Trisalus Life Sciences Inc., of Westminster, Colo., reported the start of a clinical trial assessing a treatment that combines its intravascular, tumor-directed proprietary Pressure-Enabled Drug Delivery (PEDD) approach with standard-of-care systemic chemotherapy.
The open-label trial will be conducted at Roger Williams Medical Center as a single-arm, dose-escalation phase I study of patients with unresectable pancreatic adenocarcinoma. The trial’s goal is to enroll nine patients. If dose-limiting toxicities are not encountered, a total of 18 patients will be enrolled.
PEDD with Smartvalve technology is a self-expanding, one-way micro-valve that enables optimal infusion pressures for deeper therapeutic penetration. Treatment is delivered directly into solid tumors with the goal to avoid healthy tissue while optimizing therapeutic effect.
This study is designed to assess the technical success and safety of administering oxaliplatin through retrograde venous infusion followed by systemic administration of FOLFIRI, a regimen containing folinic acid, fluorouracil and irinotecan. Secondary measures of the study include local progression-free survival, systemic progression-free survival, overall survival, radiographic response rates, serologic response rates and neurotoxicity from oxaliplatin.
“We’ve made significant advances in developing therapeutics to address various forms of cancer, but solid tumors of the pancreas have significant barriers that prevent therapies from penetrating the entire tumor. This trial will help us evaluate the role of this novel drug delivery technology in overcoming tumor infusion barriers and delivering the most toxic component of the regimen deep into the solid tumor,” said Ritesh Rathore, principal investigator for the trial.
“Our new technology to deliver therapeutics deep into an unresectable pancreatic tumor is very different,” Mary Szela, president and CEO of Trisalus, which was formerly known as Surefire Medical Inc., told BioWorld. She noted that the company’s approach accesses the tumor from the venous side, allowing for the advancement of the catheter close to the tumor site. Traditional approaches for targeted therapeutic delivery to this organ rely on the use of the arterial system. However, the terminal pancreatic arteries are not large enough to accommodate delivery devices.
Szela emphasized the technology’s micro-valve, which allows forward flow of the therapeutic. It also can create pressures that are up to about 300 mm of mercury. That’s important because pancreatic tumors are the highest pressure tumors, which explains its high rates of mortality.
According to the company, the number of newly diagnosed patients with pancreatic cancer is growing. However, less than 20% of them are suitable for surgery, highlighting the need for improved treatment options. The Centers for Disease Control and Prevention has noted that early stage pancreatic cancer usually has no symptoms and spreads quickly.
Another feature of the technology is a tiny sensor, which is about the size of an eyelash. The sensor can withstand extreme blood flow tortuosity and temperature changes. It also can guide the radiologist through the vasculature while sensing the pressure. “And importantly, it’s guiding the interventional radiologist to actually create the appropriate pressure gradient to open up those collapsed vessels and overcome the pressure, so you can get very deep, wide perfusion deep into the parenchymal tissue of a solid tumor.”
She noted that what kills patients with pancreatic cancer is the metastases to the liver. “You can’t really control the metastatic disease until you treat the tumor at its origin,” she said. To target these tumors, the technology can close off the circulation and force the drug to stay there for a period of time.
Szela added that the company has conducted large animal studies, and preclinical data has shown that about 99% of the drug remains in the tumor, with very little ending up in normal tissue.
The company is hoping that this study will take about 12 months. The aim is to validate the technique and roll it into a cell therapy trial.
“We don’t believe our approach would be in isolation. We believe [this] approach would be part of a systemic regimen, too. Our goal is to … reduce the origin of cancer, control the metastatic disease, so you can … give the systemic treatment, which is primarily treating the micrometastases, a chance to succeed. We would either do this in a neoadjuvant way, or in collaboration with a systemic treatment. It will be organ-specific, and we’ll do that disease by disease, because it would vary quite substantially.”
Previously, the company collaborated with Steven Katz, director of the Office of Therapeutic Development at the Roger Williams Medical Center, for a phase Ib clinical trial shows that administering a concentrated dose of anti-carcinoembryonic antigen-positive (CEA) CAR T cells precisely at the site of a solid tumor by means of PEDD is safe, with encouraging clinical responses. Katz served as principal investigator in the trial.
Results of the study were presented in November 2018, five patients – four pancreatic and one colorectal – with CEA+, unresectable stage IV adenocarcinoma with liver metastases who had failed one or more lines of systemic chemotherapy. Each received three hepatic artery infusions of Sorrento Therapeutics autologous anti-CEA CAR T cells. The immunotherapy was delivered by means of the PEDD technology. Among the results presented was that two of the four pancreatic cancer patients had no viable liver metastases by PET scan after the treatment.
Szela noted that it was a proof-of-concept to demonstrate safety, and the results were promising. Of the two who had the complete response, one had a durable response of 13 months and went on to live 26 months. The other is still alive. “So, we think this is a pretty profound result; you don’t see that happen.”
In the next 12 to 18 months, the company plans to transition to a therapeutic company, merging with Katz’s discovery lab, manufacturing facility and clinical operations to deliver cell therapy. In addition, the company is acquiring other immunologic agents to combine with the various regimens. So, in the next year or so, the company is aiming to have four or five clinical trials ongoing.