Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor-2α Antagonist in Patients With Previously Treated Advanced Clear Cell Renal Cell Carcinoma
Open accessAbstract
Purpose The von Hippel-Lindau tumor suppressor is inactivated in the majority of clear cell renal cell carcinomas (ccRCCs), leading to inappropriate stabilization of hypoxia-inducible factor-2α (HIF-2α). PT2385 is a first-in-class HIF-2α antagonist. Objectives of this first-in-human study were to characterize the safety, pharmacokinetics, pharmacodynamics, and efficacy, and to identify the recommended phase II dose (RP2D) of PT2385. Patients and Methods Eligible patients had locally advanced or metastatic ccRCC that had progressed during one or more prior regimens that included a vascular endothelial growth factor inhibitor. PT2385 was administered orally at twice-per-day doses of 100 to 1,800 mg, according to a 3 + 3 dose-escalation design, followed by an expansion phase at the RP2D. Results The dose-escalation and expansion phases enrolled 26 and 25 patients, respectively. Patients were heavily pretreated, with a median of four (range, one to seven) prior therapies. No dose-limiting toxicity was observed at any dose. On the basis of safety, pharmacokinetic, and pharmacodynamic profiling, the RP2D was defined as 800 mg twice per day. PT2385 was well tolerated, with anemia (grade 1 to 2, 35%; grade 3, 10%), peripheral edema (grade 1 to 2, 37%; grade 3, 2%), and fatigue (grade 1 to 2, 37%; no grade 3 or 4) being the most common treatment-emergent adverse events. No patients discontinued treatment because of adverse events. Complete response, partial response, and stable diseas…
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A phase I trial of PT2385 reported grade 3 anemia in 10% of patients.
“A phase I trial of PT2385 reported grade 3 anemia in 10% of patients (46).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [46]
Clinical evaluation revealed on-target inhibition of HIF-2α activity in both tumor and normal tissues, reflected by reduced erythropoietin levels and treatment-associated anemia that was predominantly low-grade and manageable.
“Clinical evaluation revealed on-target inhibition of HIF-2α activity in both tumor and normal tissues, reflected by reduced erythropoietin levels and treatment-associated anemia that was predominantly low-grade and manageable [412].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [412]
The most frequent on-target toxicity with HIF-2 inhibitors (PT2385; belzutifan) is anemia from suppression of renal/hepatic erythropoietin.
“The most frequent on-target toxicity with HIF-2 inhibitors (PT2385; belzutifan) is anemia from suppression of renal/hepatic erythropoietin.”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [412]
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“Anemia occurred commonly in early trials and, during prolonged belzutifan therapy, occasionally required transfusion or erythropoiesis-stimulating agents, hence the need for routine hematological monitoring [37,412,421].”
- Authors
- Courtney, K. D., Infante, J. R., Lam, E. T., Figlin, R. A., Rini, B. I., Brugarolas, J., Zojwalla, N. J., Lowe, A. M., Wang, K., Wallace, E. M., Josey, J. A., & Choueiri, T. K.
- Affiliations
- Cedars-Sinai Medical Center (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2018-03-20
- Volume
- 36
- Issue
- 9
- Pages
- 867-874
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC5946714
- OpenAlex
- W2778771081
- Cited by
- 393
- References
- 3
- Citations by year
- 2026: 26 · 2025: 37 · 2024: 32 · 2023: 52 · 2022: 47 · 2021: 66 · 2020: 63 · 2019: 45 · 2018: 24 · 2016: 1
- FWCI
- 30.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Journal of Clinical Oncology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (K12CA086913, P50CA196516)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- PT2385, clear cell renal cell carcinoma, VHL, dose escalation, recommended phase 2 dose, pharmacokinetics, pharmacodynamics, safety, anemia, peripheral edema, oral anticancer drugs
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Adult, Aged, Aged, 80 and over, Carcinoma, Renal Cell, Dose-Response Relationship, Drug, Female, Humans, Indans, Kidney Neoplasms, Male, Middle Aged, Neoplasm Metastasis, Sulfones, Basic Helix-Loop-Helix Proteins
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