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

• Published in: British journal of cancer Vol. 122; no. 11; pp. 1630 - 1637
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.05.2020; Nature Publishing Group
• Subjects: 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
• DOI: 10.1038/s41416-020-0802-1

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.