A dose escalation study of the noveloral SERD-ZN-c5 in women with ER-positive, HER2-negative advanced/metastatic breast cancer
Authors: P. Chalasani, V. Abramson, J. Mortimer, J. R. Nangia, J. Suarez, M. Suster, M. Ptaszynski, K. Kalinsky
Journal: Cancer Research (2021)

Background: ZN-c5 is an orally bioavailable selective estrogen receptor degrader (SERD) that binds potently to theestrogen receptors alpha and beta  It shows improved activity over fulvestrant in human tumor xenograft models andactivity in tumor models that are resistant to tamoxifen  This is a Phase 1/2, open-label, multicenter, dose-escalationand expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), and clinical activity of ZN-c5 insubjects 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 ongoingmonotherapy dose escalation are reported  Methods : Single agent ZN-c5 is being evaluated at sequentiallyescalating doses starting at 50 mg/day, administered orally, once daily (QD)  The endpoints are to determine amaximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D), preliminary clinical activity and tocharacterize the PK profile  Subjects must be intolerant to or have breast cancer refractory to established therapiesand to have received up to 2 prior lines of chemotherapy for the treatment of advanced breast cancer  Subjects musthave 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 15female 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 priorchemotherapy  Eleven of 15 subjects (73%) received prior fulvestrant  The cut off-date for this analysis was 30 June2020  There was no increase in incidence or severity of TEAEs with increase in dose level  The most frequentTEAEs 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, painin extremity and hypertension, none were deemed related to ZN-c5  Grade 4 events were not reported  Nobradycardia was observed  A single subject reported a Grade 1 visual field defect, not deemed related to ZN-c5  NoDLTs were reported  ZN-c5 demonstrated a best response of stable disease (SD) in 10/15 subjects (66 5%), whileprogression 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)  Thepreliminary 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 isvery well-tolerated and has promising clinical activity in patients with ER+/HER2-negative advanced breast cancerwho have disease that progressed on standard therapies  The trial with ZN-c5 in monotherapy and with palbociclibis ongoing and the RP2D has not been determined yet