TY - JOUR
T1 - Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2a antagonist in patients with previously treated advanced clear cell renal cell carcinoma
AU - Courtney, Kevin D.
AU - Infante, Jeffrey R.
AU - Lam, Elaine T.
AU - Figlin, Robert A.
AU - Rini, Brian I.
AU - Brugarolas, James
AU - Zojwalla, Naseem J.
AU - Lowe, Ann M.
AU - Wang, Keshi
AU - Wallace, Eli M.
AU - Josey, John A.
AU - Choueiri, Toni K.
N1 - Funding Information:
We thank the patients, their family members, nursing staff, study personnel, and investigators. Twist Medical provided medical writing support, funded by Peloton Therapeutics. The authors directed development of the manuscript and are fully responsible for all content and editorial decisions.
Publisher Copyright:
© 2017 by American Society of Clinical Oncology.
PY - 2018
Y1 - 2018
N2 - 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-2a (HIF-2a). PT2385 is a first-in-class HIF-2a 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-2a antagonism for the treatment of patients with ccRCC.
AB - 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-2a (HIF-2a). PT2385 is a first-in-class HIF-2a 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-2a antagonism for the treatment of patients with ccRCC.
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U2 - 10.1200/JCO.2017.74.2627
DO - 10.1200/JCO.2017.74.2627
M3 - Article
C2 - 29257710
AN - SCOPUS:85042441305
SN - 0732-183X
VL - 36
SP - 867
EP - 874
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 9
ER -