Intra-arterial Versus Intravenous Gemcitabine Administration: PK Substudy within the Phase III TIGeR-PaC Clinical Trial in Locally Advanced Pancreatic Cancer

By Paula Novelli, MD

At this year's ASCO GI Symposium (in January 2023), our team presented intra-arterial gemcitabine versus intravenous gemcitabine PK substudy data within the RenovoRx TIGeR-PaC Phase III clinical trial. In a cohort of 13 patients, 7 patients were in the intra-arterial arm and 6 patients, the intravenous arm. Despite a 30% increased concentration in infusion in the intra-arterial arm, there was an average of 50% reduction in systemic drug exposure which is significant based on the entire concept of local regional therapy in any malignancy whether pancreas or liver. For improved concentrations and less systemic chemotherapeutic toxicity, we want therapy at the site of the tumor and not systemically delivered. The PK  substudy data was not surprising to us. I see these patients over a 16-week period and they tell us that the quality of life they experience is improved during that time. We are seeing patients skiing or golfing the next day, blaming me for gaining weight  because their appetites aren’t suppressed, nausea or vomiting. It is a pleasant experience treating these patients. And when I saw the PK data presented, the outcome was certainly no surprise to me. Clearly when you're dealing with pancreatic cancer, there are significant biological and mechanical barriers: the pancreas is poorly vascularized. To be able to drive the chemotherapy treatment right to the tumor, and not systemically, is impressive. I think that the PK results are representative of our experience with the patients I've treated at the University of Pittsburgh in this study.

Describe typical patient experiences during the TIGeR-PaC study with RenovoGem™.

On a patient’s first visit within the TIGeR-PaC study, I tell them they will be coming every other week for 8 treatments -- a significant amount of time, and that, receiving chemotherapy through an intravenous port could seem to be a simpler approach, and they may be fearful of the intra-arterial route. But we always tell them by the end of your RenovoGem treatment, you're going to be bringing us donuts and you're gonna love us. And, our team's gonna really love you because we spend so much time together which is what happens almost every single time. The hugs and pleasant patient interactions, I think, are related to quality of life, and having a physician available there during that entire period of the infusion. So I thought that was something maybe independent of the of the PK data but it really was something that was important to us and to the patients developing that relationship. And that relationship was only enhanced by them telling us that they were gaining so much of their life back during this treatment phase and still being treated effectively with really good quality of life. They weren't missing events or holidays with family. They weren't not eating because they weren't losing weight. Their hair was growing back; it was just a pleasant experience for all our patients and for that reason, the PK data did not surprise me at all.

With RenovoGem, how is treatment directed at pancreatic solid tumors? Why is this important?

Often with intra-arterial therapies, there is a feeding artery, and we deliver the catheters directly to the feeding arteries of the tumor. In this procedure, we're actually pumping or perfusing through the vessel wall, which is very specific to pancreatic cancer. There are significant biologic and mechanical barriers with the treatment of pancreas tumors;  there is very limited vascularity and the neo vascularity isn't what it is in other types of malignancies that we treat with trans-arterial therapies. With RenovoGem, trans-arterial micro-profusion allows us to bring the chemotherapy directly through the vessel wall and treat the tumor. We know how it diffuses into the tumor, and it doesn't wash out as the PK data suggests.  Currently, I think that there  are not good options for treating through these mechanical and physiologic barriers in this type of cancer. I think this potential therapy option is ingenious.

What is your experience as an investigator and clinical site using RenovoGem in patients enrolled in the TIGeR-PaC study?

In 2019, we first started treating with RenovoGem. Last week, I spoke to a patient that is now 21 months out of my treatment. We often just follow up with patients to see how they are doing. This patient was in Florida with his 101-year-old mother and taking her on a trip and is planning to come back and visit with us and talk about his experience. In this study, I think this is a good example that really shows not just efficacy and treatment effect, but also, certainly QOL (quality of life). For this gentleman, he was pleased enough with his therapy, to come back and discuss it with our program.

What are your thoughts on the possible outcome of TIGeR-PaC's upcoming interim analysis? 

I think, the interim results will suggest that the intra-arterial arm is effective, and that we're going to realize that there is likely utility in additional intra-arterial therapy beyond the treatment arm. I think that even advancing the study to more advanced patients versus just treating the primary tumor will be beneficial.

