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Phase 1 study of th...
Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma.
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- Rowinsky, Eric K (författare)
- Vivolux AB,NEXTTOBE AB, Sweden
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- Paner, Agne (författare)
- Rush University Cancer Center,Rush Univ, IL 60612 USA
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- Berdeja, Jesus G (författare)
- Sarah Cannon Research Institute,Sarah Cannon Res Inst, TN USA
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- Paba-Prada, Claudia (författare)
- Dana-Faber Cancer Institute,Dana Farber Canc Inst, MA 02115 USA
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- Venugopal, Parameswaran (författare)
- Rush University Cancer Center,Rush Univ, IL 60612 USA
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- Porkka, Kimmo (författare)
- Helsinki University Hospital Comprehensive Cancer Center,Univ Helsinki, Finland; Helsinki Univ Hosp, Finland
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- Gullbo, Joachim (författare)
- Vivolux AB,NEXTTOBE AB, Sweden
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- Linder, Stig (författare)
- Linköpings universitet,Karolinska Institutet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Karolinska Inst, Sweden
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- Loskog, Angelica S., 1973- (författare)
- Uppsala universitet,Klinisk immunologi,NEXTTOBE AB, Sweden; Uppsala Univ, Sweden
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- Richardson, Paul G (författare)
- Dana-Farber Cancer Institute,Dana Farber Canc Inst, MA 02115 USA
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- Landgren, Ola (författare)
- Memorial Sloan Kettering Cancer Center,Mem Sloan Kettering Canc Ctr, NY 10021 USA
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(creator_code:org_t)
- 2020-03-03
- 2020
- Engelska.
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Ingår i: Investigational new drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 38:5, s. 1448-1453
- Relaterad länk:
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https://link.springe...
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https://liu.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- This phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2 mg/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. 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 mg/kg, however, two patients treated at the 1.2 mg/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's 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- 19S proteasome
- Multiple myeloma
- Protein deubiquitinase inhibitor
- Pulmonary toxicity
- VLX1570
Publikations- och innehållstyp
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Till lärosätets databas
- Av författaren/redakt...
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Rowinsky, Eric K
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Paner, Agne
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Berdeja, Jesus G
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Paba-Prada, Clau ...
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Venugopal, Param ...
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Porkka, Kimmo
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visa fler...
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Gullbo, Joachim
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Linder, Stig
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Loskog, Angelica ...
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Richardson, Paul ...
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Landgren, Ola
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Uppsala universitet
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Karolinska Institutet
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Linköpings universitet