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

Muhammad S. Beg, Andrew J. Brenner, Jasgit Sachdev, Mitesh J Borad, Yoon Koo Kang, Jay Stoudemire, Susan Smith, Andreas G. Bader, Sinil Kim, David S. Hong

Research output: Contribution to journalArticle

287 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalInvestigational New Drugs
DOIs
StateAccepted/In press - Dec 5 2016

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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    Beg, M. S., Brenner, A. J., Sachdev, J., Borad, M. J., Kang, Y. K., Stoudemire, J., Smith, S., Bader, A. G., Kim, S., & Hong, D. S. (Accepted/In press). Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Investigational New Drugs, 1-9. https://doi.org/10.1007/s10637-016-0407-y