Dataset Information

Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer.

ABSTRACT:

Purpose

We describe the clinical pharmacology characterization of giredestrant in a first-in-human study.

Experimental design

This phase Ia/Ib dose-escalation/-expansion study (NCT03332797) evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of giredestrant in estrogen receptor-positive HER2-negative locally advanced/metastatic breast cancer. The single-agent dose-escalation stage evaluated giredestrant 10, 30, 90, or 250 mg once daily. The dose-expansion stage evaluated single-agent giredestrant at 30, 100, and 250 mg once daily. Dose-escalation and -expansion phases also evaluated giredestrant 100 mg combined with palbociclib 125 mg.

Results

Following single-dose oral administration, giredestrant was rapidly absorbed and generally showed a dose-proportional increase in exposure at doses ranging from 10 to 250 mg. At the 30 mg clinical dose, maximum plasma concentration was 266 ng/mL (50.1%) and area under the concentration-time curve from 0 to 24 hours at steady state was 4,320 ng·hour/mL (59.4%). Minimal giredestrant concentrations were detected in urine, indicating that renal excretion is unlikely to be a major elimination route for giredestrant. Mean concentration of 4beta-hydroxycholesterol showed no apparent increase over time at both the clinical dose (30 mg) and a supratherapeutic dose (90 mg), suggesting that giredestrant may have low CYP3A induction potential in humans. No clinically relevant drug-drug interaction was observed between giredestrant and palbociclib. Giredestrant exposure was not affected by food and was generally consistent between White and Asian patients.

Conclusions

This study illustrates how the integration of clinical pharmacology considerations into early-phase clinical trials can inform the design of pivotal studies and accelerate oncology drug development.

Significance

This work illustrates how comprehensive clinical pharmacology characterization can be integrated into first-in-human studies in oncology. It also demonstrates the value of understanding clinical pharmacology attributes to inform eligibility, concomitant medications, and combination dosing and to directly influence late-stage trial design and accelerate development.

SUBMITTER: Malhi V

PROVIDER: S-EPMC10722959 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Publications

Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer.

Malhi Vikram V Agarwal Priya P Gates Mary R MR Liu Lichuan L Wang Jianshuang J De Bruyn Tom T Lam Scott S Eng-Wong Jennifer J Perez-Moreno Pablo P Chen Ya-Chi YC Yu Jiajie J

Cancer research communications 20231201 12

<h4>Purpose</h4>We describe the clinical pharmacology characterization of giredestrant in a first-in-human study.<h4>Experimental design</h4>This phase Ia/Ib dose-escalation/-expansion study (NCT03332797) evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of giredestrant in estrogen receptor-positive HER2-negative locally advanced/metastatic breast cancer. The single-agent dose-escalation stage evaluated giredestrant 10, 30, 90, or 250 mg once daily. The ...[more]

PMID: 38019116

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Dataset Information

Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer.

Purpose

Experimental design

Results

Conclusions

Significance

Publications

Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer.

Similar Datasets

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