A phase 0 analysis of ixazomib in patients with glioblastoma

Quillin,Joseph; Patel,Rikesh; Herzberg,Eric; Alton,Denny; Bikzhanova,Galina; Geisler,Lisa; Olson,Jeffrey

doi:10.3892/mco.2020.2114

A phase 0 analysis of ixazomib in patients with glioblastoma

Authors:
- Joseph Quillin
- Rikesh Patel
- Eric Herzberg
- Denny Alton
- Galina Bikzhanova
- Lisa Geisler
- Jeffrey Olson
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Affiliations: Department of Neurosurgery, Emory University, Atlanta, GA 30322, USA, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA, Covance Laboratories, Inc., Madison, WI 53704, USA
Published online on: August 13, 2020 https://doi.org/10.3892/mco.2020.2114
Article Number: 43

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Abstract

Improving overall survival in recurrent glioblastoma remains a challenge, and drugs acting by unique mechanisms are urgently required. Ixazomib is an orally‑administered proteasome inhibitor used in combination with lenalidomide and dexamethasone to treat patients with multiple myeloma who have received at least one prior therapy. However, ixazomib's ability to reach brain tumors has not been studied during its development. The aim of the present study (ClinicalTrials.gov, NCT02630030) was to establish and quantify ixazomib's presence in glioblastoma. The present study investigated 3 patients with recurrent glioblastoma after administration of oral ixazomib citrate (MLN 9708) at a fixed 4.0 mg dose within a 3‑hpreoperative window. A total of 2 blood samples were taken from each patient at the time of incision, tumor sampling and closure. Brain tumor samples were collected during tumor resection. These samples were then used to measure the plasma and brain tumor tissue concentration of the biologically‑active form of ixazomib (MLN 2238). Patient 1 had plasma concentrations of ixazomib averaging 26.2, 21.8 and 15.3 ng/ml at incision, tumor sampling and closure, respectively. The brain tumor tissue concentration was 7.88 ng/g. Patient 2 had the same interval and brain tumor tissue measurements of 19.0, 18.0 and 8.93 ng/ml, and 2.03 ng/g. Patient 3 had plasma concentration interval measurements of 25.6, 36.2 and 28.7 ng/ml. Multiple brain tumor tissue samples were taken in patient 3, with an average tissue ixazomib concentration of 3.37 ng/g. Ixazomib was found at plasma concentrations commensurate with its previously established pharmacokinetic profile without clinically relevant drug‑related adverse events. Ixazomib reaches glioblastoma tissues at measurable concentrations at the time of tumor resection, confirming target tissue delivery. This justifies the phase I study of ixazomib in recurrent glioblastoma currently in development.