The data may show that this can be standard of care for not just locally advanced pancreatic cancer but even more distant metastatic disease, along with systemic therapy which is a paradigm that we use in, local regional therapies in the liver, whether it's HCC or colorectal cancers.  Combining systemic and local regional therapies, we've noticed that in a number of studies there is really no injury to the vessel wall which I guess isn’t that surprising, so it’s safe, and I think that we will use this as standard of care in not just locally advanced, even patients that have more progressive disease. And I think that the reasons are obvious. We definitely see therapeutic benefit and see patients that can still receive systemic therapy for other aspects of their systemic disease but controlling the primary tumor site I think can be quite beneficial. Years ago, when we interviewed a patient with extreme longevity survival, there was a press release that went viral, all over the world, like New Zealand, everywhere. I think that once we get our interim results and we may show that, this therapy doesn't have to be limited to this cycle, but patients can continue with virtually very little toxicity.

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What other cancers could this therapy be beneficial in treating?

I introduced the concept of this therapy for cholangiocarcinoma (bile duct cancer) to the group many years ago. Now, we are in the final stages of FDA approval for that clinical trial, and I am the national Principal Investigator. There are certain types of cancers that we aren't able to deliver intra-arterial concentrated chemotherapy to that are with the same physiologic or mechanical barriers as with cholangiocarcinoma. In 2019-2020, we started working on this and now we are close to finally piecing it all together to make it happen. I think it would be very effective in that patient population. The anatomy is quite amenable to treatment with RenovoGem.  The fact that we are not injuring vessels with repeated therapy makes me very comfortable to treat the hepatic artery in these patients.

What are the available treatment options today for patients diagnosed with locally advanced pancreatic cancer and cholangiocarcinoma?

We really have no validated or effective second line therapy, so there is no competition there for cholangiocarcinoma. However, there are percutaneous options for treating a locally advanced pancreas cancer, but none as effective, straightforward or easy to facilitate  as RenovoGem. What I'm trying to say is that some of the percutaneous, like ablative options, may not be effective and I don't think that they are as readily available as this type of treatment platform . Catheter-based therapies are the main treatment options that we use for any patient with catheter directed chemo delivery.

How important is the entire treatment team working together in utilizing RenovoGem for LAPC patients within the TIGeR-PaC study?

One of the things that's that I've learned in oncology studies that require an interventional radiologist (IR), you really have to have the IR people on board as the co-Principal Investigator or the local Principal Investigator because that can make or break a study. You have to have buy-in from the interventional radiologist and a collaborative approach; you're just not ordering a procedure, you're ordering a consultation. I want to emphasize the importance of having an interventional radiologist as a key member of that team really will drive an IR study especially when you are bringing a patient back over a 16 week period. These can be time-consuming procedures. The IR doc should be a leader to drive the study. 

Why is treatment with RenovoGem exciting as a treatment option for locally advanced pancreatic cancer patients?

For decades we've been using  a simple catheter for the delivery of chemotherapy treatment into direct tumor vessels and we had to recognize that it's not going to work for all types of cancers. I think that this is definitely a paradigm shift  for certain types of cancers, locally advanced pancreatic cancer. We will explore more clinical opportunities for RenovoGem, and we hope to be involved as well.

How impactful is RenovoGem to patients and their caregivers?  

For patients during the COVID pandemic, only the patient could come into the hospital.  The families were driving from, for example, 3 - 4 hours away and these people were sitting in a cold car for hours waiting for their family members to be treated. Because we keep the patient there, and they were willing to bring these patients and hang out in a cold car as nobody was allowed in the hospital during those days. And that was because the families appreciated the treatment and I thought that was fantastic. We didn't lose any patients during COVID from the study. We were able to support the patients. These are outpatient procedures, but they had to stay a mandatory amount of time for vital signs. I thought this spoke volumes that these people are being driven from hours away and their families couldn't even go into McDonald's, they were sitting in a cold car. It just showed how impressed even the family was with the results they were seeing.

How would you plan intra-arterial gemcitabine treatment via RenovoGem and is it considered personalized treatment?  

We look at the relationship of the tumor in the pancreas, it could be in different locations in the pancreas to the blood vessels for determining treatment. We study that location and we develop a plan that will drive the drug directly through vessel to the tumor  – this is our pre-procedural planning. I tend to just look at images and often wait to see what I can see on an arteriogram to determine where to treat. It has been effective and it is not difficult. It's the basic catheter skills that we as interventional radiologists develop over years.

What is RenovoGem?

