![]() The expansion portion is now open to enrollment. 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. Additional objectives include evaluation of pharmacokinetics and pharmacodynamics of SY-5609 in combination with gem +/- nab-pac. Key objectives of expansion cohorts are to describe efficacy, defined by progression-free survival, overall response rate, and DCR. 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. There are 80+ professionals named 'Monish Sharma', who use LinkedIn to exchange information, ideas, and opportunities. Objectives of the expansion cohorts include evaluation of safety and efficacy of SY-5609 in combination with gem +/- nab-pac. View the profiles of professionals named 'Monish Sharma' on LinkedIn. 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. 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). The expansion portion of this Phase 1 study will evaluate SY-5609 in combination with gem +/- nab-pac in mPDAC pts. Therefore, combining SY-5609 with gem +/- nab-paclitaxel (nab-pac) offers a potential new treatment strategy for metastatic PDAC (mPDAC). ![]() SY-5609 also potentiates gemcitabine (gem) activity in PDAC cells in vitro and in xenografts in vivo (Henry 2021). 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. Mutant KRAS is a potent stimulator of mitogenic MAPK signaling and downstream transcriptional programs for cell proliferation. Oncogenic KRAS mutations are prevalent in PDAC. 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. ![]() 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). 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. Background: SY-5609 is an oral, selective, potent CDK7 inhibitor that targets two fundamental processes in cancer: transcription and cell cycle control. ![]()
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