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1	Porter KR, McCarthy BJ, Freels S, Kim Y and Davis FG: Prevalence estimates for primary brain tumors in the United States by age, gender, behavior, and histology. Neuro Oncol. 12:520–527. 2010.PubMed/NCBI View Article : Google Scholar
2	Omuro A and DeAngelis LM: Glioblastoma and other malignant gliomas: A clinical review. JAMA. 310:1842–1850. 2013.PubMed/NCBI View Article : Google Scholar
3	Voss P and Grune T: The nuclear proteasome and the degradation of oxidatively damaged proteins. Amino Acids. 32:527–534. 2007.PubMed/NCBI View Article : Google Scholar
4	Bladé J, Cibeira MT and Rosiñol L: Bortezomib: A valuable new antineoplastic strategy in multiple myeloma. Acta Oncol. 44:440–448. 2005.PubMed/NCBI View Article : Google Scholar
5	Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S and Elliott PJ: Proteasome inhibitors: A novel class of potent and effective antitumor agents. Cancer Res. 59:2615–22. 1999.PubMed/NCBI
6	Yin D, Zhou H, Kumagai T, Liu G, Ong JM, Black KL and Koeffler HP: Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM). Oncogene. 24:344–354. 2005.PubMed/NCBI View Article : Google Scholar
7	Kubicek GJ, Werner-Wasik M, Machtay M, Mallon G, Myers T, Ramirez M, Andrews D, Curran WJ Jr and Dicker AP: Phase I trial using proteasome inhibitor bortezomib and concurrent temozolomide and radiotherapy for central nervous system malignancies. Int J Radiat Oncol Biol Phys. 74:433–439. 2009.PubMed/NCBI View Article : Google Scholar
8	Kong XT, Nguyen NT, Choi YJ, Zhang G, Nguyen HN, Filka E, Green S, Yong WH, Liau LM, Green RM, et al: Phase 2 study of bortezomib combined with temozolomide and regional radiation therapy for upfront treatment of patients with newly diagnosed glioblastoma multiforme: Safety and efficacy assessment. Int J Radiat Oncol Biol Phys. 100:1195–1203. 2018.PubMed/NCBI View Article : Google Scholar
9	Styczynski J, Olszewska-Slonina D, Kolodziej B, Napieraj M and Wysocki M: Activity of bortezomib in glioblastoma. Anticancer Res. 26:4499–4503. 2006.PubMed/NCBI
10	Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, et al: Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: An open-label phase 1/2 study. Lancet Oncol. 15:1503–1512. 2014.PubMed/NCBI View Article : Google Scholar
11	Kumar SK, Bensinger WI, Zimmerman TM, Reeder CB, Berenson JR, Berg D, Hui AM, Gupta N, Di Bacco A, Yu J, et al: Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 124:1047–1055. 2014.PubMed/NCBI View Article : Google Scholar
12	Richardson PG, Baz R, Wang M, Jakubowiak AJ, Laubach JP, Harvey RD, Talpaz M, Berg D, Liu G, Yu J, et al: Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 124:1038–1046. 2014.PubMed/NCBI View Article : Google Scholar
13	Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M, Berger A, Yu J, Yang Y, Hales P, Bruzzese F, et al: Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res. 70:1970–1980. 2010.PubMed/NCBI View Article : Google Scholar
14	Chauhan D, Tian Z, Zhou B, Kuhn D, Orlowski R, Raje N, Richardson P and Anderson KC: In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res. 17:5311–5321. 2011.PubMed/NCBI View Article : Google Scholar
15	Gupta N, Diderichsen PM, Hanley MJ, Berg D, van de Velde H, Harvey RD and Venkatakrishnan K: Population pharmacokinetic analysis of ixazomib, an oral proteasome inhibitor, including data from the phase III TOURMALINE-MM1 study to inform labelling. Clin Pharmacokinet. 6L:1355–1368. 2017.PubMed/NCBI View Article : Google Scholar
16	Gentile M, Offidani M, Vigna E, Corvatta L, Recchia AG, Morabito L, Morabito F and Gentili S: Ixazomib for the treatment of multiple myeloma. Expert Opin Investig Drugs. 24:1287–1298. 2015.PubMed/NCBI View Article : Google Scholar
17	Gupta N, Zhao Y, Hui AM, Esseltine DL and Venkatakrishnan K: Switching from body surface area-based to ﬁxed dosing for the investigational proteasome inhibitor ixazomib: A population pharmacokinetic analysis. Br J Clin Pharmacol. 79:789–800. 2015.PubMed/NCBI View Article : Google Scholar
18	Kummar S, Rubinstein L, Kinders R, Parchment RE, Gutierrez ME, Murgo AJ, Ji J, Mroczkowski B, Pickeral OK, Simpson M, et al: Phase 0 clinical trials: Conceptions and misconceptions. Cancer J. 14:133–137. 2008.PubMed/NCBI View Article : Google Scholar
19	Burger PC, Heinz ER, Shibata T and Kleihues P: Topographic anatomy and CT correlations in the untreated glioblastoma multiforme. J Neurosurg. 68:698–704. 1988.PubMed/NCBI View Article : Google Scholar
20	Louis DN, Ohgaki H, Wiestler OD and Cavenee WK (eds.): WHO Classification of Tumours of the Central Nervous System. (Revised 4th edition), IARC, Lyon, 2016.
21	Wu W, Lamborn KR, Buckner JC, Novotny PJ, Chang SM, O'Fallon JR, Jaeckle KA and Prados MD: Joint NCCTG and NABTC prognostic factors analysis for high-grade recurrent glioma. Neuro Oncol. 12:164–172. 2010.PubMed/NCBI View Article : Google Scholar