SY-1365 is a first-in-class, potent, selective covalent CDK7 inhibitor currently under phase I evaluation in expansion cohorts including ovarian cancer (OC) patients (pts) to assess safety, biologic and anti-tumor activity of SY-1365 alone and in combination with carboplatin (CP), and correlation of activity with RB pathway changes (RbC).
Expansion cohort pts received single agent (SA) SY-1365 BIW at doses ranging from 53-80 mg/m2 administered IV over 1 or 2 hrs for 3 of 4 wks/cycle. CP was given at AUC4 or 5 on day 1 of a 3 wk cycle with SY-1365 at 53 mg/m2 QW days 1 and 8. Clinical activity and safety were assessed by RECIST 1.1 and CTCAEv5, respectively. Apoptotic and cell proliferation markers were evaluated in tumor tissue from pts with paired biopsies. RbC in tumor and plasma samples were evaluated for correlation with SY-1365 activity.
As of 6/14/19, 80 total pts were enrolled, 33 in dose escalation, and 47 in expansion cohorts including 15 receiving SA and 3 receiving SY-1365+CP that were evaluated for response. Overall median duration (N=80) on SY-1365 treatment was 30.5 days (1-232). Adverse events (AEs) were generally low grade and reversible, occurring mostly on the day of dosing. Frequent (≥15%) AEs of any causality included headache, nausea, vomiting, fatigue, diarrhea, decreased appetite, abdominal pain, thrombocytopenia, anemia, infusion-related reaction, and dehydration. There were no treatment-related deaths. Of the expansion pts evaluated for response, 33% (5/15) receiving SA and 100% (3/3) receiving SY-1365+CP had SD as the best response, with the longest pt on SA for 114 days and on CP combination for 232 days. Available tumor biopsies demonstrate evidence of apoptosis in post-dose tumor tissue in 3 of 4 pts, with early evidence of RbC associated with SD in OC pts.
Emerging tolerability findings suggest predominantly low grade, reversible AEs, primarily on days of dosing. Early clinical activity demonstrates SD in both SA and CP combination cohorts with evidence supporting increased apoptosis in tumor tissue and associations of clinical activity with RbC. PK/PD guided dose optimization is in progress. Updated data will be presented.
Clinical trial identification
NCT03134638 - May 1, 2017