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

Abstract

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/m2 for hepatocellular carcinoma (HCC) and 93 mg/m2 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.

Role of microRNAs in Diagnosis, Prognosis and Management of Multiple Myeloma

“…In fact, MRX34, a liposomal miR-34a mimic, is the first human phase I clinical trial of miRNA cancer therapy in all patients with advanced solid tumors [ 171 ]. Although the trial was closed early due to serious immune-mediated adverse effects that resulted in the death of four patients, the dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy [ 172 ]. The combination treatment with miR-34a has been shown to enhance the anti-tumor activity of other anti-cancer agents (γ-secretase inhibitor, sirtinol and zoledronic acid) in MM cells, through various mechanisms [ 173 ].…”

Non-Coding RNAs: Regulating Disease Progression and Therapy Resistance in Hepatocellular Carcinoma

“…They are relatively non-toxic, and because of their size, they have less chance to induce an immune response. A phase 1 study with MRX34, a liposomal miR-34a mimic, showed manageable toxicity profile in most patients and some clinical activity in HCC patients [193]. Although the study needed to be terminated because of serious adverse effects in some patients, it established the proof-of-concept for miRNA-based therapy.…”

RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges

“…As the maximum tolerated dose was revealed to be 110 mg/m 2 in patients without hepatocarcinoma, a high incidence of adverse events (e.g., 100% all grades and 38% grade 3 among all patients), such as fever, fatigue, back pain, nausea, diarrhea, anorexia, and vomiting, was found among patients with liver cancer receiving treatment with MRX34 (10-50 mg/m 2 , i.v., biweekly) who required palliative management with dexamethasone premedication. Nevertheless, MRX34 did exhibit antitumor activity among patients with refractory advanced solid tumors (Beg et al, 2017;Hong et al, 2020), offering valuable insight into the development of miRNA therapeutics.…”