Pancreatic Cancer Clinical Trials Redefined: Data, Design and Hope for Tough-to-Treat Tumors

Pancreatic cancer remains one of the deadliest cancers worldwide, with a five-year survival rate of 10%. Despite decades of research, few meaningful advances have been made, and most patients are left with limited treatment options and poor prognoses.

In an interview with Xtalks, Dan Schmitt, President and CEO of Actuate Therapeutics, shares how the company is working to shift that reality with a novel GSK-3β inhibitor designed to extend survival and improve quality of life for patients facing one of the toughest cancers to treat.

Pancreatic cancer remains a formidable clinical challenge, marked by late diagnoses, aggressive disease progression and limited treatment options.

However, Schmitt doesn’t shy away from this reality. “Pancreatic is infamous in cancer drug development. It’s where the rate of failure is extremely high because the cancer is very difficult to treat just from the biology of it.”

Actuate’s investigational therapy targets GSK-3β, an enzyme central to tumor growth and survival. By inhibiting this target, the therapy disrupts cancer cell pathways responsible for tumor progression, chemotherapy resistance and suppressed cell death.

“What makes us different is this combination effect of direct effect on tumorigenic processes, but also indirect effect through upregulation of immune response to the tumor as well,” Schmitt said. “That’s why we’re seeing responses in terms of tumor burden reduction and significant increase in overall survival.”

Doubling Survival in Pancreatic Cancer

At ASCO 2025, Actuate shared results that could mark one of the most meaningful advances in pancreatic cancer in over a decade.

In the randomized Phase II study (Actuate-1801 Part 3B), patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) receiving Actuate’s investigational GSK-3β inhibitor plus gemcitabine/nab-paclitaxel (GnP) achieved a median overall survival of 10.1 months vs 7.2 months with GnP alone. Patients treated with the GSK-3β inhibitor in combination with GnP experienced a 37% reduction in the risk of death compared to those receiving the standard regimen.

In patients who completed at least one 4-week cycle of therapy, the GSK-3β inhibitor with GnP extended the median survival to 12.5 months compared to 8.5 months on GnP alone, a 43% reduction in the risk of death.

“The last meaningful increase in overall survival was 13 years ago,” Schmitt said. “Ours is showing almost three months at this point. Now remember 1.7, 1.8, now we’re at three. And if you look at the patients who were on long enough to get a full cycle, it’s a four-month increase in overall survival.”

In patients with liver metastases, the GSK-3β inhibitor in conjunction with the standard chemotherapy delivered a 2.5-fold improvement in one-year overall survival and a 38% reduction in the risk of death, an outcome rarely achieved in this population.

Meaningful Outcomes Without Added Toxicity

Equally striking, the improved survival came without additional toxicity. “What we’re seeing in this trial is that patients actually feel better on the combination than they do on the standard of care alone,” Schmitt said. “The combination of ‘we’ve got a drug that can double or triple your likelihood of survival for a year or longer with no meaningful clinical toxicity,’ that is the major outcome of that clinical study.”

Patients reported tangible improvements in quality of life, returning to daily activities such as golf, travel and social events. “It’s an exceptional profile for a new chemo drug going into this disease,” Schmitt added.

Beyond survival, secondary outcomes showed consistent benefits across the board:

• Disease control rate: 53.4% vs 44.8%
• Overall response rate: 37.9% vs 29.3%
• Progression-free survival: 6.9 months vs 5.6 months

Expanding Possibilities Through Combination Therapies

In a time where combination approaches are redefining oncology, Actuate’s GSK-3β inhibitor could serve as a core therapy that complements multiple treatment modalities.

“We’ve treated over 500 patients and combined it with over eight different standards of care with no new safety signals,” Schmitt said. “It’s got potential to be combined with new therapeutics. We just announced a trial in combination with a PD-1 inhibitor… KOLs at ASCO mentioned that they see this as a backbone therapy across metastatic, locally advanced, first-line and second-line disease.”

That broad compatibility opens doors to integrate their lead candidate with immune checkpoint inhibitors, RAS inhibitors and other targeted therapies. “We’re not a competitive play. We are a combination play,” Schmitt emphasized. “This will be a combination field for a very long time.”

Extending Innovation to Rare Cancers

While pancreatic cancer remains the company’s lead indication, Actuate’s science has also shown promise in Ewing sarcoma, a rare pediatric cancer with few options.

“This young man had advanced refractory Ewing sarcoma,” Schmitt recalled. “Within two cycles of the GSK-3β inhibitor plus topotecan/cyclophosphamide, he was a complete responder, and he’s been a complete responder for the last two years.”

The company now plans a Phase I/II registration trial spanning pediatric, adolescent and adult refractory Ewing sarcoma. “My mantra is, if you’ve got something for kids with cancer, you should do something for kids with cancer,” Schmitt said.

Engaging Regulators with Data and Purpose

With strong clinical results and a growing safety record, Actuate is preparing for discussions with the FDA and EMA regarding potential registration.

“We are showing major increases in overall survival, statistically significant increases in overall survival,” Schmitt said. “Is this data enough for the clinical component of an NDA for registration? That’s the discussion that’ll occur in the first quarter of next year.”

He added, “There hasn’t been a major advance in pancreatic cancer in 13 years. We’ve got a drug that doubles or triples the likelihood of survival for a year and longer with no notable clinical toxicity. Why would you hold that away from tens of thousands of patients just to do 400 more?”

Leadership Grounded in Collaboration

Schmitt’s approach to leadership mirrors Actuate’s scientific strategy, which is pragmatic, data-driven and deeply collaborative.

“I brought a stable of best-of-breed consultants with me who I’ve worked with over the years,” he said. “We like each other, we trust each other and we know what our expertise lanes are.”

That network-driven model enables the company to operate efficiently while pursuing ambitious clinical goals.

It also reflects Schmitt’s belief that leadership in biotech requires humility as much as vision, knowing when to rely on trusted experts and when to push boundaries.

From Vision to Milestone

For Schmitt, being listed on the Russell 2000 and 3000 indices represents more than financial recognition; it’s validation of the company’s vision and resilience.

“Being added to that means that you’ve grown the company in a public stock to a level where it’s recognized with a measure of stability and potential growth,” Schmitt said. “For us to have made those transitions and continue to show not only growth in terms of our development, but growth in terms of the investment community’s belief in us, it is a major milestone in the company’s history and direction.”

Founded in 2015 and publicly listed in 2024, Actuate has moved quickly from concept to clinical momentum. Schmitt credits his nearly four decades in the pharmaceutical and biotech industries for shaping a leadership style grounded in discipline and collaboration.

“You learn the requirements of developing a drug in large pharma and then you learn leadership in a large pharma organization and then you learn how to do that in a smaller organization and what skill sets you need in the people around you,” he explained. “You learn best practices and you learn from worst practices. That’s what I’ve been able to do and bring to Actuate, a set of experiences that allow me to fully develop drugs in an efficient manner.”

A Pipeline in a Molecule

With over 500 patients treated, patents extending exclusivity to 2043 and expanding studies across solid tumors and rare diseases, Actuate’s GSK-3β inhibitor could anchor a new class of combination therapies.

“We have clinical data showing significant potential in pancreatic, non-small-cell lung, colorectal, leukemia, lymphomas and sarcomas. All we have to do is run the trials and execute,” said Schmitt.

As he looks ahead, Schmitt remains focused on what drives him most, transforming data into hope. “We have a lot of safety data and a lot of compelling efficacy data. We’re very proud of the work to date, and we look forward to taking it to the next step in those regulatory discussions.”