Discussion
toxicity, NCT04546009, DDIs
SEPARATION, METASTATIC BREAST CANCER
This phase Ia/Ib dose-escalation/-expansion study illustrates opportunities in oncology drug development from a clinical pharmacology perspective, where integration of clinical pharmacology considerations into early-phase clinical trials can accommodate an accelerated oncology development timeline by providing insights for patient eligibility, concomitant medications, and combination regimens for late-stage studies. The enhanced understanding of the pharmacokinetic profile, dose linearity, metabolic pathway, food effect, DDI potential, impact of race, and appropriate dosing when giredestrant is administered with palbociclib informed the design of pivotal trials.The proposed starting dose for this study was 10 mg once daily, which was projected to be efficacious based on results from nonclinical xenograft models and is approximately 10-fold lower than the calculated maximum recommended starting dose based on the severely toxic dose in 10% of animals from a rat toxicity study (Genentech data on file). In this study, we characterized pharmacokinetics over a wide dose range (10–250 mg) with sufficient exposure separation across different dose levels. Furthermore, the interindividual pharmacokinetic variability observed was in line with that of small molecule drugs in oncology patients ([The study design also included early assessment of metabolism and excretion through metabolite identification and measurement of giredestrant concentration in urine. The exploratory metabolite identification indicated that an apparently prominent metabolite in humans was absent, which reduced the risk of metabolite-related safety concerns and DDI. The observed minimal renal elimination of giredestrant suggests that renal function is unlikely to have a clinically relevant impact on giredestrant exposure and that the risk for renal transporter-related DDIs with giredestrant is low.
We found no clinically relevant DDI between giredestrant and palbociclib, a CYP3A substrate. The low DDI potential observed in this phase I study supported phase III evaluation of giredestrant combined with palbociclib as first-line therapy for metastatic breast cancer in the persevERA trial (NCT04546009). In contrast, another SERD, amcenestrant, induced CYP3A at therapeutic dose levels, with increasing induction observed with increasing dose (The exploratory food effect assessment in this phase I study showed a lack of food effect on giredestrant exposure and guided the dosing recommendation regarding meal intake in late-stage studies. The exploratory food effect assessment was based on patient-reported food diaries, which provided a convenient method for collecting patient meal information; however, the precision of food diaries depends on the accuracy of patient reporting and may not capture exact details of the timing or amount of each patient's caloric and fat consumption. The lack of food effect was subsequently confirmed in a dedicated food effect study in healthy subjects (NCT04274075). From a practical perspective, the absence of a food effect on pharmacokinetics offers greater flexibility and improves patient convenience. Among the other SERDs in clinical development a food effect was observed with elacestrant and rintodestrant. Specifically, it appears food was used to improve rintodestrant bioavailability (A unique aspect of this phase I study was the preliminary assessment of the impact of race on giredestrant exposure. Early-phase clinical trials often enroll a less diverse population (Insights generated in the current study informed phase II [aceIERA (NCT04576455; ref. 