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.
microRNA miR-34a Experimental therapeutics Phase I trial Advanced solid tumors
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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 was obtained from all individual participants included in the study.
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