US trial testing new med in combo with approved drug for pancreatic cancer
Recruiting underway for 400 adults with genetic mutation called RAS G12D
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A large U.S. clinical trial is now underway to test a newly approved pancreatic cancer drug in combination with an experimental therapy in people with pancreatic adenocarcinoma (PDAC) — the cancer’s most common type — whose tumor harbors a specific genetic mutation called RAS G12D.
The late-stage study, dubbed RASolute 309 (NCT07805954), is testing Rasonque (daraxonrasib) — approved in the U.S. in August — alongside an investigational compound called zoldonrasib. Run by Revolution Medicines, the developer of both therapies, the trial will mainly evaluate the effects of the oral treatment combo on tumor progression and survival outcomes in adults with metastatic PDAC, meaning the cancer has spread beyond the pancreas to other parts of the body.
The Phase 3 trial, now recruiting participants at the Moffitt Cancer Center in Tampa, Florida, is expected to involve approximately 400 people ages 18 and older. To be eligible, patients may not have received any prior treatment in the metastatic setting.
Revolution announced that, as of early October, the study was already dosing patients. Alan Sandler, MD, chief development officer at Revolution, said in a company press release that the trial “marks an important milestone in our efforts to advance a range of potential treatment options for patients with RAS-driven cancers across tumor types and treatment settings.”
Some trial participants will be treated with a standard chemotherapy regimen called gemcitabine and nab-paclitaxel (GnP). Others will receive the investigational oral combo of zoldonrasib and Rasonque, which is indicated for use in the U.S. for certain adults with metastatic PDAC who have received prior lines of treatment.
Early data show combo therapy more effective than either drug alone
Sandler noted that “RAS G12D is the most common RAS variant in PDAC.”
RAS is a protein that normally helps control cell growth. In many tumors, mutations cause this protein to become overactive, driving the abnormal growth of cancer cells. One such cancer-driving RAS mutation is G12D.
Both Rasonque and zoldonrasib are oral medications designed to inhibit RAS activity. Specifically, Rasonque is engineered to block multiple different mutated versions of this protein, while zoldonrasib is tailored specifically to target the protein carrying the G12D mutation.
According to Revolution, data from preclinical studies and early clinical tests suggest that combining the two approaches may lead to better RAS inhibition — and, consequently, less cancer growth — than either drug by itself.
Initial clinical data showed that Rasonque plus zoldonrasib delivered compelling antitumor activity in patients with previously treated metastatic PDAC, with a manageable safety and tolerability profile.
“In preclinical studies, the combination of RAS(ON) multi-selective and G12D-selective inhibitors achieved deeper and more sustained suppression of RAS signaling than either agent alone, accompanied by greater tumor control,” Sandler said. “Likewise, initial clinical data showed that Rasonque plus zoldonrasib delivered compelling antitumor activity in patients with previously treated metastatic PDAC, with a manageable safety and tolerability profile.
Those data informed the design of the ongoing Phase 3 trial, Sandler said. The study, launched in August, is expected to run through 2029. According to Revolution, the trial will be held globally, though no other testing locations have been announced.
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