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Phase 1 study of alisertib (MLN8237) and weekly irinotecan in adults with advanced solid tumors

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Abstract

Purpose

Aurora kinases are overexpressed or amplified in numerous malignancies. This study was designed to determine the safety and tolerability of the Aurora A kinase inhibitor alisertib (MLN8237) when combined with weekly irinotecan.

Methods

In this single-center phase 1 study, adult patients with refractory advanced solid tumors received 100 mg/m2 irinotecan intravenously on day 1 and 8 of a 21-day cycle. Alisertib at planned escalating dose levels of 20–60 mg was administered orally twice per day on days 1–3 and 8–10. Patients homozygous for UGT1A1*28 were excluded. The primary objective was the safety of alisertib when combined with irinotecan to determine the maximum tolerated dose (MTD). Secondary objectives included overall response rate by RECIST and pharmacokinetics in a planned expansion cohort of patients with colorectal cancer treated at the MTD.

Results

A total of 17 patients enrolled at three dose levels. Dose-limiting toxicities included diarrhea, dehydration, and neutropenia. The MTD of alisertib combined with weekly irinotecan was 20 mg twice per day on days 1–3 and 8–10. One fatal cardiac arrest at the highest dose level tested was deemed possibly related to drug treatment. One partial response in 11 efficacy evaluable patients (9%) occurred in a patient with small cell lung cancer. The study was terminated prior to the planned expansion in patients with colorectal cancer.

Conclusion

In contrast to prior results in a pediatric population, adult patients did not tolerate alisertib combined with irinotecan at clinically meaningful doses due to hematologic and gastrointestinal toxicities. The study was registered with ClinicalTrials.gov under study number NCT01923337 on Aug 15, 2013.

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Funding

This study was supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. The study was also supported by the National Cancer Institute under award P30CA093373. During the study, Dr. Semrad was also supported by the NCI under Award Number K12CA138464.

Author information

Authors and Affiliations

  1. Gene Upshaw Memorial Tahoe Forest Cancer Center, 10121 Pine Avenue, Truckee, CA, USA

    Thomas J. Semrad

  2. Division of Hematology/Oncology, University of California, Davis Comprehensive Cancer Center, Sacramento, CA, USA

    Thomas J. Semrad, Edward J. Kim, I-Yeh Gong, Tianhong Li, Scott Christensen, Mili Arora, Jonathan W. Riess, David R. Gandara & Karen Kelly

  3. Kaiser Permanente, Sacramento, CA, USA

    I-Yeh Gong

Authors
  1. Thomas J. Semrad
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Corresponding author

Correspondence to Thomas J. Semrad.

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Conflict of interest

Dr. Semrad reports grants (to the University of California, Davis for conduct of this study) from Millennium Pharmaceuticals, Inc.; Dr. Kim reports personal fees from Eisai, personal fees from Celgene, grants from BMS, grants from Astellas, grants from Samumed, grants from Boston Biomedical, grants from Halozyme, grants from EpicentRx, grants from Merck, grants from Oncomed, grants from Dynavax, personal fees from Lilly, grants from NGM Biopharmaceuticals, grants from Erytech, grants from Fibrogen, grants from Eureka Therapeutics, outside the submitted work; Dr. Gong has nothing to disclose; Dr. Li reports personal fees from Eisai, grants from Pfizer, grants from Merck, grants from Eureka, grants from OncoImmune (OncoC4), grants from Hengrui, grants from Tempus, outside the submitted work; Dr. Christensen has nothing to disclose; Dr. Arora has nothing to disclose; Dr. Riess reports personal fees from Blueprint, personal fees and non-financial support from Novartis, personal fees and non-financial support from Boehringer Ingelheim, personal fees from Celgene, non-financial support from AstraZeneca, personal fees and non-financial support from Spectrum, personal fees from Loxo Oncology, personal fees from Genentech, personal fees from Medtronic, non-financial support from Merck, non-financial support from Revolution Medicines, outside the submitted work; Dr. Gandara has nothing to disclose; Dr. Kelly reports grants and personal fees from Takeda.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study protocol was reviewed and approved by the institutional review board of the University of California, Davis.

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All patients provided written informed consent before treatment.

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Semrad, T.J., Kim, E.J., Gong, IY. et al. Phase 1 study of alisertib (MLN8237) and weekly irinotecan in adults with advanced solid tumors. Cancer Chemother Pharmacol 88, 335–341 (2021). https://doi.org/10.1007/s00280-021-04293-3

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  • DOI: https://doi.org/10.1007/s00280-021-04293-3

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