increased AST increased Back pain Blood ALP increased GGT increased Granulocytopenia Musculoskeletal pain Neutrophil count increased Pain in extremity Pulmonary embolism Spinal cord compression Vomiting
0
4 (67)
5 (83)
6 (100)
15 (79)
0 0 0 0 0 0 0 0 0 0 0 0 0
3 1 1 1 1 1 1 0 0 0 1 0 0
4 0 0 0 0 0 0 1 1 0 0 0 1
4 1 0 0 0 0 0 0 0 1 0 1 0
11 2 1 1 1 1 1 1 1 1 1 1 1
0
1 (17)
(50) (17) (17) (17) (17) (17) (17)
(17)
0
(67)
(17) (17)
(17)
0
(67) (17)
(17) (17)
(58) (11) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5)
1 (5)
Schedule B; patients with AE, n (%)a; AZD1152 dose (mg) 200 (N = 4) 300 (N = 3) 450 (N = 23) 550 (N = 5) 650 (N = 5) 1 (25)
2 (67)
0 0 0 0 0 0 0 0 0 1 (25) 0 0 0
2 (67) 0 0 0 0 1 (33) 0 0 0 0 1 (33) 0 0
5 1 1 1 1 0 1 1 0 0 0 1 0
0 0 0 0 0
1 (33) 0 0 0 0
0 0 0
0 0 0
a
11 (48)
Total (N = 40)
5 (100)
5 (100)
24 (60)
5 (100) 4 (80) 1 (20) 0 0 0 0 0 0 0 0 0 0
5 3 1 0 0 0 0 0 1 0 0 0 1
17 8 3 2 1 1 1 1 1 1 1 1 1
(43) (20) (8) (5) (3) (3) (3) (3) (3) (3) (3) (3) (3)
0 0 1 (4) 1 (4) 1 (4)
0 1 (20) 0 0 0
0 0 0 0 0
1 1 1 1 1
(3) (3) (3) (3) (3)
1 (4) 1 (4) 1 (4)
0 0 0
0 0 0
1 (3) 1 (3) 1 (3)
(22) (4) (4) (4) (4) (4) (4)
(4)
(100) (60) (20)
(20)
(20)
Patients with multiple events in the same category are counted only once in that category; patients with events in more than one category are counted once in each of those categories. AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma glutamyl transferase; INR, International Normalized Ratio.
original article
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At least 1 CTCAE grade ‡3 Neutropenia Leukopenia Febrile neutropenia Fatigue Abdominal pain Anorexia AST increased Bacteremia Constipation Cough Drug toxicity Dyspnea Inferior vena caval occlusion INR increased Malaise Pain in extremity Pneumonia Post-op wound infection Pyrexia Sepsis Vomiting
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Table 3. Patients with at least one CTCAE grade ‡3 by AZD1152 dose and dosing schedule
11 830 19 280 7.080 33.72 15.61 (42.84) 11 230 (8.494) (47.79) 30 010 (1.879) (19.91) 6.738 (23.51) (71.59) 18.33 (1.859) (81.09) 53.26 (21.81) 6613 10 620 7.373 51.77 19.85 (22.72) (22.60) (18.74) (20.46) (22.55) (34.90) 9215 (7.06) 21 780 (16.08) 6.548 (46.60) 20.66 (63.15) 54.94 7037 10 460 6.629 43.01 19.62 (15.28) (11.68) (11.38) (11.64) (16.19) (50.03) 7696 (52.22) 19 990 (5.026) 6.727 (42.97) 15.01 (27.00) 50.12 2470 3572 9.292 83.98 35.95 (6.436) (4.518) (4.200) (4.404) (7.510) 2879 7470 7.001 26.77 88.42 (19.41) (14.96) (65.03) (16.32) (33.59) %) %) %) %) %) (CV, (CV, (CV, (CV, (CV, Gmean Gmean Gmean Gmean Gmean
Active moiety of the pro-drug AZD1152. Cmax, maximum plasma (peak) drug concentration; AUC, area under plasma concentration–time curve; t½, half-life; CL, total clearance; Vss, volume at steady state; Gmean, geometric mean; CV, coefficient of variation.
a
1168 1807 4.785 110.7 53.31 Cmax (ng/ml) AUC (ngh/ml) t½ (h) CL (l/h) Vss (l)
(24.84) 13 010 (24.52) (26.69) 33 640 (23.36) (8.705) 6.915 (12.11) (34.16) 19.32 (23.68) (55.37) 57.61 (28.35)
200 mg (N = 4) 300 mg (N = 3) 450 mg (N = 23) 550 mg (N = 5) 650 mg (N = 5) AZD1152 AZD1152-hQPA AZD1152 AZD1152-hQPA AZD1152 AZD1152-hQPA AZD1152 AZD1152-hQPA AZD1152 AZD1152-hQPA Parameter (unit)
436 | Boss et al.
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in vivo. Based on the working mechanism of AZD1152, tumor cells may need to proliferate a few times before they kill themselves. In preclinical models, tumors have an extremely high proliferation rate, which perhaps makes them more susceptible to the actions of AZD1152. In humans, however, the growth rate is slower and perhaps we need to be more patient and even accept initial growth before a reduction is seen. With regards to the optimal treatment schedule for AZD1152, this study investigated a 2-h infusion. However, preclinical studies with AZD1152 have revealed prolonged drug administration to be more effective, and this has also been reported in a phase I study using AT9283 [21]. More research is needed to establish optimal treatment schedules for AZD1152 and other aurora kinase inhibitors. The use of validated biomarkers will be essential in future studies to assess the activity of these drugs. Assessing the phosphorylation of Histone H3 for instance is a useful tool for evaluating the degree of Aurora B inhibition [22]. Due to the absence of these data in the reported study, it remains difficult to draw conclusions on the most effective dose and schedule of AZD1152. The efficacy of AZD1152 in combination with other drug classes is also under investigation. Treatment with AZD1152 was found to be synergistic with a variety of chemotherapeutic agents in preclinical studies, including irinotecan, docetaxel (Taxotere), vinorelbine, gemcitabine, oxaliplatin and 5fluorouracil [23], and with vincristine and topoisomerase inhibitors in leukemia cell lines [24]. Combining AZD1152 with radiotherapy might also provide a promising strategy since the compound potentiates the radiation response in p53deficient cancer cells [25]. In summary, the MTD of AZD1152 was 200 mg for the 7-day dosing schedule and 450 mg for the 14-day dosing schedule. Neutropenia and leukopenia were the most frequently reported AEs and DLT of AZD1152 in this patient population. Overall, AZD1152 displayed a manageable tolerability profile on either dosing regimen, and there were no associated safety concerns. Further studies are assessing AZD1152 in patients with hematooncologic malignancies.
funding AstraZeneca (AstraZeneca study number D1531C00001).
acknowledgements MPL would like to acknowledge The Netherlands Organization for Scientific Research for funding his training with a personal grant (AGIKO). We thank Dr Colette O’Sullivan, from Scriva Medical Communications, who provided medical writing assistance funded by AstraZeneca.
disclosures PKS, OA, DW and SD, AstraZeneca. Consultant/advisory role: JHS, AstraZeneca. Stock ownership: OA and DW, AstraZeneca. Research funding: JHS.
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Table 4. Plasma pharmacokinetic parameters of AZD1152 and AZD1152-hQPAa, following a single 2-h infusion every 14 days (schedule B)
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