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Clinical Study

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.

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Fig. 1: MRX34 pharmacodynamics.
Fig. 2: Chromogenic in situ hybridisation (CISH) staining of pre- (baseline) and post-MRX34 treatment (treated) liver biopsies from patients with various advanced solid tumours.
Fig. 3: Responses in patients treated with MRX34.

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Acknowledgements

We thank patients and their families as well as co-investigators and study teams for making this study possible. Assistance with medical writing and editing was provided by David E. Egerter, PhD, funded by Mirna Therapeutics. Kathrina Marcelo-Lewis, PhD of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center also assisted in editing this paper.

Author information

Authors and Affiliations

Authors

Contributions

All authors (D.S.H., Y.K.K., M.B., J.S., S.E., H.Y.L., A.J.B., K.P., J-L.L., T.Y.K., S.S., C.R.B., G.F., A.G.B., J.S., S.S., S.K., V.O.N., M.S.B.) contributed to and were involved in the conception and design of the study, provision of study materials or patients, collection and assembly of data, data analysis and interpretation, and paper writing. All authors (D.S.H., Y.K.K., M.B., J.S., S.E., H.Y.L., A.J.B., K.P., J-L.L., T.Y.K., S.S., C.R.B., G.F., A.G.B., J.S., S.S., S.K., V.O.N., M.S.B.) read and approved the final paper.

Corresponding author

Correspondence to David S. Hong.

Ethics declarations

Ethics approval and consent to participate

The study followed the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Patients were enrolled with approval from ethics committees and institutional review boards at participating institutions (UT Health Science Center, San Antonio, TX; UT Southwestern Medical Center, Dallas, TX; Scottsdale Healthcare Research Institute, Scottsdale, AZ; Mayo Clinic Cancer Center, Scottsdale, AZ; UT MD Anderson Cancer Center, Houston, TX; Asan Medical Center, Seoul, Korea; Samsung Medical Center, Seoul, Republic of Korea; Seoul National University Hospital, Seoul, Republic of Korea; Severance Hospital, Seoul Korea, USO Dallas TX; SCRI Boulder, CO), and all patients provided written informed consent before starting study-specific procedures.

Consent for publication

All patients provided written, informed consent.

Data availability

The datasets generated and/or analysed during the current study are not publicly available due proprietary restrictions but are available from the corresponding author on reasonable request.

Competing interests

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.

Funding information

Funded by Mirna Therapeutics, Inc.; The University of Texas MD Anderson Cancer Center is supported in part by the National Institutes of Health through Cancer Center Support Grant P30CA016672.

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Presented in part (preliminary results) at the AACR-NCI-EORTC International Congress on Molecular Targets and Cancer Therapeutics, Boston, MA, 5–9 November 2015; the 2016 annual meeting of the American Society of Clinical Oncology, Chicago, IL, 3–7 June 2016; and the 2016 annual meeting of the European Society for Medical Oncology, Copenhagen, Denmark, 7–11 October 2016.

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Hong, D.S., Kang, YK., Borad, M. et al. Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours. Br J Cancer 122, 1630–1637 (2020). https://doi.org/10.1038/s41416-020-0802-1

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