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01-08-2021 | Solid Tumor | Original Article

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

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

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2021

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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Title: Phase 1 study of alisertib (MLN8237) and weekly irinotecan in adults with advanced solid tumors
Authors: Thomas J. Semrad
Edward J. Kim
I-Yeh Gong
Tianhong Li
Scott Christensen
Mili Arora
Jonathan W. Riess
David R. Gandara
Karen Kelly
Publication date: 01-08-2021
Publisher: Springer Berlin Heidelberg
Keywords: Solid Tumor
Neutropenia
Diarrhea
Diarrhea
Colorectal Cancer
Colorectal Cancer
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2021
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-021-04293-3

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