The Phase 1 trial (NCT04247126) is a multi-center, open-label, dose-escalation study that plans to enroll approximately 60 people with advanced forms of ovarian, breast, colorectal, or lung cancer, or with solid tumors harboring alterations in the Rb pathway — a signaling cascade often inactivated in many types of cancers.
Recruitment is underway at two clinical sites in the U.S., in Michigan and Texas. More information is available here.
The study’s main goal is to assess the safety and tolerability of escalating doses of SY-5609 and establish a maximum tolerated dose. Additional study goals include assessing the compound’s anti-tumor activity, pharmacokinetic and pharmacodynamic properties, and potential predictive biomarkers, including Rb pathway alterations.
Pharmacokinetics studies how a medication is absorbed, distributed, metabolized, and then eliminated from the body, while pharmacodynamics studies the effects a drug has in the body.
“We have designed our Phase 1 trial to move efficiently through dose escalation and to increase the chances of seeing early signals of clinical activity by focusing on patient populations we believe are most likely to respond,” David Roth, MD, chief medical officer of Syros, said in a press release.
After an optimal dose has been established, Syros is planning a future expansion of the trial to test SY-5609 alone and in combination with other therapies, in multiple patient groups. Topline data from the study is expected by the end of the year, and additional dose-escalation data, including clinical activity, in mid-2021.
SY-5609 is a highly selective, oral cyclin-dependent kinase 7 (CDK7) inhibitor. CDK7 is an enzyme that promotes cell cycle progression and cell division, and also controls transcription, which is the process by which DNA is transformed into RNA, leading to gene expression, or activation.
By targeting and inhibiting the activity of CDK7, SY-5609 seeks to prevent cancer cells from multiplying and expanding uncontrollably. It also aims to reduce the expression of certain cancer-driving genes.
The medication has shown strong anti-tumor activity in animal models of different types of solid cancers, halting tumor growth in a dose-dependent manner.
“SY-5609 is a potentially transformative targeted approach for a range of difficult-to-treat cancers,” Roth said.
“CDK7 inhibition attacks two fundamental processes in cancer: increased expression of cancer-driving genes, and uncontrolled cell cycle progression. Based on this dual mechanism and the exquisite selectivity and preclinical potency of SY-5609, we believe it could provide a profound benefit for patients in dire need of new therapies,” he added.
Preclinical studies in animals models of lung, breast, and ovarian cancer have shown the anti-tumor effects of SY-5609 to be stronger — triggering deeper and more sustained responses — in the presence of alterations in the Rb pathway.
The therapy also has been found to be effective when used in combination with Faslodex (fulvestrant), by AstraZeneca, against treatment-resistant models of estrogen receptor-positive breast cancer — including those resistant to both Faslodex and a CDK4/6 inhibitor.
“SY-5609 has demonstrated compelling preclinical activity in a range of cancer models, and we are excited to further investigate it in this Phase 1 study,” commented Kyriakos P. Papadopoulos, MD, co-director of clinical research at South Texas Accelerated Research Therapeutics (START), and a clinical investigator in the trial.
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