GoKawiilStudy design and patients
ARC-20 is an ongoing, multicentre, phase I, open-label, dose-escalation and dose-expansion study (Extended Data Fig. 1) conducted at clinical sites across the USA, Australia and South Korea (Supplementary Table 1). ARC-20 was designed to establish the safety and biologically active dose of casdatifan and to directly link the depth of HIF-2α inhibition to pharmacodynamic effects, tumour biology and clinical benefit in refractory metastatic ccRCC.
Safety decisions were guided by a dose-escalation committee (DEC) and a safety-review committee (SRC). The DEC reviewed cohort-level safety and DLT data to guide dose escalation and dose clearance for expansion, while the SRC evaluated safety during the dose-expansion stage. The DEC and SRC were not independent of the study sponsor. Final decisions regarding continuation or termination of the trial or its components were made under sponsor governance and were informed by committee recommendations. Access to interim information was restricted to authorized study personnel and committee members and was kept confidential. Further details, including the composition of the DEC and SRC, are provided in the study protocol (Supplementary Information).
The ARC-20 study was registered on 7 September 2022 with clinicaltrials.gov (NCT05536141). Before the study was initiated, an institutional review board or independent ethics committee at each study site approved the protocol and other relevant study materials (Supplementary Table 1; the protocol is provided in the Supplementary Information). All of the patients or their legally authorized representatives provided written informed consent before enrolment; patients were not compensated monetarily for their participation in this trial. This study was conducted in full accordance with the Declaration of Helsinki, Council for International Organizations of Medical Sciences, the International Council for Harmonisation and all regional laws and regulations.
Preliminary findings from ARC-20 were previously presented at the EORTC-NCI-AACR Symposium, 23 to 25 October 2024, Barcelona, Spain37; American Society of Clinical Oncology Genitourinary Cancers Symposium, 30 May to 3 June 2025, Chicago, Illinois38; Kidney Cancer Research Summit, 17 to 18 July 2025, Boston, Massachusetts39; and American Society of Clinical Oncology Genitourinary Cancers Symposium, 26 to 28 February 2026, San Francisco, California40.
Dose-escalation stage
The dose-escalation stage was performed using a standard 3 + 3 design with a 21-day DLT evaluation period. The safety, tolerability and preliminary efficacy of casdatifan monotherapy were evaluated at doses ranging from 20–200 mg QD in patients with solid tumours for whom no standard-of-care therapies were available. The starting dose of 20 mg QD was selected on the basis of the totality of nonclinical data and findings from the first-in-human study of casdatifan in healthy participants (ARC-14)2, which suggested manageable toxicity at this dose. The dose range of 20–200 mg QD was selected to enable evaluation of a broad range of exposures and to inform clinical development. Patients were enrolled on a rolling basis in sets of three. After three patients in a set were dosed, enrolment was paused until the 3-week treatment cycle was completed. Dosing then resumed by adding another set of three to the same dose level or by escalating to the next dose level, according to the 3 + 3 design. The maximum tolerated dose corresponded to the highest dose at which the DLT incidence was below 33%. Further details on methodology for the dose-escalation stage are reported in Supplementary Table 2. Specific criteria for dose discontinuation, dose modification and dosing delays are provided in the study protocol (Supplementary Information).
Dose-expansion stage
Dose-expansion cohorts were designed to further characterize the safety, tolerability and efficacy of casdatifan (as monotherapy and as combination therapy) at dose levels selected on the basis of on data from the preceding dose-escalation stage. This report focused on patients who received casdatifan monotherapy. Dose-expansion cohorts were permitted to initiate before completion of dose escalation, provided that the dose had cleared DLT evaluation. The patients were eligible to participate if they were aged at least 18 years with histologically confirmed metastatic ccRCC, received previous treatment in the locally advanced or metastatic setting with an anti-PD-L1/anti-PD-1 inhibitor and a VEGFR TKI, were HIF-2α inhibitor naive, had a creatinine clearance of at least 40 ml min−1 and had at least 1 measurable tumour lesion based on RECIST v.1.1. The patients must also have had an ECOG performance status of 0 or 1 and adequate organ and marrow function. Further details on patient eligibility are shown in Supplementary Table 3.
The patients in each cohort received casdatifan monotherapy in 21-day cycles and continued treatment until occurrence of unacceptable toxicity, disease progression, loss to follow-up, withdrawal from the study, death or study termination, whichever occurred first. Stopping rules for each dose-expansion cohort included the occurrence of any of the following: treatment-related grade 5 adverse events in at least 10% of patients; two or more treatment-related, non-laboratory grade 4 adverse events; or grade 4 treatment-related hypoxia or anaemia in at least 25% of patients. Specific criteria for dose discontinuation, dose modification and dosing delays were prespecified in the study protocol (Supplementary Information).
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