Advertisement

Investigational New Drugs

, Volume 35, Issue 2, pp 180–188 | Cite as

Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors

  • Muhammad S. BegEmail author
  • Andrew J. Brenner
  • Jasgit Sachdev
  • Mitesh Borad
  • Yoon-Koo Kang
  • Jay Stoudemire
  • Susan Smith
  • Andreas G. Bader
  • Sinil Kim
  • David S. Hong
PHASE I STUDIES

Summary

Purpose Naturally occurring tumor suppressor microRNA-34a (miR-34a) downregulates the expression of >30 oncogenes across multiple oncogenic pathways, as well as genes involved in tumor immune evasion, but is lost or under-expressed in many malignancies. This first-in-human, phase I study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumors. Patients and Methods Adult patients with solid tumors refractory to standard treatment were enrolled in a standard 3 + 3 dose escalation trial. MRX34 was given intravenously twice weekly (BIW) for three weeks in 4-week cycles. Results Forty-seven patients with various solid tumors, including hepatocellular carcinoma (HCC; n = 14), were enrolled. Median age was 60 years, median prior therapies was 4 (range, 1–12), and most were Caucasian (68%) and male (57%). Most common adverse events (AEs) included fever (all grade %/G3%: 64/2), fatigue (57/13), back pain (57/11), nausea (49/2), diarrhea (40/11), anorexia (36/4), and vomiting (34/4). Laboratory abnormalities included lymphopenia (G3%/G4%: 23/9), neutropenia (13/11), thrombocytopenia (17/0), increased AST (19/4), hyperglycemia (13/2), and hyponatremia (19/2). Dexamethasone premedication was required to manage infusion-related AEs. The MTD for non-HCC patients was 110 mg/m2, with two patients experiencing dose-limiting toxicities of G3 hypoxia and enteritis at 124 mg/m2. The half-life was >24 h, and Cmax and AUC increased with increasing dose. One patient with HCC achieved a prolonged confirmed PR lasting 48 weeks, and four patients experienced SD lasting ≥4 cycles. Conclusion MRX34 treatment with dexamethasone premedication was associated with acceptable safety and showed evidence of antitumor activity in a subset of patients with refractory advanced solid tumors. The MTD for the BIW schedule was 110 mg/m2 for non-HCC and 93 mg/m2 for HCC patients. Additional dose schedules of MRX34 have been explored to improve tolerability.

Keywords

microRNA miR-34a Experimental therapeutics Phase I trial Advanced solid tumors 

Notes

Acknowledgements

We thank the patients and their families as well as the 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.

Compliance with ethical standards

Conflicts of interest

Muhammad S. Beg has consulting/advisory roles at Bayer, Celgene, and Ipsen, and has received research funding from Celgene, Mirna, and Precision Biologics, and travel expenses from Mirna and Precision Biologics. Andrew J. Brenner has consulting/advisory roles at NanoTX and Teleflex Medical, holds intellectual property with NanoTX, and has received research funding from Mirna and Threshold, and travel expenses from Vascular Biogenics. Jasgit Sachdev has a consulting/advisory role at Celgene and has received honoraria from Celgene. Mitesh Borad has no relationships to disclose. Yoon-Koo Kang has consulting/advisory roles at Lilly/ImClone, Novartis, Ono, Genentech, and Taiho, and has received research funding from Bayer, Novartis, and Genentech. Jay Stoudemire, Susan Smith, Andreas G. Bader, and Sinil Kim are, or were at the time of the study, employed by Mirna and own stock in Mirna; Dr. Bader additionally is an inventor on patents and patent applications assigned to Mirna, and Dr. Kim additionally owns stock in Pfizer. David S. Hong has received research funding from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Genentech, Lilly, Merck, Mirati, Mirna, Novartis, and Pfizer, and travel expenses from Loxo and Mirna.

