Background: RO4929097 is a potent and oral selective inhibitor of γ-secretase (GSI), producing inhibitory activity of Notch 1–4 signaling in tumor cells. Preclinical studies have demonstrated synergism of GSIs in combination with endocrine therapy, in ERα-positive xenografts. This suggests that optimal treatment of ER+ BC would benefit from an antiestrogen and GSI combination.

Materials and Methods: To explore the safety, tolerability and preliminary antitumor activity of Exemestane (25 mg/d) with R04929097 combination, we conducted a Phase Ib trial in patients with ER+/ HER2− MBC, whose disease relapsed during treatment with or within 6 months of discontinuation of an adjuvant nonsteroidal aromatase inhibitor or Tamoxifen, or whose MBC progressed during treatment with 1st or 2nd line endocrine therapy. Goserelin (3.6 mg q28 days Sub-Q) was given to all premenopausal patients. R04929097 was administered orally daily for 3 consecutive days, followed by 4 days off on a 21 day cycle. Doses of R04929097 were escalated on a standard 3+3 design over 5 doses (20, 30, 45, 90, and 140 mg). Patients were fully evaluated for dose limiting toxicity (DLT) for 3 weeks. Patients were treated until disease progression or occurrence of unacceptable toxicity.

Results: A total of 15 patients were enrolled. Median age was 56; average number of chemotherapies received in the adjuvant or metastatic setting was 3.3. Eleven patients had received adjuvant endocrine therapy. One patient received this as 1st line endocrine therapy, eleven patients received this study as 2nd line endocrine therapy; and three patients received this study as 3rd line endocrine therapy in the metastatic setting. Of the 14 patients evaluable, 1 had a partial response, 6 had stable disease, and 7 had progressive disease. All patients have discontinued the study at this time, 11 due to progression, 2 due to toxicity, and 1 withdrew after beginning protocol therapy. Twenty percent of patients had stable disease for six months or greater. Of the patients with stable disease for six months, one patient progressed at 9 months and 2 patients progressed at 10 months. The most common toxicities were 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 (13.0%) and rash (6.3%). There were no grade 4 toxicities. Rash was the only DLT and was seen at 140 mg.

Conclusion: The combination of R04929097 and Exemestane was overall well tolerated, but MTD was not determined as access to drug ended. Further studies with GSIs in combination with endocrine therapy are warranted on the basis of a favorable safety profile and preliminary evidence of stable disease seen in patients with ER+ MBC refractory to previous endocrine therapies. PK, PD and biomarker analysis is ongoing.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-14-04.