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Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2\u00a0mg\/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day\u00a0cycle. Due to its poor aqueous solubility, VLX1570 was formulated in polyethylene glycol, polyoxyethylated castor oil, and polysorbate 80 and administered as a brief intravenous (IV) infusion via a central venous catheter. Anti-myeloma effects were noted at doses at or above 0.6\u00a0mg\/kg, however, two patients treated at the 1.2\u00a0mg\/kg dose level experienced severe, abrupt, and progressive respiratory insufficiency, which was associated with diffuse pulmonary infiltrates on imaging studies, similar to those rarely noted with bortezomib and other inhibitors of the 20S proteasome, culminating in death. Although the contribution of VLX1570\u2019s formulation to the pulmonary toxicity could not be ruled out, the severity and precipitous nature of the toxicity and the steep relationship between dose and toxicity, the study was discontinued. Despite the severe pulmonary toxicity noted with VLX1570, efforts directed at identifying DUB inhibitors with greater therapeutic indices appear warranted based on the unique mechanism of action, robustness of preclinical antitumor activity, and activity of the DUB inhibitors in MM resistant to PIs targeting the 20S proteasome subunit.<\/jats:p>","DOI":"10.1007\/s10637-020-00915-4","type":"journal-article","created":{"date-parts":[[2020,3,3]],"date-time":"2020-03-03T09:02:48Z","timestamp":1583226168000},"page":"1448-1453","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":107,"title":["Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and\/or refractory multiple myeloma"],"prefix":"10.1007","volume":"38","author":[{"given":"Eric K.","family":"Rowinsky","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agne","family":"Paner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus G.","family":"Berdeja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Paba-Prada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parameswaran","family":"Venugopal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimmo","family":"Porkka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Gullbo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stig","family":"Linder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8583-6138","authenticated-orcid":false,"given":"Angelica","family":"Loskog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul G.","family":"Richardson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ola","family":"Landgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,3]]},"reference":[{"key":"915_CR1","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1124\/pr.117.015370","volume":"71","author":"TA Thibaudeau","year":"2019","unstructured":"Thibaudeau TA, Smith DM (2019) A practical review of proteasome pharmacology. 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J.G.B. has received honoraria for consulting for the following: Takeda, Bristol-Myers Squibb, Karyopharm, CRISPR Therapeutics, Celgene, Kite Pharma, Servier, Janssen, Amgen, BioClinica, and Prothena.P.G.R has received research funding from Celgene, Takeda, and Oncopeptides, P.G.R. has received honoraria from participating on advisory boards for Celgene, Janssen, Takeda, Karyopharm, and Oncopeptides. O.L. was supported by the Memorial Sloan Kettering Core Grant (P30 CA008748). He received research funding from the National Institutes of Health, United States Food and Drug Administration, Multiple Myeloma Research Foundation, International Myeloma Foundation, Leukemia and Lymphoma Society, Perelman Family Foundation, Rising Tides Foundation, Amgen, Celgene, Janssen, Takeda, Glenmark., Seattle Genetics, and Karyopharm.O.L. has received honoraria from participating on advisory boards from: Adaptive, Amgen, Binding Site., Bristol-Myers Squib, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer. O.L. serves on Independent Data Monitoring Committees for clinical trials sponsored by Takeda, Merck, and Janssen.A.P., C.P-P., P.V., and K.P. declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"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.This article does not contain any studies with animals performed by any of the authors. The study protocol was approved by the Medical Ethics Committees of the participating institutions.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Informed consent was obtained from all individual participants included in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}