Phase I and pharmacological study of the novel aurora kinase inhibitor AZD1152

3008 Background: AZD1152 is a specific aurora kinase inhibitor, selective for Aurora B, currently undergoing Phase I evaluation in patients with advanced solid malignancies. AZD1152 induces p53 independent cellular multinucleation and polyploidy, resulting in apoptosis. It is rapidly converted to the active moiety (AZD1152-HQPA) in plasma. This is the first human study, aimed at determining the maximum tolerated dose, dose limiting toxicities (DLT), pharmacokinetic profile (PK), and to recommend a dose and schedule for further clinical evaluation. Methods: AZD1152 is being administered as a 2-hour IV infusion given weekly in a dose-escalating manner, utilizing an accelerated titration design in patients for whom no other therapy of proven benefit exists. Patients with WHO-PS of 0-2 and adequate bone marrow, liver and renal function were eligible. Results: To date, a total of 13 patients have been recruited: 10M/3F, median age 58 yrs (range 52–71). Patients had colon cancer (n = 3), melanoma (n = 2), or various other solid tumors. Doses were escalated from 100 mg to 200, 300 and 450 mg. DLT was CTC grade 4 neutropenia in 3 patients at 450 mg, signifying a non-tolerated dose on this schedule. Bone marrow recovery was generally noted by 2 wks post-dose. Problematic non-hematological toxicities have not been reported to date. Five patients have remained on therapy for >12 wks (2 × 12+ wks, 16+ wks, 20+ wks and 28+ wks, respectively). AZD1152 is rapidly converted to AZD1152-HQPA with an apparent dose proportional increase in the systemic exposures of both. Population PK analysis of AZD1152-HQPA in the first eight patients revealed a linear three compartment model with clearance 22.4 ± 1.03 L/h. Interoccasion variability was low (CV 5.7%). Conclusions: To date, AZD1152 has been well tolerated when administered IV over 2 hours on a weekly schedule at doses up to 300 mg, however further patients are being enrolled to confirm. Neutropenia is the DLT at 450 mg and no other clinically significant toxicities have been reported. Both AZD1152 and AZD1152-HQPA appeared to have linear kinetics. Significant disease stabilization observed in this rapidly progressive disease setting supports continued clinical development. [Table: see text]

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Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients With Advanced Cancers

Journal of Clinical Oncology ◽

10.1200/jco.2009.21.8487 ◽

2009 ◽

Vol 27 (31) ◽

pp. 5262-5269 ◽

Cited By ~ 53

Author(s):

Nancy L. Lewis ◽

Lionel D. Lewis ◽

Joseph P. Eder ◽

Nandi J. Reddy ◽

Feng Guo ◽

...

Keyword(s):

Growth Factor ◽

Phase I ◽

Kinase Inhibitor ◽

Single Agent ◽

Human Study ◽

Growth Factor Receptor ◽

Systemic Exposure ◽

Maximum Tolerated Dose ◽

Platelet Derived Growth Factor ◽

Time Curve

Purpose This phase I, first-in-human study evaluated the safety, tolerability, pharmacokinetics, and maximum-tolerated dose (MTD) of an oral platelet-derived growth factor receptor inhibitor, CP-868,596. Patients and Methods Patients with advanced solid tumors were eligible. Dose escalations were performed in three groups with two formulations: uncoated on an empty stomach (UES), uncoated with food (UFED), and film-coated (FC) without food. Initial dose escalation in the UES group was followed by parallel escalations in the UFED and FC groups. Results Fifty-nine patients enrolled. CP-868,596 was escalated from 100 mg to 340 mg daily in the UES group, from 60 mg to 100 mg twice daily in the UFED group, and from 100 mg once daily to 140 mg twice daily in the FC group. MTDs were 200 mg daily in the UES group and 100 mg twice daily in the FC group; MTD was not reached at 100 mg twice daily in the UFED group. Dose-limiting toxicities included hematuria, increased γ-glutamyltransferase or ALT, insomnia, and nausea/vomiting. Most treatment-related AEs were of grades 1 to 2 severity; nausea, vomiting, and diarrhea were reported most frequently. Administration with food generally improved tolerability. CP-868,596 was absorbed slowly; systemic exposure parameters appeared to increase greater than proportionally with dose. Mean serum concentrations exceeded the preclinically predicted minimal efficacious concentration (ie, 16 ng/mL) at all dosages. Food and film coating apparently increased interpatient variability of the maximum observed plasma concentration and the area under the concentration-time curve. No objective responses were reported, and eight patients achieved stable disease (mean duration, 5.7 months). Conclusion CP-868,596 potentially demonstrated greater than dose-proportional pharmacokinetics. The recommended dosage of 100 mg twice daily with food was well tolerated. Additional development as a single agent in selected populations or in combination with chemotherapy in broader populations is warranted.

