Julie A Means-Powell1, Ingrid A Mayer2, Roohi Ismail-Khan3, Luis Del Valle4, Debra Tonetti5, Vandana G Abramson2, Melinda S Sanders2, Richard M Lush6, Claudia Sorrentino7, Samarpan Majumder7, Lucio Miele8. 1. Vanderbilt-Ingram Cancer Center, Nashville, TN; Present address: Tennessee Oncology, Springfield, TN. 2. Vanderbilt-Ingram Cancer Center, Nashville, TN. 3. Moffitt Cancer Center, Tampa, FL. 4. Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center and Louisiana Cancer Research Center, New Orleans, LA; Department of Pathology, Louisiana State university Health, New Orleans, LA. 5. Department of Pharmaceutical Sciences, University of Illinois at Chicago School of Pharmacy, Chicago, IL. 6. Vanderbilt-Ingram Cancer Center, Nashville, TN; Section of Hematology/Oncology, Present address: George Washington University Cancer Center, Washington D.C, USA. 7. Department of Genetics, Louisiana State University Health Sciences Center School of Medicine, New Orleans. 8. Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center and Louisiana Cancer Research Center, New Orleans, LA; Department of Genetics, Louisiana State University Health Sciences Center School of Medicine, New Orleans. Electronic address: lmiele@lsuhsc.edu.
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.
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.
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