A Phase II Trial of Alisertib (MLN8237) in Salvage Malignant Mesothelioma

Our plain-English summary of A Phase II Trial of Alisertib (MLN8237) in Salvage Malignant Mesothelioma, by C.M. Gay, Y. Zhou, J.J. Lee, et al (The Oncologist, 2020).

The study

• Authors: C.M. Gay, Y. Zhou, J.J. Lee, X.M. Tang, W. Lu, I.I. Wistuba, R. Ferrarotto, D.L. Gibbons, B.S. Glisson, M.S. Kies, G.R. Simon, J.V. Heymach, A.S. Tsao
• Journal: The Oncologist
• Published: 2020;25(10):e1457-e1463
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Lessons Learned: Treatment with the Aurora kinase A inhibitor yields often durable disease control, but limited tumor regression, in heavily pretreated patients with unresectable malignant pleural or peritoneal mesothelioma. In a limited sample size, MYC copy-number gain or gene amplification, a candidate predictive biomarker for alisertib, did not correlate with improved response numbers or patient outcomes.

Background: Malignant mesothelioma is an aggressive disease for which few effective therapies are available. The Aurora family kinases are critical for mitotic fidelity and highly expressed in mesothelioma, wherein their inhibition leads to growth arrest in vitro. We evaluated the efficacy of alisertib, an Aurora A kinase inhibitor, in relapsed malignant mesothelioma.

Methods: Twenty-six patients with previously treated, unresectable pleural or peritoneal mesothelioma were enrolled on a single-arm, single-institution phase II trial of alisertib at a dosage of 50 mg twice daily for 7 of every 21 days. The primary endpoint was 4-month disease control rate. Secondary endpoints included overall response rate, progression free survival, overall survival, safety/toxicity, and correlation of endpoints with MYC copy number.

Results: Of the 25 evaluable patients treated on study, 8 (32%) experienced 4-month disease control, surpassing the futility endpoint. There were no confirmed partial or complete responses. Median progression-free and overall survival were 2.8 months and 6.3 months, respectively. No associations between MYC copy number and outcomes were observed.

Conclusion: Alisertib has modest activity in this unselected malignant mesothelioma population. Several patients achieved durable disease control. Although the study did meet its prespecified futility endpoint, the sponsor elected to close the trial at the interim analysis.

© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.

In plain English

This single-arm phase II trial at MD Anderson Cancer Center in Houston did not study asbestos exposure. From June 2015 to August 2016, 26 previously treated patients with inoperable pleural or peritoneal mesothelioma took alisertib, 50 mg twice daily for 7 of every 21 days. Of 25 evaluable patients, 8 (32%) had 4-month disease control, above the 30% futility threshold. None had a confirmed tumor response; one (4.0%) had a minor response and 13 (52.0%) had stable disease. Median progression-free survival was 2.8 months (95% confidence interval 1.3 to 4.0) and median overall survival was 6.3 months (95% confidence interval 5.7 to 11.1). Most side effects were grade 1 or 2; none reached grade 4. One patient died on study, of causes judged unrelated to the drug. Only two to five of 22 tested tumors had a MYC gain. No correlation with outcomes appeared, but the authors called this analysis underpowered. The sponsor ended enrollment after changing its plans for the drug. The authors concluded that alisertib had limited activity but was well tolerated, and that Aurora kinase inhibitors merit further study in mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Single-arm, single-institution phase II clinical drug trial using a Simon minimax two-stage design, ended at the interim analysis
• Who was studied: 26 patients enrolled June 2015 to August 2016 at the University of Texas MD Anderson Cancer Center (24 male, 2 female; median age 69, range 44 to 85; 21 epithelioid and 5 biphasic mesothelioma). All had previously treated, unresectable pleural or peritoneal mesothelioma. 25 were evaluable.
• Exposure: No asbestos exposure was studied. The exposure was treatment with alisertib (MLN8237), an Aurora A kinase inhibitor, at 50 mg by mouth twice daily for 7 of every 21 days.
• Main results:
  • Primary endpoint: 8 of 25 evaluable patients (32%) had disease control at 4 months, against a target of more than 30%
  • No confirmed responses. Among the 25 evaluable patients, 1 (4.0%) had a minor response as best response and 13 (52.0%) had stable disease as best response
  • Median progression-free survival was 2.8 months (95% CI 1.3 to 4.0) and median overall survival was 6.3 months (95% CI 5.7 to 11.1)
  • 123 adverse events were reported, mostly grade 1 (69.1%) and grade 2 (21.1%), with a 9.8% grade 3 toxicity rate
  • No grade 4 toxicities were reported
  • Of the 26 enrolled patients, 8 (30.8%) needed a dose interruption
  • One patient died on study; the respiratory and renal failure involved were judged not related to the study drug
  • Tissue from 22 patients was tested for MYC copy number. Two to five tumors showed MYC gain, depending on the criteria used, with no correlation with response, duration of response or survival
  • The sponsor ended enrollment because of a shift in development strategy for alisertib
• The authors' conclusion: The authors concluded that alisertib's activity in this setting was limited, but the drug was well tolerated and safe, and that further exploration of Aurora kinase inhibitors in mesothelioma is warranted.
• Limitations the authors state:
  • The MYC biomarker analysis was underpowered because the study ended early and few MYC copy number gains were found
  • There were no confirmed objective responses
  • Comparisons of progression-free survival with other trials have the limits of cross-study comparisons

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Unresectable, Peritoneal Mesothelioma, Biomarker, Mesothelioma, Overall Survival.

Related studies

• Phase I trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma — A.S. Tsao, N. Harun, et al. (2014)
• Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial — L.M. Krug, H.L. Kindler, et al. (2015)
• Phase I Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemonaive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905) — A.S. Tsao, J. Moon, et al. (2017)
• Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial — A. Scherpereel, J. Mazieres, et al. (2019)
• Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial — B. Geoerger, H.J. Kang, et al. (2020)
• Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial — P.E. Van Schil, P. Baas, et al. (2010)

Browse more research in The Oncologist, or return to medical research.