Trial: Study of Casdatifan and Cabozantinib Ve…

Trial Details

Sponsor: Arcus Biosciences, Inc. (industry)

Phase: 3

Start date: Sept. 8, 2025

Planned enrollment: 720

Trial ID: NCT07011719

More trial details at ClinicalTrials.gov

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Investigational Drug AI Analysis

Show for: casdatifan (AB521)

Overview

Casdatifan (AB521) is an oral, small‑molecule hypoxia‑inducible factor‑2 alpha (HIF‑2α) inhibitor in development for clear cell renal cell carcinoma (ccRCC) and other tumors. Clinical activity has been reported from the ongoing Phase 1/1b ARC‑20 trial in previously treated metastatic ccRCC, and a Phase 3 study (PEAK‑1) of casdatifan plus cabozantinib has been initiated. (ascopubs.org)

Mechanism of action

Casdatifan selectively and allosterically inhibits HIF‑2α–dependent transcription, with minimal activity against HIF‑1α in preclinical models. In vitro and xenograft studies demonstrated inhibition of HIF‑2α–driven tumor biology, reductions in pharmacodynamic markers, and tumor regressions; activity was also observed in endothelial cells and M2‑polarized macrophages. (pubmed.ncbi.nlm.nih.gov)

Clinical development

Phase 1/1b ARC‑20 (NCT05536141): dose‑escalation and expansion evaluating casdatifan as monotherapy and in combination (cabozantinib; zimberelimab) in ccRCC and other solid tumors. (clinicaltrials.ucbraid.org)
Phase 3 PEAK‑1: randomized, double‑blind study of casdatifan + cabozantinib vs placebo + cabozantinib in advanced ccRCC (IO‑experienced). Site listings indicate initiation in 2025. (dana-farber.org)

Efficacy

Monotherapy (ARC‑20; heavily pretreated metastatic ccRCC; data cutoff January 3, 2025 unless noted) - 50 mg BID (n=32): confirmed ORR 25% (95% CI 11.5–43.4); median PFS 9.7 months (95% CI 5.5–NE). Disease control rate (DCR) 81%. (investors.arcusbio.com)
- 50 mg QD (n=28): confirmed ORR 32% (95% CI 15.9–52.4); median PFS not reached at 12‑month median follow‑up. DCR 86%. (investors.arcusbio.com)
- 100 mg QD tablet (go‑forward dose; n=27): confirmed ORR 33% (95% CI 16.5–54.0); median PFS not reached at ~5‑month median follow‑up. DCR 85%. (investors.arcusbio.com)

ASCO GU 2025 abstract reported safety/efficacy across multiple monotherapy doses in ARC‑20 (Rapid Oral, Abstract 441). (ascopubs.org)

Combination with cabozantinib (ARC‑20 expansion; IO‑experienced ccRCC; ASCO 2025) - Casdatifan 100 mg QD + cabozantinib 60 mg QD: confirmed ORR 46% (11/24; 95% CI 26–67) at 5.3‑month median follow‑up; CR 4%, PD 4%. (investors.arcusbio.com)

More recent sponsor updates (August–October 2025) describe pooled monotherapy analyses across four cohorts (n=121) with confirmed ORR 35% and median PFS 12.2 months (cohort‑pooled), with mPFS not reached in the 100‑mg QD cohort (DCO August 15, 2025). Interpret with caution pending peer‑reviewed presentation/publication. (investors.arcusbio.com)

Safety

The emerging safety profile is consistent with the HIF‑2α inhibitor class. In ARC‑20 monotherapy cohorts, no unexpected safety signals were observed; class‑typical anemia and hypoxia occurred, with few discontinuations attributed to these events. In the cabozantinib combination cohort (n=42 safety population), grade ≥3 treatment‑related AEs included anemia (24% attributable to casdatifan) and hypoxia (7% attributable to casdatifan); no casdatifan‑related grade 4/5 events were reported, and only two patients discontinued any drug, none discontinuing both. (investors.arcusbio.com)

TrialFetch AI Analysis

Goal: Evaluate whether adding casdatifan to cabozantinib improves progression-free survival versus cabozantinib plus placebo in adults with advanced or metastatic clear cell renal cell carcinoma previously treated with anti–PD-1/PD-L1 therapy.

