title: Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors.
abstract: 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 Cmaxand 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/m2for non-HCC and 93 mg/m2 for HCC patients. Additional dose schedules of MRX34 have been explored to improve tolerability.
authors.affiliation: Division of Hematology/Oncology, University of Texas (UT) Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-8852, USA. Muhammad.Beg@UTSouthwestern.edu.
authors.forename: Muhammad S
authors.initials: MS
authors.lastname: Beg
authors.affiliation: UT Health Science Center, San Antonio, TX, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brenner
authors.affiliation: Scottsdale Healthcare Research Institute, Scottsdale, AZ, USA.
authors.forename: Jasgit
authors.initials: J
authors.lastname: Sachdev
authors.affiliation: Mayo Clinic Cancer Center, Scottsdale, AZ, USA.
authors.forename: Mitesh
authors.initials: M
authors.lastname: Borad
authors.affiliation: Asan Medical Center, Seoul, South Korea.
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
authors.affiliation: Mirna Therapeutics, Inc, Austin, TX, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Stoudemire
authors.affiliation: Mirna Therapeutics, Inc, Austin, TX, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Smith
authors.affiliation: Mirna Therapeutics, Inc, Austin, TX, USA.
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Bader
authors.affiliation: Mirna Therapeutics, Inc, Austin, TX, USA.
authors.forename: Sinil
authors.initials: S
authors.lastname: Kim
authors.affiliation: UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D035683:MicroRNAs / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008875:Middle Aged; D053758:Nanoparticles / Q000008:administration & dosage / Q000009:adverse effects; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; C522425:MIRN34 microRNA, human; D035683:MicroRNAs
keywords: Advanced solid tumors; Experimental therapeutics; Phase I trial; miR-34a; microRNA