New Trial to Find Biomarkers to Guide Treatment

Advocacy Groups | <b>Let's Win! Pancreatic Cancer Foundation</b>

Doctors Jennifer Knox and Elizabeth Jaffee lead the PASS-01 trial using biomarkers and other measures to choose individualized treatment.

Researchers across the world are exploring new ways to more effectively treat metastatic pancreatic cancer.

Although some progress has been made, there are still too many patients who don’t respond to the standard chemotherapeutic regimens of gemcitabine plus nab-paclitaxel (GA) or modified FOLFIRINOX (mFFX). Complicating matters is that discovering this lack of response often comes after patients are already weakened by advancing disease or side effects from the treatment itself. To combat those issues, physician–scientists are investigating a different approach: studying the cells within malignant pancreas tumors to look for biomarkers that may provide a clue to better guide treatment choices.

One such study is called PASS-01: Pancreatic Adenocarcinoma Signature Stratification for Treatment. Sponsored by the Princess Margaret Cancer Centre (Toronto), the trial is a collaboration with Johns Hopkins Medicine (Baltimore), Cold Spring Harbor Laboratory (Cold Spring Harbor, New York), Ontario Institute for Cancer Research (Toronto), Dana-Farber Cancer Institute (Boston), Memorial Sloan Kettering Cancer Center (New York), BC Cancer Agency (Vancouver), Northwell Health (Long Island, New York). The trial is being conducted by the Stand Up To Cancer Pancreatic Cancer Convergence Dream Team, funded by the Pancreatic Cancer Collective—an initiative of the Lustgarten Foundation and Stand Up To Cancer—as well as Stand Up To Cancer Canada and Pancreatic Cancer Canada.

“Our PASS-01 trial has both patients and clinician investigators excited because the goal is to offer a ‘state of the science’ approach to better understand each patient’s cancer and what drugs may work best,” says Jennifer Knox, M.D., Clinician Investigator, Princess Margaret Cancer Centre, and study chair.

The researchers are using innovative biomarker detection strategies, personalized tumor models, and high content molecular profiling to not only attempt to treat patients optimally today but to better understand and optimize treatments for patients in the coming years, Knox says. “We bring together some of the finest pancreatic cancer researchers in North America, and the team is poised to make a tangible impact for patients quickly,” she adds. “We hope this study will impact researchers around the world to modify their research plans to make longer strides in improving survival for pancreas cancer patients.”

“This trial is absolutely critical,” says Elizabeth Jaffee, M.D., Professor of Oncology and Deputy Director of the Sidney Kimmel Cancer Center at Johns Hopkins, and the trial’s U.S. study chair. The hope is to recruit about 150 patients at participating sites, which include the collaborators. Although GA and mFFX improve duration of survival for some patients, “We need to do much better in identifying much earlier those patients who potentially will have a good response versus ