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Phase I/II, offene, randomisierte Studie zur Sicherheit, Wirksamkeit und Pharmakokinetik von Letrozol plus PD 0332991 (oraler CDK-4/6-Inhibitor) sowie Letrozol Monosubstanz zur 1st-Line-therapie ER-posiiver, HER2-negativer postmenopausaler Frauen mit fort
Prof. Dr. Thomssen, E. Kantelhardt
This study will test the activity of PD 0332991 in combination with letrozole for the first-line treatment of postmenopausal patients with ER+, HER2 negative ABC. The medical need of this patient population is high, as progression free survival is less than 1 year and overall survival is approximately 3 years.
Letrozole has been selected as background treatment as it is approved, commercially available, well known and considered a standard of care for the first line hormonal treatment of patients with ER+ ABC.
As the combination of letrozole and PD 0332991 has never been tested before, the study will include a Phase 1 portion to confirm the safety and tolerability of the combination. No PD 0332991 dose escalation will be applied, as toxicities are expected to be mild and the safety profiles of the two compounds are not expected to overlap. However, safety will be closely monitored and PD 0332991 dose de-escalation will be promptly implemented on the basis of observed toxicities.
The Phase 1 portion will also evaluate whether there is a significant drug-drug interaction between PD 0332991 and letrozole. Letrozole is predominately metabolized by CYP3A4 and CYP2A6. In human liver microsomes, letrozole is not an inhibitor of CYP1A2, 2C9, 2D6, and 3A4. The drug is a strong inhibitor of CYP2A6 and a moderate inhibitor of CYP2C19.
PD 0332991 is a CYP3A4 substrate, but is not an inhibitor of the primary CYP enzymes (IC50 > 30µM for 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4). Based on in vitro studies in human hepatocytes, PD 0332991 has a low potential to induce CYP3A4 activity.
However, as both letrozole and PD 0332991 are both metabolized by CYP3A4, a PK assessment of a letrozole-PD 0332991 interaction is warranted.
The novel mechanism of action of PD 0332991, the encouraging safety and PK profiles observed in the initial clinical studies, the cell cycle deregulation observed in breast cancer, the reported interactions between estrogens and cell cycle proteins, and the preclinical evidence that PD 0332991 is highly active in ER+ cell lines indicate that the exploration of the letrozole plus PD 0332991 combination in breast cancer is justified.



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