Statement of human rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10637_2016_407_MOESM1_ESM.docx (26 kb)
ESM 1 (DOCX 26 kb)

References

  1. 1.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297CrossRefPubMedGoogle Scholar
  2. 2.
    Londin E, Loher P, Telonis AG et al (2015) Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs. PNAS 23:E1106–E1115Epub FebruaryCrossRefGoogle Scholar
  3. 3.
    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866CrossRefPubMedGoogle Scholar
  5. 5.
    Esquela-Kerscher A, Slack FJ (2006) Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 6:259–269CrossRefPubMedGoogle Scholar
  6. 6.
    Kasinski AL, Slack FJ (2011) MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy. Nat Rev Cancer 11:849–864CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Jansson MD, Lund AH (2012) MicroRNA and cancer. Mol Oncol 6:590–610CrossRefPubMedGoogle Scholar
  8. 8.
    Bader AG (2012) miR-34–a microRNA replacement therapy is headed to the clinic. Front Genet 3: article 120Google Scholar
  9. 9.
    Cortez MA, Ivan C, Valdecanas D, Wang X et al (2016) PDL1 regulation by p53 via miR-34. J Natl Cancer Inst 108:djv303CrossRefPubMedGoogle Scholar
  10. 10.
    Bader AG, Brown D, Winkler M (2010) The promise of microRNA replacement therapy. Cancer Res 70:7027–7030CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Trang P, Wiggins JF, Daige DL et al (2011) Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice. Mol Ther 19:1116–1122CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bader AG, Brown D, Stoudemire J et al (2011) Developing therapeutic microRNAs for cancer. Gene Ther 18:1121–1126CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Daige CL, Wiggins JF, Priddy L et al (2014) Systemic delivery of a miR-34a mimic as a potential therapeutic for liver cancer. Mol Cancer Ther 13:2352–2360CrossRefPubMedGoogle Scholar
  14. 14.
    Kelnar K, Peltier HJ, Leatherbury N et al (2014) Quantification of therapeutic miRNA mimics in whole blood from non-human primates. Anal Chem 86:1534–1542CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    He L, He X, Lim LP et al (2007) A microRNA component of the p53 tumor suppressor network. Nature 447:1130–1134CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Hermeking H (2010) The miR-34 family in cancer and apoptosis. Cell Death Differ 17:193–199CrossRefPubMedGoogle Scholar
  17. 17.
    Zhao J, Lammers P, Torrance CJ et al (2013) TP53-independent function of miR-34a via HDAC1 and p21(CIP1/WAF1). Mol Ther 21:678–686Google Scholar
  18. 18.
    Lee CH, Subramanian S, Beck AH et al (2009) MicroRNA profiling of BRCA1/2 mutation-carrying and non-mutation-carrying high-grade serous carcinomas of ovary. PLoS One 4:e7314CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hagman Z, Larne O, Edsjo A et al (2010) miR-34c is downregulated in prostate cancer and exerts tumor suppressive functions. Int J Cancer 127:2768–2776CrossRefPubMedGoogle Scholar
  20. 20.
    Nakatani F, Ferracin M, Manara MC et al (2012) miR-34a predicts survival of Ewing's sarcoma patients and directly influences cell chemo-sensitivity and malignancy. J Pathol 226:796–805CrossRefPubMedGoogle Scholar
  21. 21.
    Jamieson NB, Morran DC, Morton JP et al (2012) MicroRNA molecular profiles associated with diagnosis, clinicopathologic criteria, and overall survival in patients with resectable pancreatic ductal adenocarcinoma. Clin Cancer Res 18:534–545CrossRefPubMedGoogle Scholar
  22. 22.
    Hiyoshi Y, Schetter AJ, Okayam H et al (2015) Increased microRNA-34b and -34c predominantly expressed in stromal tissues is associated with poor prognosis in human colon cancer. PLoS One 10:e0124899CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Wang J, Dan G, Zhao J et al (2015) The predictive effect of overexpressed miR-34a on good survival of cancer patients: a systematic review and meta-analysis. Onco Targets Ther 8:2709–2719PubMedPubMedCentralGoogle Scholar
  24. 24.
