Abstract PS12-20: A dose escalation study of the novel oral SERD-ZN-c5 in women with ER-positive, HER2-negative advanced/metastatic breast cancer

Background: ZN-c5 is an orally bioavailable selective estrogen receptor degrader (SERD) that binds potently to the estrogen receptors alpha and beta. It shows improved activity over fulvestrant in human tumor xenograft models and activity in tumor models that are resistant to tamoxifen. This is a Phase 1/2, open-label, multicenter, dose-escalation and expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), and clinical activity of ZN-c5 in subjects with advanced/metastatic estrogen receptor (ER) positive/ human epidermal growth factor receptor (HER2) negative breast cancer, both as monotherapy and in combination with palbociclib. The results from the ongoing monotherapy dose escalation are reported. Methods: Single agent ZN-c5 is being evaluated at sequentially escalating doses starting at 50 mg/day, administered orally, once daily (QD). The endpoints are to determine a maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D), preliminary clinical activity and to characterize the PK profile. Subjects must be intolerant to or have breast cancer refractory to established therapies and to have received up to 2 prior lines of chemotherapy for the treatment of advanced breast cancer. Subjects must have a documented prior response to endocrine therapy for advanced/metastatic disease (SD, PR, or CR) lasting > 6 months or disease recurrence after at least 24 months of adjuvant endocrine treatment. Results: A total of 15 female subjects (median age 57 years, range 51 - 89 years) were enrolled across 5 cohorts (3 subjects/dose level). The dose levels were 50, 75, 100, 150, and 300 mg/day. The subjects had a median of 4 prior therapies for advanced/metastatic disease, with a median of 3 prior hormonal-based therapies and a median of 1 prior chemotherapy. Eleven of 15 subjects (73%) received prior fulvestrant. The cut off-date for this analysis was 30 June 2020. There was no increase in incidence or severity of TEAEs with increase in dose level. The most frequent TEAEs reported in > 1 subject were nausea (33%), arthralgia, cough, musculoskeletal pain and vomiting (20% each), alanine aminotransferase increased, anemia, back pain, blood alkaline phosphatase increased, breast pain, diarrhea, fatigue, gamma-glutamyl transferase increased, headache, hypophosphatemia, myalgia and skin mass (13% each). Grade 3 events were COVID-19, hypercalcemia, arthralgia, back pain musculoskeletal chest pain, pain in extremity and hypertension, none were deemed related to ZN-c5. Grade 4 events were not reported. No bradycardia was observed. A single subject reported a Grade 1 visual field defect, not deemed related to ZN-c5. No DLTs were reported. ZN-c5 demonstrated a best response of stable disease (SD) in 10/15 subjects (66.5%), while progression of disease (PD) was reported in 5/15 subjects (33.5%). The clinical benefit rate (CBR, SD ≥ 24 weeks) was 40%. In addition, the progression free survival (PFS) was a median of 3.8 months (95% [CI], 1.6 to 6.3). The preliminary PK was characterized by fast absorption with median Tmax values of 1 - 2 hrs. The exposures were approximately dose-proportional at the dose levels of 50 - 100 mg and less than dose-proportional between 100 - 300 mg. No ZN-c5 accumulation after 15 days of QD dosing was observed. The estimated mean elimination half-lives ranged between 11 - 18 hrs. Conclusion: This monotherapy dose escalation study demonstrates that ZN-c5 is very well-tolerated and has promising clinical activity in patients with ER+/HER2-negative advanced breast cancer who have disease that progressed on standard therapies. The trial with ZN-c5 in monotherapy and with palbociclib is ongoing and the RP2D has not been determined yet. Citation Format: Pavani Chalasani, Vandana Abramson, Joanne Mortimer, Julie R Nangia, Jose Suarez, Matt Suster, Mieke Ptaszynski, Kevin Kalinsky. A dose escalation study of the novel oral SERD-ZN-c5 in women with ER-positive, HER2-negative advanced/metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-20.