In a phase I trial reported in the Journal of Clinical Oncology, Courtney et al found that a first-in-class hypoxia-inducible factor-2α (HIF-2α) antagonist (PT2385) was active in patients with previously treated advanced clear cell renal cell carcinoma (RCC).
Study Details
In the first-in-human study, 26 patients received PT2385 at doses of 100 to 1,800 mg twice daily during a dose-escalation phase and 25 received the recommended phase II dose of 800 mg twice daily during the dose-expansion phase. Patients had locally advanced or metastatic clear cell RCC that had progressed during one or more prior regimens, including a VEGF inhibitor. Patients had a median of 4 prior therapies (range = 1–7).
Responses
No dose-limiting toxicity was observed at any dose during the dose-escalation phase. Among 50 patients evaluable for efficacy, complete response was observed in 1 (2%), partial response in 6 (12%), and stable disease in 26 (52%). At data cutoff, 8 patients remained on study, with 13 patients being on study ≥ 1 year. At median follow-up of 17.5 months, 25% of patients had a progression-free survival of > 14 months.
Adverse Events
The most common adverse events were anemia (35% grade 1 or 2, 10% grade 3), peripheral edema (37% grade 1 or 2, 2% grade 3), and fatigue (37% grade 1 or 2). No patients discontinued treatment due to adverse events. Hypoxia occurred in 18% of patients (all receiving ≥ 800 mg twice daily) and was of grade 3 in 10%.
The investigators concluded, “PT2385 has a favorable safety profile and is active in patients with heavily pretreated [clear cell RCC], validating direct HIF-2α antagonism for the treatment of patients with [clear cell RCC].”
The study was supported by Peloton Therapeutics.
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