New pancreatic cancer therapy moves into Phase 2/3 clinical testing
SIL204 trial begins with first site activated at Tel Aviv medical center
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Silexion Therapeutics has launched a Phase 2/3 clinical trial testing its experimental therapy SIL204 in combination with standard-of-care chemotherapy in people with pancreatic cancer.
The first trial site, at Tel Aviv Sourasky Medical Center in Israel, has been activated and cleared to begin screening people with locally advanced pancreatic cancer, meaning the cancer has spread beyond the pancreas to nearby structures but has not spread to distant organs.
That site, which was activated last month, is expected to begin dosing patients after screening gets underway. Additional sites in Israel and Germany are expected to join the trial over the next few months.
SIL204 advances from preclinical work into Phase 2/3 testing
“We have transitioned SIL204 from a preclinical and regulatory-preparation asset into an active Phase 2/3 clinical program,” Ilan Hadar, chairman and CEO of Silexion, said in a company press release announcing its latest financial results and business updates. “With clinical trial authorization from [Germany’s drug regulator] added to the previously received approval from the Israeli Ministry of Health, and the successful initiation of our first clinical site at Tel Aviv Sourasky Medical Center at the end of July, our focus has shifted entirely to clinical execution.”
Most pancreatic cancers harbor mutations in the KRAS gene. This gene normally acts like an on-off switch to help control cell growth, but mutations can get the switch stuck in the on position, driving abnormal cell growth that ultimately leads to cancer.
Two KRAS mutations — G12D and G12V — are reported in more than 75% of cases of pancreatic adenocarcinoma, the most common form of pancreatic cancer. SIL204 is an RNA-based therapy designed to silence mutated KRAS by targeting its messenger RNA, preventing production of the mutated KRAS protein and thereby helping to suppress tumor growth.
SIL204 is Silexion’s next-generation KRAS-targeting therapy. Its first-generation therapy, called Loder, showed a promising signal in an exploratory analysis of people with locally advanced pancreatic cancer whose tumors carried G12D or G12V mutations in a Phase 2 trial (NCT01676259).
In addition to its direct anti-tumor activity, preclinical studies of SIL204 found changes in three key immune pathways that together may make cancer cells more susceptible to immune attack, a process known as immune sensitization.
Taken together, the findings supported an immune-sensitization pattern across studies of pancreatic and lung cancer cells carrying four KRAS mutations: G12D, G12V, G12C, and G12R.
“We continued to expand the scientific profile of SIL204 with new immuno-oncology data supporting a coordinated immune-sensitization signature across four KRAS mutations, reinforcing the rationale for future combination with anti-PD-(L)1 checkpoint inhibitors,” Hadar said.
Preclinical findings point to potential immunotherapy combinations
This class of immunotherapy, which includes Keytruda (pembrolizumab), works by blocking immune checkpoints such as PD-1/PD-L1, which normally act as brakes on immune responses. Blocking these signals can help immune cells recognize and attack cancer cells more effectively.
In the ongoing Phase 2/3 trial, SIL204 will be administered directly into the pancreatic tumor and also given systemically, allowing it to circulate through the body to address metastatic disease, in combination with standard-of-care chemotherapy.
The trial will begin with an initial safety run-in group of approximately 18 participants, followed by expansion to sites worldwide for a randomized cohort of approximately 166 participants.
Silexion began manufacturing clinical supplies of SIL204 in May with a leading global manufacturing partner, “further supporting the operational readiness of the program,” the release stated.
Because SIL204 is designed to target a broad range of KRAS mutations and these variants are also common in other solid tumors, including colorectal and lung cancers, the company believes the therapy may have therapeutic potential in these other cancers.
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