ARO-HIF2, an investigational tumor-targeting medicine utilizing the Targeted RNAi molecule (TRiM) platform from Arrowhead Pharmaceuticals, Inc., may be a safe and effective treatment for patients with clear cell renal cell carcinoma (ccRCC), according to a press release by the organization.

The AROHIF21001 study (NCT04169711) is a phase 1b dose-finding study in patients with advanced ccRCC that is designed to evaluate the safety of single-agent ARO-HIF2 while also determining the recommended phase 2 dose. An estimated 50 participants will be enrolled in the study.

The primary end point of the study is the number of participants with adverse events (AEs) possibility or probably related to treatment up to 2 years from the first dose. Secondary end points include the pharmacokinetics of ARO-HIF2, the systemic clearance derived from an intravenous dose or area under the plasma concentration versus time to curve, the amount of drug excreted in the urine over one dosing interval through 4 hours post-dose, the renal clearance calculated by Ae, 0-4 h/AUC0-4h, the fraction excreted, overall response rate (ORR), duration of response (DOR), time to response, progression-free survival (PFS), and overall survival (OS).

The study was composed of a single-arm where patients received multiple doses of ARO-HIF2 by intravenous infusion. At the time of the most recent interim results, the study had progressed to 3 cohorts. In cohort 1, patients receive an intravenous injection of the agent at 225 mg a week. In cohort 2, it is 525 mg weekly. In cohort 3, patients received 1050 mg weekly.

In order to participate, patients must be 18 years old or older, not be pregnant, willing to provide informed consent, have histologically confirmed locally advanced or metastatic ccRCC that has progressed during or after at least 2 therapeutic regimens which must include vascular endothelial growth factor (VEGF)-targeting therapy and checkpoint inhibitor therapy, have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, a life expectancy of 3 months or longer, and adequate organ function at screening.

Patients with a history of untreated brain metastasis, leptomeningeal disease, or spinal cord compression are not eligible to participate. Additionally, patients who have failed to recover from reversible AEs of prior anti-cancer therapy, have a history of solid organ or stem cell transplantation, currently using a VEGF inhibitor or an immune checkpoint inhibitor, among others, are also not eligible to participate.

According to the most recent interim analysis, 17 patients have been enrolled. Seven have been enrolled in cohort 1 while 10 have been enrolled in cohort 2. In total, 9 out of the 17 patients enrolled have evaluable tumor samples and 7 of those 9 patients demonstrated a reduction in HIF2a, with a mean reduction of -48% (range, -9% to -82%).

In cohort 2 specifically, 1 patient had a partial response with approximately 65% tumor shrinkage and 5 had achieved stable disease. For 4 of the patients with stable disease, treatment duration lasted between 12 and 24 weeks.

ARO-HIF2 has also proved to be relatively well-tolerated, with no cases of anemia related to the agent having been reported.

The AROHIF21001 phase 1b study is designed to evaluate safety as well as preliminary pharmacodynamics and efficacy in an advanced ccRCC patient population. We believe that in the first two dose cohorts investigational ARO-HIF2 is showing clear signs of meaningful target engagement and some potentially early signs of efficacy in at least one patient. This is an encouraging start for the study, said James Hamilton, MD, MBA, senior vice president of discovery and translational medicine at Arrowhead, in a press release.

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ARO-HIF2 Shows Signals of Activity, Safety in Clear Cell Renal Cell Carcinoma - Targeted Oncology

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