Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours

Background In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours. Methods Adults with various solid tumours refractory t...

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Vydáno v:British journal of cancer Ročník 122; číslo 11; s. 1630 - 1637
Hlavní autoři: Hong, David S., Kang, Yoon-Koo, Borad, Mitesh, Sachdev, Jasgit, Ejadi, Samuel, Lim, Ho Yeong, Brenner, Andrew J., Park, Keunchil, Lee, Jae-Lyun, Kim, Tae-You, Shin, Sangjoon, Becerra, Carlos R., Falchook, Gerald, Stoudemire, Jay, Martin, Desiree, Kelnar, Kevin, Peltier, Heidi, Bonato, Vinicius, Bader, Andreas G., Smith, Susan, Kim, Sinil, O’Neill, Vincent, Beg, Muhammad S.
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 26.05.2020
Nature Publishing Group
Témata:
692/4028/67/1059/153
692/4028/67/1059/602
Adult
Aged
Aged, 80 and over
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - adverse effects
Antineoplastic Agents - pharmacokinetics
Biomedical and Life Sciences
Biomedicine
Cancer Research
Cancer therapies
Dexamethasone
Drug Resistance
Dyspnea
Epidemiology
Female
Fever
Gene expression
Hepatocellular carcinoma
Humans
Leukocytes
Liposomes - adverse effects
Liposomes - pharmacokinetics
Liver cancer
Male
Maximum Tolerated Dose
MicroRNAs
MicroRNAs - administration & dosage
MicroRNAs - adverse effects
MicroRNAs - pharmacokinetics
Middle Aged
miRNA
Molecular Medicine
Nanoparticles - administration & dosage
Nanoparticles - adverse effects
Nausea
Neoplasms - drug therapy
Oncology
Patients
Pharmacodynamics
Respiration
Solid tumors
Toxicity
Tumors
ISSN:0007-0920, 1532-1827, 1532-1827
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Shrnutí:Background In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours. Methods Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles. Results Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m 2 for hepatocellular carcinoma (HCC) and 93 mg/m 2 for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting ≥4 cycles (median, 19 weeks, range, 11–55). Conclusion MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy. Clinical trial registration NCT01829971.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0007-0920
1532-1827
1532-1827
DOI:10.1038/s41416-020-0802-1