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Clinical Trial
. 2025 May 15;31(10):1847-1855.
doi: 10.1158/1078-0432.CCR-24-2618.

A Phase I Dose-Escalation Study of the HIF-2 Alpha Inhibitor DFF332 in Patients with Advanced Clear-Cell Renal Cell Carcinoma

Sumanta K Pal #  1 , Alice Bernard-Tessier  2 , Peter Grell  3 , Xin Gao  4 , Ritesh R Kotecha  5 , Joel Picus  6 , Filippo de Braud  7   8 , Shunji Takahashi  9 , Alvin Wong  10 , Cristina Suárez  11 , Javier A Otero  12 , Nicole Kundamal  12 , Xin Yang  12 , Sherif Sharaby  12 , Mike Roy  13 , Patrizia Barzaghi-Rinaudo  14 , Nizar M Tannir #  15
Affiliations
Clinical Trial

A Phase I Dose-Escalation Study of the HIF-2 Alpha Inhibitor DFF332 in Patients with Advanced Clear-Cell Renal Cell Carcinoma

Sumanta K Pal et al. Clin Cancer Res. .

Abstract

Purpose: Mutations or silencing of the von Hippel-Lindau tumor suppressor gene accumulate hypoxia-inducible factors (HIF). HIF-2α is implicated in the oncogenesis of ∼50% of patients with clear-cell renal cell carcinoma (ccRCC) but has been considered "undruggable." DFF332, an orally administered novel allosteric inhibitor of HIF-2α, showed dose-dependent antitumor efficacy in preclinical models of ccRCC.

Patients and methods: This first-in-human study evaluated the safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamics of DFF332 in patients with heavily pretreated advanced ccRCC. Preliminary data from the dose escalation of DFF332 monotherapy, administered orally at 50 or 100 mg weekly or 25, 50, 100, or 150 mg once daily in 28-day treatment cycles, are reported.

Results: As of January 15, 2024, 40 patients (median age, 62.5 years) received DFF332 for a median duration of 12.1 weeks. Overall, two patients (5%) achieved a partial response, and 19 (48%) achieved stable disease as the best overall response. DFF332 showed a favorable safety profile, with treatment-related adverse events occurring in 25 patients (63%). Only five patients (13%) experienced treatment-related anemia, and no hypoxia was observed. The only serious treatment-related adverse event, hypertension, was reported in one patient. The maximum tolerated dose was not reached.

Conclusions: Although clinical responses were limited in the doses evaluated, dose exploration halted prematurely, making it difficult to draw definitive conclusions about the efficacy of DFF332. Further investigation is required to establish a recommended dose regimen, assess its efficacy and safety, and evaluate its full potential as a partner in combination studies.

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Conflict of interest statement

