PROACTIVE Trial to Use Neoadjuvant Approach in Unresectable Pancreatic Adenocarcinoma

The pilot trial is planning to enroll 20 patients who are deemed inoperable but do not have metastatic disease.

Results of an ongoing pilot study will determine whether the addition of neoadjuvant chemotherapy plus a novel surgical approach will allow for R0 resection in patients with locally advanced or unresectable pancreatic adenocarcinoma, which could significantly help improve survival outcomes, explained principal investigator Steven R. Grossman, MD, PhD.

Grossman, a cancer physician-in-chief for the University of Southern California (USC) Norris Cancer Hospital, and deputy director for cancer services for the USC Norris Comprehensive Cancer Center, explained that there is a significant unmet need for these patients who cannot undergo resection. Therefore, the pilot PROACTIVE trial (NCT06132087) will comprise the use of neoadjuvant chemotherapy, followed by surgical removal and reconstruction of locally advanced pancreas tumors that are attached to arteries.^1,2

“We’re extrapolating to say that we believe we’re going to offer a cure for some subset of patients who we can get through a R0 resection,” Grossman said in an interview with CancerNetwork^®.

In the interview, Grossman provided details on the ongoing trial and how it has the potential to shift the pancreatic cancer paradigm.

CancerNetwork: What are the current standards of care for patients in the locally advanced and unresectable setting? What are the unmet needs that led to this type of trial?

Grossman: There is an enormous unmet need. We’re excited about this trial, and starting to approach what is a very complicated situation for this type of patient. Broadly, pancreatic adenocarcinoma is the most common histology of pancreatic cancers; over 90% of them are adenocarcinoma. It’s a terrible diagnosis. We have been inching up to 5-year survival [rates]. When I started a couple of decades ago, the 5-year survival rate was 7%, and it’s doubled. Now it's 13% at 5 years—that is in all-comers and that includes all the resectable [patients] and those who are unresectable or metastatic.

That said, we don’t use stages as much as we use broad categories in pancreatic cancer. [First,] there is resectable and locally advanced, which then falls into 2 [categories]. One is borderline resectable, meaning you could technically [perform surgery], but we often give upfront chemotherapy to make the resection less technically difficult, if possible. Then unresectable nonmetastatic disease is what we’re targeting in this [trial]. This means it is technically unresectable given current operative standards, but there is no evidence of metastatic spread to distant organs and such. Then, there is stage IV metastatic disease with distant spread.

Of those categories, my partner and colleague here at USC, Dr Yuri Genyk, has been pioneering if you will—at least here on the West Coast—arterial reconstruction techniques to gain access to this population of patients who are considered unresectable or locally advanced. Only a few surgeons across the country are doing this. It’s not considered a standard of care. You won’t see it in the National Comprehensive Cancer Network [NCCN] guidelines, and that’s why it's a clinical trial right now.

Now, he has piloted this in a case series, which he’s putting together for publication. He has probably operated on 20 or 30 patients using arterial reconstruction techniques, and he does have some long-term survivors. Under current guidelines, patients who are unresectable with arterial involvement are given chemotherapy and radiation and ultimately do not survive. [This is] because the only way to gain long-term survival if they had cancer is still to have a complete resection, an R0 resection, and negative margins.

We’re using [Genyk’s] innovative surgical techniques to reconstruct some of the arteries local to the pancreas, including the [superior mesenteric artery], and the celiac axis. He comes from a transplant surgery background, and he is a liver transplant surgeon. When you transplant a liver, you have to reconnect the arteries and veins and often reconstruct, so he’s bringing those liver transplant techniques to pancreatic cancer.

We put together this very unusual, if you will, clinical trial, especially for me, a gastrointestinal medical oncologist, in that the protocol itself is just the surgery. This means that we will deem patients eligible who have locally advanced disease or unresectable with arterial involvement and must have had neoadjuvant chemotherapy with typical FOLFIRINOX [leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin] or gemcitabine/nab-paclitaxel [Abraxane] for at least 2 months and up to 6 months. That way, we’re casting a broad net to our community partners as well as to patients who get their physician's choice of neoadjuvant chemotherapy in the community, and then we will screen them and evaluate them for eligibility to protocol and hopefully take them in surgery. Then we’ll follow them for about 3 years out for survival with typical surveillance. If they didn’t complete 6 months of chemotherapy upfront, they’ll be allowed to complete 6 months of adjuvant therapy as well.

