Document Type
Article
Publication Date
10-28-2021
Publication Title
Clinical Breast Cancer
Abstract
Preclinical studies: have demonstrated a complex cross-talk between Notch and estrogen signaling in ERα-positive breast cancer. Gamma-secretase inhibitors (GSIs) are investigational agents that block the cleavage and activation of Notch receptors. In animal models of endocrine-resistant breast cancer, combinations of tamoxifen and GSIs produce additive or synergistic efficacy, while decreasing the intestinal toxicity of GSIs. However, results of a clinical trial of a GSI-endocrine therapy combination in the metastatic setting have not been published to date, nor had the safety of such combinations been investigated with longer term treatment. We conducted a phase 1b dose escalation trial (NCT01149356) of GSI RO4929097 with exemestane in patients with ERα+, metastatic breast cancer (MBC) Study objectives: To determine the safety, tolerability and maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of RO4929097 when administered in combination with exemestane in patients with estrogen receptor positive metastatic breast cancer Results: We enrolled 15 patients with MBC. Of 14 evaluable patients, one had a partial response, 6 had stable disease and 7 progressive disease. Twenty % of patients had stable disease for ≥ 6 months. Common toxicities included nausea (73.3%), anorexia (60%), hyperglycemia (53.3%), hypophosphatemia (46.7%), fatigue (66.7%) and cough (33.0%). Grade 3 toxicities were uncommon, and included hypophosphatemia (13%) and rash (6.3%). Rash was the only DLT observed at 140 mg/d. Results suggest a possible recommended phase 2 dose of 90 mg/d. Ten patients with evaluable archival tissue showed expression of PKCα, which correlated with expression of Notch4. Mammospheres from a PKCα-expressing, endocrine-resistant T47D cell line were inhibited by a GSI-fulvestrant combination Conclusions: Our data indicate that combinations including endocrine therapy and Notch inhibitors deserve further investigation in endocrine-resistant ERα-positive breast cancer.
First Page
103
Last Page
114
PubMed ID
34903452
Volume
22
Issue
2
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Recommended Citation
Means-Powell, Julie A.; Mayer, Ingrid A.; Ismail-Khan, Roohi; Del Valle, Luis; Tonetti, Debra; Abramson, Vandana G.; Sanders, Melinda S.; Lush, Richard M.; Sorrentino, Claudia; Majumder, Samarpan; and Miele, Lucio, "A Phase Ib Dose Escalation Trial Of Ro4929097 (a Γ-secretase Inhibitor) In Combination With Exemestane In Patients With Er + Metastatic Breast Cancer (mbc)" (2021). School of Medicine Faculty Publications. 1346.
https://digitalscholar.lsuhsc.edu/som_facpubs/1346
10.1016/j.clbc.2021.10.013