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Updated: Jan 26, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Phase I Study of Aurora A Kinase Inhibitor Alisertib (MLN8237) in Combination With Selective VEGFR Inhibitor
Hiral A Shah1,2, James H Fischer3, Neeta K Venepalli1
1Department of Medicine, Division of Hematology/Oncology.
Objectives:
Pazopanib is a multikinase angiogenesis inhibitor. Alisertib is a highly selective inhibitor of mitotic Aurora A kinase. There is preclinical evidence that mitosis-targeting agents exhibit antiangiogenic effects. Thus, the combination of these 2 agents may have a synergistic effect on tumor vasculature. The primary objective of this study is to determine the optimal tolerated dose (OTD) for alisertib and pazopanib.
Materials And Methods:
This phase 1b study evaluated the OTD of alisertib twice a day, on days 1 to 7 with pazopanib, once a day, continuously in a 21-day cycle, both taken orally. Disease response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 every 2 cycles. OTD cohort was expanded to assure safety and perform pharmacokinetics analysis.
Results:
A total of 27 patients received treatment. Seventy-seven percent of the patients had received at least 3 prior chemotherapy regimens. Dose-limiting toxicities occurred in dose level (DL) 2+ (grade 4 thrombocytopenia and grade 3 mucositis) and DL 3 (grade 3 liver transaminases elevation and grade 3 abdominal pain). The OTD was determined to be DL 2: alisertib 20 mg twice daily and pazopanib 600 mg daily. Pharmacokinetic analysis revealed that clearance of alisertib was reduced by ∼40% in the presence of pazopanib compared with clearance in the absence of pazopanib. Fourteen patients had stable disease and 2 patients had a partial response.
Conclusions:
The combination of alisertib with pazopanib demonstrates manageable safety and early clinical evidence of antitumor activity in patients with advanced malignancies (NCT01639911).
Insights
The combination of alisertib and pazopanib showed manageable safety and antitumor effects in advanced cancers. The optimal tolerated dose was determined to be alisertib 20 mg twice daily and pazopanib 600 mg daily.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Pazopanib is a multikinase inhibitor targeting angiogenesis.
- Alisertib inhibits Aurora A kinase, a mitotic target.
- Preclinical data suggest antiangiogenic effects of mitosis-targeting agents.
Purpose of the Study:
- Determine the optimal tolerated dose (OTD) of alisertib and pazopanib combination therapy.
- Evaluate the safety and tolerability of the combined treatment regimen.
- Assess early clinical activity and pharmacokinetic interactions.
Main Methods:
- Phase 1b study design.
- Oral administration of alisertib (twice daily, days 1-7) and pazopanib (daily, continuous) in 21-day cycles.
- Response evaluation using RECIST v1.1; safety and pharmacokinetic analyses performed.
Main Results:
- Twenty-seven patients treated; 77% had received ≥3 prior chemotherapy regimens.
- Dose-limiting toxicities observed at higher dose levels.
- OTD established as alisertib 20 mg BID and pazopanib 600 mg daily.
- Alisertib clearance reduced by ~40% with pazopanib co-administration.
- 14 patients had stable disease; 2 patients had a partial response.
Conclusions:
- The combination of alisertib and pazopanib exhibits manageable safety.
- Early clinical evidence of antitumor activity in advanced malignancies.
- The determined OTD provides a basis for further clinical investigation.
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