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Clinical Trial
. 2022 Feb;22(2):103-114.
doi: 10.1016/j.clbc.2021.10.013. Epub 2021 Oct 28.

A Phase Ib Dose Escalation Trial of RO4929097 (a γ-secretase inhibitor) in Combination with Exemestane in Patients with ER + Metastatic Breast Cancer (MBC)

Julie A Means-Powell  1 , Ingrid A Mayer  2 , Roohi Ismail-Khan  3 , Luis Del Valle  4 , Debra Tonetti  5 , Vandana G Abramson  2 , Melinda S Sanders  2 , Richard M Lush  6 , Claudia Sorrentino  7 , Samarpan Majumder  7 , Lucio Miele  8
Affiliations
Clinical Trial

A Phase Ib Dose Escalation Trial of RO4929097 (a γ-secretase inhibitor) in Combination with Exemestane in Patients with ER + Metastatic Breast Cancer (MBC)

Julie A Means-Powell et al. Clin Breast Cancer. 2022 Feb.

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.

Keywords: Endocrine-refractory metastatic breast cancer; Gamma secretase inhibitor; Notch.

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Conflict of interest statement

The authors declare no conflicts of interest related to this study.

Figures

Figure 1.
Figure 1.
Timeline of clinical responses of individual patients on this study at each dose level.
Figure 2.
Figure 2.
Correlation between AUC(0–24h) and dose in treatment cycle 1.
Figure 3.
Figure 3.
Trough concentration of RO4929097 versus dose, evaluated at cycle 1, dosing 1 (C1D1), 24 hours post dosing, cycle 1, dosing 10 (C1D10), 24 hours post dosing and C1D1, 120 hours post dosing.
Figure 4.
Figure 4.
Immunohistochemistry images showing expression of Notch4 and PKCα in representative tissue samples from patients enrolled in this study. A: the cellular localization of Notch4 and PKCα coincides, and is primarily cytoplasmic in solid areas of tumors and nuclear in areas of invasion at the tumor edge. B: a different case showing striking differences in cellular localization of PKCα in different areas of the tumor. The bottom panels show a field where both invading front and a solid tumor nodule are visible, each with its distinctive PKCα localization.
Figure 4.
Figure 4.
Immunohistochemistry images showing expression of Notch4 and PKCα in representative tissue samples from patients enrolled in this study. A: the cellular localization of Notch4 and PKCα coincides, and is primarily cytoplasmic in solid areas of tumors and nuclear in areas of invasion at the tumor edge. B: a different case showing striking differences in cellular localization of PKCα in different areas of the tumor. The bottom panels show a field where both invading front and a solid tumor nodule are visible, each with its distinctive PKCα localization.
Figure 5.
Figure 5.
Correlation between mRNA levels of Notch4 and PKCα as determined by RT-PCR in the same samples examined by immunohistochemistry.
Figure 6.
Figure 6.
Mammosphere inhibitory activity of RO4929097 alone (5 μM) and in combination with fulvestrant (30 nM) in T47D:PKCα cells. A: mammosphere counts in 3 independent experiments +/− standard deviations. B: representative microphotographs of phase contrast images from mammosphere cultures. Two fields per treatment were photographed.
Figure 6.
Figure 6.
Mammosphere inhibitory activity of RO4929097 alone (5 μM) and in combination with fulvestrant (30 nM) in T47D:PKCα cells. A: mammosphere counts in 3 independent experiments +/− standard deviations. B: representative microphotographs of phase contrast images from mammosphere cultures. Two fields per treatment were photographed.
See this image and copyright information in PMC

References

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