The FDA regulates RenovoRx's flagship product candidate, RenovoGemTM (gemcitabine, an FDA-approved treatment given via our patented delivery method), as a new cancer therapeutic product. RenovoGem uses pressure-mediated gemcitabine administration across the artery wall to saturate tumor tissue with treatment. RenovoGem is now being studied via the RenovoTAMP® (RenovoRx Trans-Arterial Micro-Perfusion) therapeutic technology in a Phase III clinical development for locally advanced pancreatic cancer (LAPC). Beginning in the first half of 2023, RenovoRx plans to study RenovoGem in extrahepatic Cholangiocarcinoma (eCCA) in a Phase II trial.

Including Indications in:

Pancreatic Malignancy:

With an overall 5-year survival rate of 11%, pancreatic cancer is the second greatest cause of cancer-related mortality (Stages I-IV).

* Based on the findings of Phase I/II clinical and observational registry studies, the treatment of LAPC patients with RenovoGem enhanced patient survival and decreased adverse effects.

The TIGeR-PaC Phase III clinical trial for LAPC is now recruiting patients across the United States.

We have been granted Orphan Drug Designation for the treatment of pancreatic cancer, which would grant us seven years of orphan exclusivity to market RenovoGem for our LAPC indication upon NDA approval, assuming we are the first sponsor to obtain FDA approval for intra-arterial gemcitabine for the LAPC indication.

Cancer of the Bile Duct (extrahepatic Cholangiocarcinoma):

RenovoRx intends to investigate RenovoGem in the Phase II/III CouGAr clinical trial investigating its second application, bile duct cancer — a rare and severe kind of cancer that originates in bile ducts. Bile ducts are tiny tubes that transport bile, a digestive fluid, from the liver to the other digestive organs. eCCA begins in bile ducts located outside of the liver. The majority of persons with eCCA do not exhibit symptoms until the disease has advanced. Due to this, it is frequently challenging for professionals to make an early diagnosis.

RenovoRx has been granted Orphan Drug Designation for Cholangiocarcinoma, which, if we are the first to get FDA clearance for intra-arterial gemcitabine for the treatment of eCCA, could grant us seven years of orphan exclusivity to market RenovoGem for the eCCA indication.

Glioblastoma, Uterine Tumors, and Lung Cancer:

RenovoRx intends to initiate preclinical studies to investigate the use of RenovoGem in the treatment of different solid tumors, including locally advanced lung cancer, uterine cancers, and glioblastoma.

RenovoRx - About the company

Clinical-stage biopharmaceutical company RenovoRx aims to change cancer treatment. By directly giving IA chemotherapy to solid tumors, the business hopes to revolutionize oncology. The RenovoTAMP® (RenovoRx Trans-Arterial Micro-Perfusion) therapy platform is being studied to reduce the adverse effects of traditional care, improving patient well-being and extending life so patients may spend more time with family and friends.

RenovoTAMP, a targeted therapy platform, uses authorized chemotherapeutics with validated mechanisms of action and well-established safety and side effect profiles to improve efficacy, safety, and therapeutic window. RenovoGemTM, a new oncology therapeutic solution for unresectable locally advanced pancreatic cancer, is FDA-regulated (LAPC).

RenovoRx uses RenovoTAMP technology to securely administer targeted therapy. The technique has eight US patents and one European patent, with more US, European, and Asian patent applications pending.

RenovoRx acquired two FDA Orphan Drug Designations for intra-arterial gemcitabine for pancreatic and bile duct cancer after showing a median survival of 27.9 months in Phase I/II clinical trials compared to 12-15 months in prior studies for this patient population (cholangiocarcinoma). In the Phase III TIGeR-PaC pancreatic cancer clinical trial, this medicine is being tested for overall survival and other secondary outcomes, including quality of life. The Phase III TIGeR-PaC clinical trial enrolls unresectable LAPC patients in the US.

Paula Novelli, MD - About The Author, Credentials, and Affiliations

Paula Novelli, MD, is board-certified in interventional radiology and diagnostic radiology by the American Board of Radiology. She specializes in diagnostic radiology and vascular interventional radiology. She practices at University of Pittsburgh Physicians, Department of Radiology, and is affiliated with UPMC Children's Hospital of Pittsburgh, UPMC Magee-Womens Hospital, UPMC Passavant, UPMC Bedford, UPMC Shadyside, UPMC St. Margaret, UPMC McKeesport, UPMC Presbyterian, UPMC Mercy, UPMC Northwest, UPMC Altoona, and UPMC East. She obtained her medical degree at Georgetown University School of Medicine.

Reference

RenovoRx - Pipeline Overview. RenovoRx, 2022