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 C_max 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.

Keywords: Advanced solid tumors; Experimental therapeutics; Phase I trial; miR-34a; microRNA.

Figure 1

Blood concentration vs time profiles of miR-34a mimic showing mean values (ng/mL) at each dosing level for day 1 (left) and day 18 (right) in cycle 1. Blood samples were collected prior to infusion and at selected times post-infusion.

Figure 2. Prolonged Confirmed PR in Patient with Advanced HBV-associated HCC

Note progressive disease (pre-baseline to baseline) in lung metastases target lesions prior to enrollment in study. MRX34 BIW 50 mg/m² was initiated in August 2014, with stable disease for the initial 6 cycles and then prolonged confirmed PR lasting 48 weeks (34% maximum sum-of-diameters reduction for target lesions by RECIST 1.1). The patient remained in PR until cycle 17 when progression in a non-target lesion was noted. As of April 2016, the patient had received 2 additional cycles (19 total) of MRX34, with the size of both target and non-target lesions remaining stable.