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A phase 1 dose escalation study of BI 831266, an inhibitor of Aurora kinase B, in patients with advanced solid tumors.

Dittrich C, Fridrik MA, Koenigsberg R, Lee C, Goeldner RG, Hilbert J, Greil R - Invest New Drugs (2014)

Bottom Line: High variability in the pharmacokinetic profiles precluded definitive pharmacokinetic conclusions.One patient (4%; 32 mg) with cervical cancer demonstrated a confirmed partial response (duration 141 days, PFS 414 days).Four patients had stable disease.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Boltzmann Institute for Applied Cancer Research (LBI-ACR VIEnna) - LB Cluster Translational Oncology and Applied Cancer Research-Institution for Translational Research Vienna (ACR-ITR VIEnna), Third Medical Department, Center for Oncology and Hematology, Kaiser-Franz-Josef-Spital, Vienna, Austria, christian.dittrich@wienkav.at.

ABSTRACT
Purpose BI 831266 is a potent, selective, low-molecular-weight inhibitor of Aurora kinase B. This trial aimed to determine the maximum tolerated dose (MTD) of BI 831266 in patients with advanced solid tumors (NCT00756223; EudraCT 2008-001631-36; 1257.1). Methods BI 831266 (4-130 mg) was administered over 24 h on days 1 and 15 of a 4-week schedule. A modified 3 + 3 dose-escalation design was utilized to evaluate the MTD. Safety, pharmacokinetics, pharmacodynamics, objective response rate, progression-free survival (PFS) and exploratory biomarkers were secondary endpoints. Results Twenty-five patients received BI 831266. The most frequent tumor type was colorectal cancer (48%). One patient (130 mg) experienced a dose-limiting toxicity of grade 3 febrile neutropenia. The trial was prematurely terminated (sponsor decision) without further dose-escalation. The most frequent treatment-related adverse events (AEs) were fatigue (20%), neutropenia, alopecia (16% each), anemia, dry skin, and nausea (12% each). Treatment-related grade ≥3 AEs were neutropenia (12%), anemia (8%), and febrile neutropenia (4%); 15 patients experienced serious AEs. High variability in the pharmacokinetic profiles precluded definitive pharmacokinetic conclusions. Exploratory biomarker determination revealed consistency with the mode of action as an Aurora kinase B inhibitor. One patient (4%; 32 mg) with cervical cancer demonstrated a confirmed partial response (duration 141 days, PFS 414 days). Four patients had stable disease. Conclusion The MTD of BI 831266 was not reached because of early trial termination. BI 831266 demonstrated a generally manageable safety profile and signs of antitumor activity in some patients' solid tumors.

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CT scans of a patient with cervical cancer who experienced a confirmed PR. a and b: baseline scans; c and d: following 14 cycles of treatment with BI 831266. PR was first documented after cycle 10. PR partial response
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Fig4: CT scans of a patient with cervical cancer who experienced a confirmed PR. a and b: baseline scans; c and d: following 14 cycles of treatment with BI 831266. PR was first documented after cycle 10. PR partial response

Mentions: CT scans showing tumor shrinkage in this patient are shown in Fig. 4. An additional 4 patients (16.0 %; colorectal cancer: n = 2; pancreatic cancer: n = 1; bladder cancer: n = 1) experienced SD according to RECIST as best response. PFS among these patients ranged from 78 to 274 days. PFS in the 20 patients (80.0 %) without an objective RECIST response or SD ranged from 21 to 94 days.Fig. 4


A phase 1 dose escalation study of BI 831266, an inhibitor of Aurora kinase B, in patients with advanced solid tumors.

Dittrich C, Fridrik MA, Koenigsberg R, Lee C, Goeldner RG, Hilbert J, Greil R - Invest New Drugs (2014)

CT scans of a patient with cervical cancer who experienced a confirmed PR. a and b: baseline scans; c and d: following 14 cycles of treatment with BI 831266. PR was first documented after cycle 10. PR partial response
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4387274&req=5

Fig4: CT scans of a patient with cervical cancer who experienced a confirmed PR. a and b: baseline scans; c and d: following 14 cycles of treatment with BI 831266. PR was first documented after cycle 10. PR partial response
Mentions: CT scans showing tumor shrinkage in this patient are shown in Fig. 4. An additional 4 patients (16.0 %; colorectal cancer: n = 2; pancreatic cancer: n = 1; bladder cancer: n = 1) experienced SD according to RECIST as best response. PFS among these patients ranged from 78 to 274 days. PFS in the 20 patients (80.0 %) without an objective RECIST response or SD ranged from 21 to 94 days.Fig. 4

Bottom Line: High variability in the pharmacokinetic profiles precluded definitive pharmacokinetic conclusions.One patient (4%; 32 mg) with cervical cancer demonstrated a confirmed partial response (duration 141 days, PFS 414 days).Four patients had stable disease.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Boltzmann Institute for Applied Cancer Research (LBI-ACR VIEnna) - LB Cluster Translational Oncology and Applied Cancer Research-Institution for Translational Research Vienna (ACR-ITR VIEnna), Third Medical Department, Center for Oncology and Hematology, Kaiser-Franz-Josef-Spital, Vienna, Austria, christian.dittrich@wienkav.at.

ABSTRACT
Purpose BI 831266 is a potent, selective, low-molecular-weight inhibitor of Aurora kinase B. This trial aimed to determine the maximum tolerated dose (MTD) of BI 831266 in patients with advanced solid tumors (NCT00756223; EudraCT 2008-001631-36; 1257.1). Methods BI 831266 (4-130 mg) was administered over 24 h on days 1 and 15 of a 4-week schedule. A modified 3 + 3 dose-escalation design was utilized to evaluate the MTD. Safety, pharmacokinetics, pharmacodynamics, objective response rate, progression-free survival (PFS) and exploratory biomarkers were secondary endpoints. Results Twenty-five patients received BI 831266. The most frequent tumor type was colorectal cancer (48%). One patient (130 mg) experienced a dose-limiting toxicity of grade 3 febrile neutropenia. The trial was prematurely terminated (sponsor decision) without further dose-escalation. The most frequent treatment-related adverse events (AEs) were fatigue (20%), neutropenia, alopecia (16% each), anemia, dry skin, and nausea (12% each). Treatment-related grade ≥3 AEs were neutropenia (12%), anemia (8%), and febrile neutropenia (4%); 15 patients experienced serious AEs. High variability in the pharmacokinetic profiles precluded definitive pharmacokinetic conclusions. Exploratory biomarker determination revealed consistency with the mode of action as an Aurora kinase B inhibitor. One patient (4%; 32 mg) with cervical cancer demonstrated a confirmed partial response (duration 141 days, PFS 414 days). Four patients had stable disease. Conclusion The MTD of BI 831266 was not reached because of early trial termination. BI 831266 demonstrated a generally manageable safety profile and signs of antitumor activity in some patients' solid tumors.

Show MeSH
Related in: MedlinePlus