PALVEN: phase Ib trial of palbociclib, letrozole and venetoclax in estrogen receptor- and BCL2-positive advanced breast cancer
- Author(s)
- Muttiah, C; Whittle, JR; Oakman, C; Lindeman, GJ;
- Details
- Publication Year 2022-05,Volume 18,Issue #15,Page 1805-1816
- Journal Title
- Future Oncology
- Publication Type
- Protocol
- Abstract
- The addition of a CDK4/6 inhibitor to endocrine therapy improves progression-free and overall survival in women with metastatic estrogen receptor-positive breast cancer. In that setting, CDK4/6 inhibitors induce a potent cell-cycle arrest (which may be accompanied by tumor senescence) but fail to induce apoptotic cell death. Venetoclax is a potent inhibitor of BCL2, a pro-survival protein overexpressed in the majority of estrogen receptor-positive cancers. Pre-clinical findings indicate that venetoclax augments tumor response to the CDK4/6 inhibitor palbociclib by triggering apoptosis, including in senescent cells. The PALVEN phase Ib trial will further examine this finding. The primary objective is to identify the maximum tolerated dose and determine the recommended phase II dose for palbociclib, letrozole and venetoclax combination therapy. Clinical Trial Registration: NCT03900884 (ClinicalTrials.gov).; The current 'gold standard' treatment for estrogen receptor-positive, HER2-negative metastatic breast cancer is endocrine therapy with a CDK4/6 inhibitor. This combination improves tumor response and patient outcomes, primarily by reducing tumor cell growth. Paradoxically, less killing of tumor cells is observed in the presence of a CDK4/6 inhibitor. The authors hypothesize that co-treatment with venetoclax, an inhibitor of the BCL2 survival protein, will help trigger tumor death, thereby further improving tumor responses and patient outcomes. As a first step, combination therapy comprising letrozole, palbociclib and venetoclax will be tested in a phase I trial to identify the recommended doses for subsequent studies.; eng
- Keywords
- Antineoplastic Combined Chemotherapy Protocols; *Breast Neoplasms/pathology; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase I as Topic; Female; Humans; Letrozole/therapeutic use; Piperazines; Protein Kinase Inhibitors/therapeutic use; Proto-Oncogene Proteins c-bcl-2/genetics; Pyridines; Receptor, ErbB-2/metabolism; *Receptors, Estrogen/metabolism; Sulfonamides; Bcl-xl; Bcl2; BH3 mimetic; CDK4/6 inhibitor; apoptosis; breast cancer; estrogen receptor; senescence; senolysis; venetoclax
- Department(s)
- Medical Oncology
- PubMed ID
- 35187951
- Publisher's Version
- https://doi.org/10.2217/fon-2021-1450
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-02-07 05:05:39
Last Modified: 2025-02-07 05:08:50