Open AccessPhase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours
Author(s) -
David S. Hong,
Yoon Koo Kang,
Mitesh J. Borad,
Jasgit C. Sachdev,
Samuel Ejadi,
Ho Yeong Lim,
Andrew Brenner,
Keunchil Park,
JaeLyun Lee,
Tae You Kim,
Sang Joon Shin,
Carlos Becerra,
Gerald S. Falchook,
Jay Stoudemire,
Desiree Martin,
Kevin Kim,
Heidi J. Peltier,
Vinícius Bonato,
Andreas G. Bader,
Susan Smith,
Sinil Kim,
Vincent O’Neill,
Muhammad Shaalan Beg
Publication year - 2020
Publication title -
british journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.833
H-Index - 236
eISSN - 1532-1827
pISSN - 0007-0920
DOI - 10.1038/s41416-020-0802-1
Subject(s) - medicine , chills , adverse effect , nausea , dexamethasone , premedication , cancer , gastroenterology , oncology , surgery
Background In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours. Methods Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles. Results Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m 2 for hepatocellular carcinoma (HCC) and 93 mg/m 2 for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting ≥4 cycles (median, 19 weeks, range, 11–55). Conclusion MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy. Clinical trial registration NCT01829971.