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

Abstract

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 disease as best response were achieved by 2%, 12%, and 52% of patients, respectively. At data cutoff, eight patients remained in the study, with 13 patients in the study for ≥ 1 year. Conclusion PT2385 has a favorable safety profile and is active in patients with heavily pretreated ccRCC, validating direct HIF-2α antagonism for the treatment of patients with ccRCC.

Trial registration: ClinicalTrials.gov NCT02293980.

Figures

Fig 1.

Hypoxia-inducible factor-2α (HIF-2α) inhibition and the von Hippel-Lindau (VHL)/HIF axis in renal cell carcinoma. Abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; pVHL, VHL protein.

Fig 2.

Pharmacokinetics of PT2385. (A) Mean PT2385 plasma concentration, day 15, in all cohorts in the dose escalation phase. (Bottom) Pharmacokinetics in all patients (dose escalation and expansion cohorts; n = 32) treated with PT2385 at the recommended phase II dose (800 mg twice per day). (B) Pharmacodynamic response as assessed by decreases in the hypoxia-inducible factor-2α (HIF-2α) target erythropoietin. Plasminogen activator inhibitor-1, insulin-like growth factor-binding protein 3, and vascular endothelial growth factor A also were assessed as potential pharmacodynamic markers but no significant relationships with PT2385 exposure were observed. Abbreviations: AUClast,, area under the concentration-time curve from time 0 to the last quantifiable time point; Cmax, maximum concentration; PO, orally; SD, standard deviation; T1/2, terminal half-life; Tmax, time of maximal concentration.

Fig 3.

Maximum radiographic response (n = 49). Note that one patient discontinued the study because of clinical progression before the first scheduled radiologic assessment. Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; SLD, sum of the longest diameter.

Fig 4.

Treatment duration in all patients evaluable for response (n = 50). (*)The case of patient 11 was previously referenced.

Fig. A1.

Relationship between PT2385 exposure and progression-free survival in patients experiencing steady-state exposure trough concentrations