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Phase I Pharmacokinetic and Pharmacodynamic Study of the Aurora Kinase Inhibitor Danusertib in Patients With Advanced or Metastatic Solid Tumors

Journal of Clinical Oncology ◽

10.1200/jco.2008.21.6655 ◽

2009 ◽

Vol 27 (30) ◽

pp. 5094-5101 ◽

Cited By ~ 70

Author(s):

Neeltje Steeghs ◽

Ferry A.L.M. Eskens ◽

Hans Gelderblom ◽

Jaap Verweij ◽

Johan W.R. Nortier ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Kinase Inhibitor ◽

Systemic Exposure ◽

Aurora Kinase ◽

Aurora Kinase Inhibitor ◽

Dose Escalation Study ◽

Phase Ii Studies ◽

Nonhematologic Toxicity ◽

Biomarker Analysis

PurposeDanusertib (PHA-739358) is a small-molecule pan-aurora kinase inhibitor. This phase I dose escalation study was conducted to evaluate safety and tolerability of danusertib with additional pharmacokinetic, biomarker, and efficacy assessments.Patients and MethodsPatients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Danusertib was administered intravenously on days 1, 8, and 15 every 28 days in 6-hour or 3-hour infusion schedules (ie, 6-hour IVS or 3-hour IVS). Dose levels from 45 mg/m2in the 6-hour IVS, and from 250 mg/m2in the 3-hour IVS, were studied.ResultsFifty patients were treated. For the 6-hour IVS, the most frequently reported adverse effects were neutropenia (55%), nausea (25%), anorexia (23%), fatigue (20%), and diarrhea (18%). In the 3-hour IVS, fatigue (70%), neutropenia (60%), diarrhea (50%), and nausea (30%) were seen. Nonhematologic toxicity was mild to moderate. Neutropenia was dose limiting. The maximum-tolerated dose was 330 mg/m2for the 6-hour IVS and was not identified for the 3-hour IVS. The systemic exposure to danusertib increased linearly with dose. The infusion rate did not appear to remarkably influence the pharmacokinetics of danusertib. Biomarker analysis showed inhibition of histone H3 phosphorylation, indicative of aurora B inhibition, at doses of 190 mg/m2or greater. Stable disease was observed in 23.7% of evaluable patients, and disease stabilization occurred in 6 or more months in five patients.ConclusionDose-limiting toxicity of danusertib is neutropenia, which was short lasting and generally uncomplicated; danusertib administration had limited nonhematologic toxicity. The recommended dose of danusertib for phase II studies is 330 mg/m2infused over 6 hours on days 1, 8, and 15 every 28 days.

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A phase I schedule dependency study of the aurora kinase inhibitor MSC1992371A in combination with gemcitabine in patients with solid tumors

Investigational New Drugs ◽

10.1007/s10637-013-9950-y ◽

2013 ◽

Vol 32 (1) ◽

pp. 94-103 ◽

Cited By ~ 8

Author(s):

E. Raymond ◽

J. Alexandre ◽

S. Faivre ◽

F. Goldwasser ◽

T. Besse-Hammer ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Kinase Inhibitor ◽

Aurora Kinase ◽

Aurora Kinase Inhibitor

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The Specific Aurora Kinase Inhibitor AZD1152 Significantly Affects the Growth of Human Leukaemic Cells in an In Vivo AML Model.