What stage of PROACTIVE are you currently in?

We are just in the earliest stages. Within the last couple of months, we have received [Institutional Review Board] approval. We are in the process of screening patients right now and are now receiving neoadjuvant therapy. We are looking towards the first surgeries happening within 2 to 3 months, and we’re looking to accrue patients over a 2- to 3-year period.

What other evidence exists that this could be a good approach for patients?

[It is] limited, but we’re extrapolating as we have to in these circumstances. For those who do not go to resection with pancreatic cancer, the 5-year survival rate is 0% or close to 0% using systemic therapy and radiation. What we do know is for those patients in various trials, especially with borderline resectable disease—which is venous involvement to this case, which is arterial and beams. If you categorize the patients who got upfront treatment and did or did not go to surgery, their median survival is greatly increased if patients received an attempt at curative resection, especially in R0 resection, and upwards of almost a doubling in survival. Some of these are small numbers, but in some trials, the median survival ranged up to 21 months.

Now, this is a pilot study, and we’re only looking to accrue up to about 20 patients in this particular trial. The primary objective is to demonstrate that we can achieve a complete R0 resection, in this population of patients. That’s our primary end point right now. It’s not powered right now to look at a survival end point; a secondary end point is progression-free survival and overall survival. If we can show in this first series of trials, hopefully, that we can achieve R0 resection in a reasonable fraction of patients that go to surgery, then we're looking at a large, multi-institution trial, maybe a cooperative group trial, to extend our data.

What chemotherapy regimens are physicians given discretion to administer in the neoadjuvant setting?

It is just standard of care as per NCCN guidelines. The 2 choices would be modified FOLFIRINOX or gemcitabine with nab-paclitaxel given on a typical schedule. We’re very non-prescriptive there; we just require a minimum of 4 cycles of FOLFIRINOX for 2 months; it is generally 2 months of chemotherapy for either regimen. We allow a maximum of 6 months because sometimes patients are responding at 2 and 4 months since things are still shrinking. Sometimes it makes sense to keep going up to about 6 months, but that would be the limit. Then, there is a 28-day window to screen for eligibility and hopefully go to surgery.

Chemotherapy drug shortages have been watched even more closely since the COVID-19 pandemic. Are there any challenges or impact you foresee this having on the trial?

We track this closely in my role as the cancer physician-in-chief. This is an important topic; we have a chemotherapy dashboard where we track shortages at least every week. Right now, the shortages we’re seeing are more in the blood cancer category. There may be not quite a shortage, but we’re keeping a close eye on fluorouracil, a key component of FOLFIRINOX. As far as the other drugs gemcitabine, nab-paclitaxel, oxaliplatin, and irinotecan, we haven’t seen any shortages in recent months or years.

Is there anything else about this trial that you would like to educate the oncology community about?

The key here is to reach out to us early. If you have a patient who you think might be eligible, even if you haven’t started chemotherapy, it’s best to talk to us early on, so we can make sure that whatever you’re about to do is at least within the scope or the guidelines of the trial. That would be the No. 1 thing. The focus of this trial is on those patients who, per NCCN, ASCO [American Society of Clinical Oncology], and some of the other guidelines out there, are simply not considered inoperable, but have not yet had metastatic spread. If you have a patient like that, please reach out to us.

Reference

1. PROACTIVE: Surgical Resection Outcomes in Locally Advanced and Unresectable Pancreatic Cancer After Neoadjuvant Chemotherapy. ClinicalTrials.gov. Updated January 17, 2024. Accessed April 4, 2024. https://shorturl.at/dquB2
2. New study examines if ‘inoperable’ pancreatic tumors can be safely removed. Keck Medicine. News release. Published March 14, 2024. Accessed April 5, 2024. https://shorturl.at/brRY9