    Shin J, Danli X, Zhong XP (2013) MicroRNA-34a enhances T cell activation by targeting Diacylglycerol kinase ζ. PLoS One 8:e77983CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Cortez MA, Valdecanas D, Niknam S et al (2015) In vivo delivery of miR-34a sensitizes lung tumors to radiation through RAD51 regulation. Molecular Therapy—Nucleic Acids 4:e270CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Wang X, Li J, Dong K et al (2015) Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia. Cell Signal 27(3):443–452CrossRefPubMedGoogle Scholar
  27. 27.
    Ji Q, Hao X, Zhang M et al (2009) MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One 4:e6816CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Li N, Fu H, Tie Y et al (2009) miR-34a inhibits migration and invasion by down-regulation of c-met expression in human hepatocellular carcinoma cells. Cancer Lett 275:44–53CrossRefPubMedGoogle Scholar
  29. 29.
    Liu C, Kelnar K, Liu B et al (2011) The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 17:211–215CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Di Martino MT, Leone E, Amodio N et al (2012) Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: in vitro and in vivo evidence. Clin Cancer Res 18:6260–6270CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Zhao J, Kelnar K, Bader AG (2014) In-depth analysis shows synergy between erlotinib and miR-34a. PLOS One Feb 14:e8910Google Scholar
  32. 32.
    Wiggins JF, Ruffino L, Kelnar K et al (2010) Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res 70:5923–5930CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Craig VJ, Tzankov A, Flori M et al (2012) Systemic microRNA-34a delivery induces apoptosis and abrogates growth of diffuse large B-cell lymphoma in vivo. Leukemia 26:2421–2424CrossRefPubMedGoogle Scholar
  34. 34.
    Tolcher AW, Rodrigueza WV, Rasco DW et al (2014) A phase 1 study of the BCL2-targeted deoxyribonucleic acid inhibitor (DNAi) PNT2258 in patients with advanced solid tumors. Cancer Chemother Pharmacol 73:363–371CrossRefPubMedGoogle Scholar
  35. 35.
    Kelnar K , Bader, AB (2015) A qRT-PCR method for determining the biodistribution profile of a miR-34a mimic. Chapter 8. In: Gene therapy of solid cancers: methods and protocols, Methods in Molecular Biology, Walther W, Stein U, eds 1317:125–33Google Scholar
  36. 36.
    Szebeni J, Muggia F, Gabizon A et al (2011) Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. Adv Drug Deliv Rev 63:1020–1030CrossRefPubMedGoogle Scholar
  37. 37.
    Robbins M, Judge A, Ambegia E et al (2008) Misinterpreting the therapeutic effects of small interfering RNA caused by immune stimulation. Hum Gene Ther 19:991–999CrossRefPubMedGoogle Scholar
  38. 38.
    Chattopadhyay S (2014) Sen GC: dsRNA-activation of TLR3 and RLR signaling: gene induction-dependent and independent effects. J Interf Cytokine Res 34(6):427–436CrossRefGoogle Scholar
  39. 39.
    Chiappinelli KB, Strissel PL, Desrichard A et al (2015) Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162:974–986CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Dear AE (2016) Epigenetic modulators and the new immunotherapies. N Engl J Med 374:684–686CrossRefPubMedGoogle Scholar
  41. 41.
    Postow MA, Callahan MK, Wolchok JD (2015) Immune checkpoint blockade in cancer therapy. J Clin Oncol 33:1974–1982CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Muhammad S. Beg
    • 1
    Email author
  • Andrew J. Brenner
    • 2
  • Jasgit Sachdev
    • 3
  • Mitesh Borad
    • 4
  • Yoon-Koo Kang
    • 5
  • Jay Stoudemire
    • 6
  • Susan Smith
    • 6
  • Andreas G. Bader
    • 6
  • Sinil Kim
    • 6
  • David S. Hong
    • 7
  1. 1.Division of Hematology/OncologyUniversity of Texas (UT) Southwestern Medical CenterDallasUSA
  2. 2.UT Health Science CenterSan AntonioUSA
  3. 3.Scottsdale Healthcare Research InstituteScottsdaleUSA
  4. 4.Mayo Clinic Cancer CenterScottsdaleUSA
  5. 5.Asan Medical CenterSeoulSouth Korea
  6. 6.Mirna Therapeutics, IncAustinUSA
  7. 7.UT MD Anderson Cancer CenterHoustonUSA

Personalised recommendations