Patients: Adults with unresectable, measurable locally advanced or metastatic renal cell carcinoma with a primary clear cell component, prior progression on or after PD-1/PD-L1–based immunotherapy, KPS ≥80%, adequate organ function, and at least one RECIST 1.1 target lesion outside prior radiation fields. Key exclusions include prior HIF-2α inhibitor or cabozantinib, active second malignancy within 1 year, unresolved ≥Grade 3 toxicities, uncontrolled hypertension, and history of leptomeningeal disease or spinal cord compression.

Design: Randomized, double-blind, active-controlled, multicenter phase 3 trial enrolling approximately 720 participants. Allocation is 1:1 to experimental versus comparator arms with blinded independent central review of imaging per RECIST 1.1.

Treatments: Experimental arm: oral casdatifan plus oral cabozantinib. Comparator arm: oral placebo plus oral cabozantinib. Casdatifan (AB521) is an investigational, selective, allosteric HIF‑2α inhibitor targeting HIF‑2α–dependent transcription, a validated pathway in ccRCC. Early phase 1/1b data (ARC‑20) demonstrated antitumor activity as monotherapy and higher response rates when combined with cabozantinib, with a safety profile consistent with the HIF‑2α class (notably anemia and occasional hypoxia). Cabozantinib is an approved VEGFR/MET/AXL tyrosine kinase inhibitor commonly used in previously treated RCC.

Outcomes: Primary: progression-free survival by blinded independent central review per RECIST 1.1. Secondary: overall survival; objective response rate, duration of response, and disease control rate by blinded independent central review; incidence and severity of TEAEs and SAEs; time to first symptom deterioration on the NFKSI-DRS (items 1–9). Time horizons extend to approximately 33 months for disease control endpoints and safety, and up to 64 months for overall survival.

Burden on patient: Expected burden is moderate and similar to other phase 3 oral therapy studies in metastatic RCC. Treatment and placebo are oral without mandated intensive pharmacokinetic sampling typical of phase 1 trials. Patients will undergo regular clinic visits for safety labs, vitals, and adverse event monitoring, plus periodic cross-sectional imaging per RECIST with blinded central review, likely every 8–12 weeks, consistent with standard practice. No routine research biopsies are specified, but baseline and on-treatment assessments will require standard hematology/chemistry panels and pregnancy testing where applicable. Travel burden corresponds to scheduled imaging and follow-up visits typical for second-line RCC management; added burden relates mainly to vigilance for class-related toxicities such as anemia, hypoxia, hypertension, and cabozantinib-associated adverse events requiring monitoring and potential dose modifications.

Last updated: Nov 2025

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Status: Recruiting

A Randomized, Double-Blind, Active-Control, Multicenter Phase 3 Trial of Casdatifan and Cabozantinib Versus Placebo and Cabozantinib in Patients With Advanced Clear Cell Renal Cell Carcinoma

Trial Details

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: casdatifan (AB521)

Overview

Mechanism of action

Clinical development

Efficacy

Safety

Further reading

TrialFetch AI Analysis

Eligibility

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Sites (44)

CHU Brest - Hôpital Morvan

Hopital Saint Eloi

Institut Gustave Roussy

Krankenhaus Nordwest GmbH

Universitaetsklinikum Halle (Saale)

Universitaetsmedizin Rostock

Isala

Radboudumc

Pratia MCM Krakow

S.C Oncomed S.R.L

S.C. Sigmedical Services SRL

CHA Bundang Medical Center, CHA University

Severance Hospital, Yonsei University Health System

Hospital Clinic de Barcelona

Barts Hospital

Royal Devon and Exeter Hospital (Wonford)

City of Hope - Phoenix Cancer Center

Mayo Clinic - Phoenix

City Of Hope National Medical Center

UCLA Hematology Oncology - 100 Med Plaza

University of California San Diego Moores Cancer Center

University of California San Diego Moores Cancer Center

Yale University

Mayo Clinic in Florida

City of Hope Cancer Center Atlanta

Emory University - Atlanta

Piedmont Cancer Institute OneOncology

City of Hope - Chicago Cancer Center

Indiana University Melvin and Bren Simon Cancer Center

Norton Cancer Institute PARENT

Dana-Farber Cancer Institute

Massachusetts General Hospital

Mayo Clinic

Washington University School of Medicine

The University of Nebraska Medical Center

University of Rochester Medical Center

UNC Hospitals

Cleveland Clinic Foundation

University Hospitals Cleveland Medical Center

Compass Oncology, OR

SCRI Oncology Partners

Vanderbilt

Texas Tech University Health Science Center

The University of Utah - Huntsman Cancer Institute (HCI)