MRG-106 is an oligonucleotide inhibitor of miR-155, a microRNA with a strong mechanistic link to CTCL, selected based on its activity in mycosis fungoides (MF) cell lines. The objective of this first-in-human study is to evaluate the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary efficacy of MRG- 106 in MF patients.
This Phase 1 trial employs a dose-escalation design to evaluate intratumoral injection (IT, 75 mg/dose), subcutaneous injection or 2-hour intravenous infusion (SC/IV, ≤ 900 mg/dose) of MRG-106. Subjects were required to have biopsy-proven stage I-III MF and plaque- or tumor-stage lesions. Subjects were permitted to remain on CTCL therapy if the drug dose and regimen had not changed within the four weeks prior to study enrollment. Subjects received six doses (SC/IV) in the first 26 days of the study followed by optional weekly doses. Safety was monitored by periodic physical exam, clinical laboratory tests, and assessment of adverse events. Skin lesions were assessed by the Composite Assessment of Index Lesion Severity (CAILS) score. Total skin disease was measured by the modified Severity Weighted Assessment Tool (mSWAT). Lesion biopsies were collected in all subjects receiving IT injections and were optional in subjects receiving SC/IV administration of MRG-106.
Nineteen subjects (14M/5F, median age 61 years) have been dosed from 1 to 34 weeks. Four subjects received only IT doses; two subjects were enrolled into both the IT and SC cohorts. Thirteen subjects received either SC injections or IV infusions of MRG-106. In all cohorts, the drug was generally well-tolerated. Nineteen of 21 treatment regimens were completed as per protocol. Two subjects discontinued: One due to progressive disease prior to dosing, the other due to worsening pruritus, judged as a dose-limiting toxicity. The subject with pruritus at the 900 mg SC dose level had a possible flare of their disease after 3 doses that resolved after 3 weeks. The MTD has not yet been reached.
In the IT cohort, a reduction of ≥ 50% in the baseline CAILS score was observed in the MRG-106 treated lesions in all 4 evaluable subjects who completed dosing; such responses were maintained to the End of Study visit (Day 28 or 35). Histological examination of pre- and post-treatment biopsies of the MRG-106-injected lesion from most subjects revealed a trend in reduction in neoplastic cell density and depth; 1 subject had a complete loss of the neoplastic infiltrate. Gene expression analysis of the pre- and post-treatment biopsies showed reduction of the PI3K/AKT, JAK/STAT, and NFkB survival pathways and increased cell death consistent with the expected MRG- 106 mechanism of action. Assessment of biopsies collected from selected subjects in the systemically treated cohorts is ongoing.
In the SC and IV cohorts, fourteen of the fifteen subjects had an improvement in mSWAT score. Despite the majority of subjects having been exposed to MRG-106 for short duration (median days on active treatment, 29), 73% (11 of 15) had improvement of ≥ 25% and 40% (6 of 15) had improvement of ≥ 50%. These results suggest a clinically meaningful response to MRG-106 treatment.