Blood ◽

10.1182/blood.v108.11.162.162 ◽

2006 ◽

Vol 108 (11) ◽

pp. 162-162

Author(s):

Daniel Pearce ◽

Rajesh Odedra ◽

Robert Wilkinson ◽

Dominique Bonnet

Keyword(s):

Bone Marrow ◽

Kinase Inhibitor ◽

Aurora Kinase ◽

Scid Mice ◽

Aurora B ◽

Aurora Kinase Inhibitor ◽

Cell Content ◽

Treatment Groups ◽

The Mean

Abstract AZD1152 is a specific Aurora kinase inhibitor with selectivity for Aurora B kinase, designed to target cell division in proliferating tumour cells. It has been shown in model systems that inhibition of Aurora B kinase with AZD1152 reduces histone H3 phosphorylation (phH3) and inhibits cytokinesis, thus inducing cellular multi-nucleation and polyploidy, leading to apoptosis and cell death. Here, we present results of preliminary studies on the in vivo action of AZD1152 on the growth and development of both a human acute myeloid leukaemia (AML) cell line (HL-60) and primary AML samples in the NOD/SCID xeno-transplantation model. Two weeks of AZD1152 at 25 mg/kg/day is well tolerated in NOD/SCID mice. HL-60 cells were injected iv into sub-lethally irradiated NOD/SCID mice (n=24) and allowed to engraft in the bone marrow. Three weeks later, when malignant cell growth was well established in the bone marrow, mice were split into treatment groups. Either vehicle (n=12) or AZD1152 (25 mg/kg/day via minipump, n=12) was administered for 7 days. One AZD1152-treated group was sacrificed immediately post-treatment (n=9) and another was left for a further 2 weeks before bone marrow analysis for HL-60 cell content (defined by human CD45+/CD33+/CD19− expression). The mean percentage HL-60 cell content in the marrow of untreated mice was 64.5 ± 19.0 (range 14.0–86.6, n=11), whereas in mice that had received AZD1152 and were sacrificed at the end of dosing period, the mean percentage was 0.29 ± 0.74 (range 0–2.26, n=9; p<0.001). In AZD1152-treated mice that were left for 2 weeks post-treatment, the mean percentage of HL-60 cell content in the bone marrow was 0.008 ± 0.74 (n=3). Similar experiments were performed with two primary AML samples. AML-1 is from a patient with French-American-British (FAB)-type M1 AML and AML-2 is from a FAB-type M2 AML patient. Ten million cells from both AML samples were injected into NOD/SCID mice (n=12 for AML-1; n=6 for AML-2). Ten weeks later, mice were split into treatment groups and dosed with either control vehicle or 25 mg/kg/day of AZD1152 via minipumps for 7 days. All mice were sacrificed after 1 week of treatment in these initial experiments. The mean percentage engraftment in untreated mice was 59.7 ± 36.0 (range 6.2–84.0, n=4) for AML-1 and 21.8 ± 22.5 (range 5.9–37.7, n=2) for AML-2. Whereas, in mice that had received 25 mg/kg/day of AZD1152 for 7 days, the percentage of engraftment was 1.8 ± 1.7 (range 0.38–4.53, n=5; p<0.01) and 0.07 ± 0.07 (range 0.12–0.014, n=2) for AML-1 and AML-2, respectively. These data indicate that AZD1152 has a profound effect on the engraftment of human AML cell lines and primary AML samples in an in vivo model. Furthermore, initial results may indicate a long-term effect of AZD1152 treatment in vivo. AZD1152 is currently undergoing Phase I clinical trials in AML patients.

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