Trial in progress: Phase I study of SY-5609, a potent, selective CDK7 inhibitor, with initial expansion in adults with metastatic pancreatic cancer

TPS4180 Background: SY-5609 is an oral, selective, potent CDK7 inhibitor that targets two fundamental processes in cancer: transcription and cell cycle control. Early results from the Phase 1 dose escalation portion in patients (pts) with advanced solid tumors reported improved tolerability of the intermittent 7 days on followed by 7 days off (7/7) schedule with ongoing dose escalation beyond the continuous daily dosing maximum tolerated dose. Single-agent clinical activity was demonstrated with durable stable disease, target lesion regressions, and reduction in tumor markers observed in multiple tumor types, notably in pancreatic cancer with a disease control rate (DCR) of 38.5% (Sharma 2021). Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of 11% (ACS Cancer Facts and figures, 2022) with limited treatment options and therefore, is a disease in need of novel effective therapies. Oncogenic KRAS mutations are prevalent in PDAC. Mutant KRAS is a potent stimulator of mitogenic MAPK signaling and downstream transcriptional programs for cell proliferation. Preclinical studies have shown that CDK7 inhibition via SY-5609 inhibits tumor growth in KRAS mutant PDAC xenograft models, in many cases leading to regressions. SY-5609 also potentiates gemcitabine (gem) activity in PDAC cells in vitro and in xenografts in vivo (Henry 2021). Therefore, combining SY-5609 with gem +/- nab-paclitaxel (nab-pac) offers a potential new treatment strategy for metastatic PDAC (mPDAC). The expansion portion of this Phase 1 study will evaluate SY-5609 in combination with gem +/- nab-pac in mPDAC pts. Gem +/- nab-pac will be administered on a biweekly schedule as it has shown better tolerability and similar clinical activity compared to the standard of care (SOC) administration schedule (Rehman 2020). Methods: This is an ongoing Phase 1, multi-center study in select solid tumors, amended to open expansion cohorts for mPDAC and expected to enroll approximately 80 mPDAC pts who have progressed on SOC treatments. Objectives of the expansion cohorts include evaluation of safety and efficacy of SY-5609 in combination with gem +/- nab-pac. Key objectives of the two parallel safety lead-in cohorts 1) SY-5609 + gem and 2) SY-5609 + gem + nab-pac are safety and determination of the recommended combination dose of the doublet and triplet for subsequent cohort expansions using a 3+3 escalation design. Key objectives of expansion cohorts are to describe efficacy, defined by progression-free survival, overall response rate, and DCR. Additional objectives include evaluation of pharmacokinetics and pharmacodynamics of SY-5609 in combination with gem +/- nab-pac. SY-5609 will be administered orally once daily on a 7/7 regimen and gem +/- nab-pac will be administered intravenously, in a 4-week cycle. The expansion portion is now open to enrollment. Clinical trial information: NCT04247126.