Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours
- PMID: 32238921
- PMCID: PMC7251107
- DOI: 10.1038/s41416-020-0802-1
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.
Conflict of interest statement
D.S.H. Research/Grant Funding: AbbVie, Adaptimmune, Amgen, Astra-Zeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda Travel, Accommodations, Expenses: LOXO, MiRNA; Consulting or advisory role: Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer (Ad Board and Speakers Bureau), Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics other ownership interests: Molecular Match (Advisor), OncoResponse (founder), Presagia Inc (Advisor). Y.-K.K. consulting or advisory role: Lilly/ImClone; Novartis; Ono Pharmaceutical; Roche/ Genentech; Taiho Pharmaceutical; research funding: Bayer; Novartis; Roche/Genentech. J.Sa. Honoraria: Celgene; consulting or Advisory Role: Celgene. A.B. Honoraria: Vascular Biogenics; Consulting or Advisory Role: NanoTX; Teleflex Medical Research Funding: Mirna Therapeutics (Inst); Threshold Pharmaceuticals; Patents, Royalties, other intellectual property: NanoTx Pharmaceuticals; travel, accommodations, expenses: Vascular Biogenics. G.F. Royalties: Wolters Kluwer; Advisory role: EMD Serono; Travel: Bristol-Myers Squibb, EMD Serono, Millennium; Research funding: 3-V Biosciences, Abbvie, Aileron, American Society of Clinical Oncology, Amgen, ARMO, AstraZeneca, BeiGene, Biothera, Celldex, Celgene, Ciclomed, Curegenix, Curis, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, Ignyta, Incyte, Jacobio, Jounce, Kolltan, Loxo, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, Novartis, OncoMed, Oncothyreon, Precision Oncology, Regeneron, Rgenix, Strategia, Syndax, Taiho, Takeda, Tarveda, Tesaro, Tocagen, U.T. MD Anderson Cancer Center, Vegenics. A.G.B. employment: Mirna Therapeutics; stock and other ownership interests: Mirna Therapeutics Patents, royalties, other intellectual property: inventor on patents and patent applications assigned to Mirna Therapeutics. J.St. employment: Mirna Therapeutics; stock and other ownership interests: Mirna Therapeutics. S.S. employment: Mirna Therapeutics; stock and other ownership interests: Mirna Therapeutics. S.K. employment: Mirna Therapeutics; Leadership: Mirna Therapeutics; stock and other ownership interests: Mirna Therapeutics; Pfizer; Patents, Royalties, other intellectual property: listed as an inventor on patent applications, but no ownership interest or royalties. M.S.B. consulting or advisory role: Bayer; Celgene; Ipsen; Research funding: Celgene; Mirna Therapeutics; Precision Biologics; Travel, Accommodations, Expenses: Mirna Therapeutics; Precision Biologics. The remaining authors declare no competing interests.
Figures
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