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Clinical Trial
. 2024 Jun 3;30(11):2402-2411.
doi: 10.1158/1078-0432.CCR-23-3029.

A First-in-Human Phase 1 Study of a Tumor-Directed RNA-Interference Drug against HIF2α in Patients with Advanced Clear Cell Renal Cell Carcinoma

James Brugarolas  1 , Gregory Obara  2 , Kathryn E Beckermann  3 , Brian Rini  3 , Elaine T Lam  4 , James Hamilton  5 , Thomas Schluep  5 , Min Yi  5 , So Wong  5 , Zhongping Lily Mao  5 , Erick Gamelin  6 , Nizar M Tannir  7
Affiliations
Clinical Trial

A First-in-Human Phase 1 Study of a Tumor-Directed RNA-Interference Drug against HIF2α in Patients with Advanced Clear Cell Renal Cell Carcinoma

James Brugarolas et al. Clin Cancer Res. .

Abstract

Purpose: ARO-HIF2 is an siRNA drug designed to selectively target hypoxia-inducible factor-2α (HIF2α) interrupting downstream pro-oncogenic signaling in clear cell renal cell carcinoma (ccRCC). The aims of this Phase 1 study (AROHIF21001) were to evaluate safety, tolerability, pharmacokinetics, and establish a recommended Phase 2 dose.

Patients and methods: Subjects with ccRCC and progressive disease after at least 2 prior therapies that included VEGF and immune checkpoint inhibitors were progressively enrolled into dose-escalation cohorts of ARO-HIF2 administered intravenously at 225, 525, or 1,050 mg weekly.

Results: Twenty-six subjects received ARO-HIF2. The most common treatment emergent adverse events (AE) irrespective of causality were fatigue (50.0%), dizziness (26.9%), dyspnea (23.1%), and nausea (23.1%). Four subjects (15.4%) had treatment-related serious AEs. AEs of special interest included neuropathy, hypoxia, and dyspnea. ARO-HIF2 was almost completely cleared from plasma circulation within 48 hours with minimal renal clearance. Reductions in HIF2α were observed between pre- and post-dosing tumor biopsies, but the magnitude was quite variable. The objective response rate was 7.7% and the disease control rate was 38.5%. Responses were accompanied by ARO-HIF2 uptake in tumor cells, HIF2α downregulation, as well as rapid suppression of tumor produced erythropoietin (EPO) in a patient with paraneoplastic polycythemia.

Conclusions: ARO-HIF2 downregulated HIF2α in advanced ccRCC-inhibiting tumor growth in a subset of subjects. Further development was hampered by off-target neurotoxicity and low response rate. This study provides proof of concept that siRNA can target tumors in a specific manner.

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Figures

Figure 1. Summary of treatment duration with tumor response in the three cohorts'. Cohort 1 (225 mg ARO-HIF2), Cohort 2 (525 mg ARO-HIF2), and Cohort 3 (1050 mg ARO-HIF2). Abbreviations: A, Subject A; B, Subject B; PD, progressive disease; PR, partial response; SD, stable disease.
Figure 1.
Summary of treatment duration with tumor response in the three cohorts'. Cohort 1 (225 mg ARO-HIF2), Cohort 2 (525 mg ARO-HIF2), and Cohort 3 (1050 mg ARO-HIF2). Abbreviations: A, Subject A; B, Subject B; PD, progressive disease; PR, partial response; SD, stable disease.
Figure 2. Waterfall plot of best sum of diameters percentage of change for target lesions. Among the 6 subjects with a percentage of change in target lesion size in the SD range (between −30% and +20%) who had PD, 4 subjects had PD of a non-target lesion, 1 subject had a new lesion, and 1 subject had both PD in a non-target lesion and a new lesion. Abbreviations: A, Subject A; B, Subject B; PD, progressive disease; PR, partial response; SD, stable disease.
Figure 2.
Waterfall plot of best sum of diameters percentage of change for target lesions. Among the 6 subjects with a percentage of change in target lesion size in the SD range (between −30% and +20%) who had PD, 4 subjects had PD of a non-target lesion, 1 subject had a new lesion, and 1 subject had both PD in a non-target lesion and a new lesion. Abbreviations: A, Subject A; B, Subject B; PD, progressive disease; PR, partial response; SD, stable disease.
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References

    1. Kaelin WG Jr. The von Hippel-Lindau tumor-suppressor protein and clear cell renal carcinoma. Clin Cancer Res 2007;13:680s–4s. - PubMed
    1. Schodel J, Grampp S, Maher ER, Moch H, Ratcliffe PJ, Russo P, et al. . Hypoxia-inducible transcription factors, and renal cancer. Eur Urol 2016;69:646–57. - PMC - PubMed
    1. Shen C, Kaelin WG Jr. The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer Biol 2013;23:18–25. - PMC - PubMed
    1. Linehan WM, Ricketts CJ. The Cancer Genome Atlas of renal cell carcinoma: findings and clinical implications. Nat Rev Urol 2019;16:539–52. - PubMed
    1. Nickerson ML, Jaeger E, Shi Y, Durocher JA, Mahurkar S, Zaridze D, et al. . Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res 2008;14:4726–34. - PMC - PubMed

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