Phase I study of MRX34, a liposomal miR 34a mimic, administered twice weekly in patients with advanced solid tumors
SummaryPurpose 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.
Investigational New Drugs