Your browser doesn't support javascript.
A dose escalation study of the noveloral SERD-ZN-c5 in women with ER-positive, HER2-negative advanced/metastatic breast cancer
Cancer Research ; 81(4 SUPPL), 2021.
Article in English | EMBASE | ID: covidwho-1186399
ABSTRACT

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.

Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Cancer Research Year: 2021 Document Type: Article

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Cancer Research Year: 2021 Document Type: Article