New Phase III Clinical Trial Actively Recruiting

A phase III clinical trial of a new drug is hoping to make immunotherapy more effective for pancreatic cancer patients with metastatic disease.

One of the hallmarks of pancreatic cancer is what scientists call the “immunosuppressive” environment of the tumor itself. The tumor microenvironment is filled with cells that suppress the immune system’s ability to fight the cancer, leading to rapid disease progression. Immunotherapy has dramatically changed the outlook for many patients with cancer, but so far it hasn’t fared as well in treating pancreatic cancer. However, there is a major push to find ways to potentially boost the effectiveness of immunotherapy in pancreatic cancer, mostly through combination treatments. A new trial called PRISM-1 is hoping to do just that.

The study, sponsored by Arcus Biosciences, hinges on a small molecule inhibitor called quemliclustat. The drug blocks an enzyme called CD73, which is involved in producing a chemical called adenosine within the tumor microenvironment. Adenosine can lead to a decrease in the immune system’s response towards cancer. Elevated CD73 expression is found in 40 to 60 percent of pancreatic cancer patients, and studies show it seems to correlate with poor clinical outcomes.

“It (quemliclustat) interferes with (a pathway) involved in adenosine metabolism,” explains Zev Wainberg, M.D., M.Sc., co-director of the GI Oncology Program at UCLA Health in Los Angeles, California, and a principal investigator on the study. “KRAS-mutated cancers, like more than 90 percent of pancreatic cancers, are very dependent on this pathway. So, blocking the pathway, in combination with chemotherapy, is really a very logical scientific approach.”

About PRISM-1

Investigators are studying whether participants with metastatic pancreatic cancer live longer on a treatment combining quemliclustat plus the chemotherapy regimen of nab-paclitaxel/gemcitabine. The trial compares participants who receive the chemotherapy regimen/new drug combination with another group that receives chemotherapy and a placebo. The trial will also assess tolerability and safety.

The trial is randomized so the treatment each participant receives will be chosen randomly by a computer program. The trial is “double-blinded,” meaning neither the doctors nor participants will decide—or even know—who gets quemliclustat and who gets the placebo. However, it is estimated about two-thirds of the participants will receive quemliclustat plus chemotherapy. The other one-third of the participants will receive chemotherapy plus a placebo. The study hopes to recruit more than 600 participants at more than 30 sites around the world.

“It’s fair to say I’m hopeful,” says Wainberg. “We just launched the phase III recently and we’re going to be actively recruiting over the next year. We have some really good data from our phase II trial so we’re moving forward.”

Promising Data from Phase II Study

In a presentation at the 2024 ASCO GI Conference, Wainberg reviewed data from a phase Ib trial dubbed ARC-8. In this study, researchers investigated quemliclustat by itself or in combination with a drug called zimberelimab (an anti-programmed cell death protein-1 monoclonal antibody) along with nab-paclitaxel/gemcitabine. All participants were diagnosed with advanced metastatic pancreatic cancer and none had been treated.

In the 122-patient cohort, those who received 100mg of quemliclustat alongside chemotherapy as a first-line treatment showed improved survival outcomes compared to historical benchmarks. The quemliclustat group had a 37 percent reduction in risk of death and a 5.9-month improvement in median overall survival compared to the matched control arm.

The study was “very interesting” because it included a synthetic control arm (a control group based on existing published data from patients, rather than a new group of patients) of patients treated with gemcitabine/nab-paclitaxel, using AI, explains Wainberg. “Pancreatic cancer is rare, so there is a small patient population and that’s one of the reasons to use a synthetic control arm,” he adds. “The other is that there is already a lot of data from randomized phase II and III trials on patients treated with gemcitabine/nab-paclitaxel. A synthetic arm is really very efficient since it reduces the number of patients needed for a study so the trial timeline is shorter and costs are reduced.”

Other parameters like ECOG performance status (level of physical activity and day-to-day functioning), surgical history, and the presence of liver metastasis were also matched between the two arms. The most common Grade 3 or higher side effects noted in subgroups that received quemliclustat were neutropenia and anemia. 

Because the study was well-designed, safe, tolerable, and had a large study population of more than 120 patients, “you have enough comfort (the results) were a real finding,” Wainberg says. “The study showed improvements in meaningfully prolonging survival compared to what we typically observe in metastatic patients who receive chemotherapy alone. For more than 30 years that’s been the standard of care and we really need much better treatments for these patients. But we also need the randomized data from the phase III trial before we can get really excited.”

Wainberg believes ongoing research like this will have a positive impact on pancreatic cancer. “We now have second generation immunotherapy targeted agents as well as vaccine strategies and KRAS-specific targeted drugs. I’m hopeful that in a few years we can carve up this disease into different cohorts treating it in a more personalized way. Pancreatic cancer is a very difficult disease and we still need to learn more about its biology, but compared to where we were just a few years ago it’s a different story and there really is reason for optimism.”

We encourage you to consult your physicians for clinical trials that may be right for you. The website ClinicalTrials.gov provides more details about this trial as well as many others. You can visit the Let’s Win Trial Finder for a list of all active pancreatic cancer clinical trials.