S.K. Pal reports other support from Novartis during the conduct of the study as well as personal fees from MJH Life Sciences, IntrinsiQ, and PeerView and other support from CRISPR Therapeutics, Ipsen, and Exelixis outside the submitted work. A. Bernard-Tessier reports personal fees from AAA-Novartis, AstraZeneca, Astellas, Bayer, Bouchara-Recordati, Janssen, and Orion and other support from Roche outside the submitted work. P. Grell reports personal fees from Bristol Myers Squibb, Roche, Servier, and Merck outside the submitted work. X. Gao reports personal fees from Flare Therapeutics, Loxo/Lilly, Arvinas, ADC Therapeutics, Hinova Pharmaceuticals, and Bayer outside the submitted work. R.R. Kotecha reports grants from Novartis during the conduct of the study as well as grants from Pfizer, Takeda, Allogene Therapeutics, Arsenal Bio, Exelixis, and Xencor and personal fees from Eisai outside the submitted work. F. de Braud reports nonfinancial support from Novartis; personal fees from Bristol Myers Squibb, Menarini, Incyte, and MSD; and personal fees and nonfinancial support from AstraZeneca and Roche outside the submitted work. S. Takahashi reports grants and personal fees from Novartis during the conduct of the study as well as grants and personal fees from Daiichi Sankyo, Eisai, Bayer, Taiho Pharmaceutical, MSD, Chugai Pharmaceutical, Bristol Myers Squibb, Ono Pharmaceutical, Lilly, and Sanofi and grants from Boehringer Ingelheim, Amgen, AstraZeneca, Astellas Pharma, Seattle Genetics, and Pfizer outside the submitted work. C. Suárez reports grants from Ipsen during the conduct of the study as well as other support from Bristol Myers Squibb, Astellas, Ipsen, Pfizer, Roche, Sanofi Aventis, and Bayer outside the submitted work. J.A. Otero reports personal fees and other support from Novartis during the conduct of the study, as well as personal fees and other support from Novartis and personal fees from Memorial Sloan Kettering Cancer Center outside the submitted work. S. Sharaby reports employment with Novartis and ownership of Novartis stocks. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Antitumor activity. (A) Best percentage change from baseline in tumor size per RECIST version 1.1 criteria and (B) duration of exposure to DFF332. a25 mg once daily; b100 mg once daily; cfour patients had target tumor shrinkages as reflected in the plot and had an overall response of PD due to either new lesions or worsening of nontarget lesions at that same RECIST evaluation. All patients were permitted to continue treatment at the discretion of the physician who assessed that they benefited from the study treatment, and none are ongoing at the data cutoff; dintrapatient dose escalations or reductions are reported in five patients: (i) from 100 mg once weekly to 25 mg once daily on study day 251; (ii) from 100 mg once weekly to 25 mg once daily on study day 232, to 50 mg once daily on study day 288, to 100 mg once daily on study day 400; (iii) from 25 mg once daily to 12.5 mg once daily on study day 113; (iv) from 25 mg once daily to 50 mg once daily on study day 110, and (v) from 50 mg once daily to 100 mg once daily on study day 337. n, number of patients with RECIST data; N, total number of patients treated; NE, not evaluable; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.
Figure 2.
Figure 2.
PK profile mean (SD) plasma concentration–time profiles for DFF332 at varying doses on cycle 2 day 1 and cycle 3 day 1 for (A) once daily and (B) once weekly, respectively. (C) Simulated DFF332 plasma concentration–time profiles. Black dotted lines represent estimated trough DFF332 concentration (1,760 ng/mL) at the dose of maximum efficacy (10 mg/kg/d) in 786-O and SKRC01 xenograft mouse models; in (C), curved lines show mean DF332 concentration; shaded regions indicate interpatient variability.
Figure 3.
Figure 3.
Change in erythropoietin levels from before the first dose to cycle 1 day 8.
Figure 4.
Figure 4.
IHC expression analysis of HIF-1α and HIF-2α: (A) HIF-1α versus HIF-2α baseline H-score in patients receiving DFF332, (B) evolution of HIF-1α and HIF-2α with DFF332 therapy, and (C) representative images. In (A), the size of the bubble is proportional to the percentage change in tumor sum of longest diameters; “±” indicates increase/decrease. IHC analysis is reported for patients for whom the full dataset (IHC on the baseline biopsy, baseline and on-treatment staining, or both) is available. In (C), tumor sections were stained using a fully automated system (Ventana Discovery Benchmark, Ventana Medical System) with a rabbit monoclonal anti-HIF-2α, clone D6T8V (Cat. No. 59973; Cell Signaling Technology), or with a rabbit monoclonal anti-HIF-1α, clone EP118 (Cat. No. BSB2520; Bio SB), primary antibody. The percentage of stained tumor cells and tumor positivity was scored using an H-score (0–300) by a certified pathologist. Scale bar, 80 μm. IHC, immunohistochemical; NE, nonevaluable; PD, progressive disease; PR, partial response; SD, stable disease.
See this image and copyright information in PMC

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