TY - JOUR
T1 - Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours
AU - Hong, David S.
AU - Kang, Yoon Koo
AU - Borad, Mitesh
AU - Sachdev, Jasgit
AU - Ejadi, Samuel
AU - Lim, Ho Yeong
AU - Brenner, Andrew J.
AU - Park, Keunchil
AU - Lee, Jae Lyun
AU - Kim, Tae You
AU - Shin, Sangjoon
AU - Becerra, Carlos R.
AU - Falchook, Gerald
AU - Stoudemire, Jay
AU - Martin, Desiree
AU - Kelnar, Kevin
AU - Peltier, Heidi
AU - Bonato, Vinicius
AU - Bader, Andreas G.
AU - Smith, Susan
AU - Kim, Sinil
AU - O’Neill, Vincent
AU - Beg, Muhammad S.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Cancer Research UK.
PY - 2020/5/26
Y1 - 2020/5/26
N2 - 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/m2 for hepatocellular carcinoma (HCC) and 93 mg/m2 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.
AB - 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/m2 for hepatocellular carcinoma (HCC) and 93 mg/m2 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.
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U2 - 10.1038/s41416-020-0802-1
DO - 10.1038/s41416-020-0802-1
M3 - Article
C2 - 32238921
AN - SCOPUS:85083065314
SN - 0007-0920
VL - 122
SP - 1630
EP - 1637
JO - British journal of cancer
JF - British journal of cancer
IS - 11
ER -