Abstract CT327: Multicenter phase I study of MRX34, a first-in-class microRNA miR-34 mimic liposomal injection
Authors: Beg Muhammad Shaalan , Borad Mitesh , Sachdev Jasgit , Hong David S. , Smith Susan , Bader Andres , Stoudemire Jay , Kim Sinil , Brenner Andrew 
Published: May 2015

Abstract
Background: MRX34 is a liposome-formulated double-stranded mimic of tumor suppressor microRNA-34 (miR-34), which is lost or expressed at reduced levels in many solid and hematologic malignancies. miR-34 functions in the p53 tumor suppressor pathway and regulates the expression of more than 20 cancer-related genes including BCL2, E2F3, HDAC1, MET, MEK1, CDK4/6, PDGFR-ɑ, SIRT1, WNT1/3, NOTCH-1, β-catenin, CD44, Nanog and AXL. miR-34 also suppresses stem-like properties in cancer cells and sensitizes cancer cells to cytotoxic and targeted therapies. A multicenter phase I clinical trial of MRX34 is being conducted in patients with unresectable hepatocellular carcinoma or metastatic cancer with liver involvement.
Methods: Eligible patients are enrolled in a standard 3 + 3 dose escalation study at MRX34 starting dose of 10 mg/m2, administered IV on days 1, 4, 8, 11, 15, and 18 of 28-day cycles. Dexamethasone premedication was added after the first 2 dose levels. The primary objective is to determine the RP2D, and secondary objectives include assessments of safety, PK and objective response rate (ORR). Response is evaluated by CT/MRI every 8 weeks. Once RP2D has been established, expansion cohort will be treated at the RP2D, with specific focus on determining biological response in tumor biopsy material. The latter will include assessing tumor uptake of miR-34 mimic and down-regulation of target gene expression as was observed in animal models of cancer.
Results: Twenty-five patients received study drug, and enrollment is currently ongoing at the 5th dose level (70 mg/m2) and MTD has not been reached. There were 18 Caucasians, 15 males, with a median age of 62.5 years and a median of 4 prior treatments. Liposomal formulation-associated infusion reactions have been observed as characterized by the following treatment emergent adverse events (AEs) out of 20 patients: fever (13), chills (12), fatigue (12), thrombocytopenia (8), diarrhea (8), back/flank pain (6), nausea (6), and neutropenia (4). Most common Gr 3/4 AEs were neutropenia (4), thrombocytopenia (3), fatigue (2), AST/ALT elevation (4) and back/flank pain (2). Addition of pre-dose dexamethasone with higher dose levels ameliorated infusion reactions. One patient died on study from disease progression. One dose-limiting toxicity was observed at the 2nd dose level (20 mg/m2; Gr 3 acute kidney injury associated with nausea, vomiting, diarrhea and dehydration) and one at the 5th dose level (70 mg/m2; Gr 3 increased AST).
Conclusions: MRX34 has a manageable safety profile in patients with unresectable primary liver cancer or metastatic cancer with liver involvement. Determination of the R2PD, assessment of clinical response, and analyses of molecular markers are ongoing.
Citation Format: Muhammad Shaalan Beg, Mitesh Borad, Jasgit Sachdev, David S. Hong, Susan Smith, Andres Bader, Jay Stoudemire, Sinil Kim, Andrew Brenner. Multicenter phase I study of MRX34, a first-in-class microRNA miR-34 mimic liposomal injection. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT327. doi:10.1158/1538-7445.AM2014-CT327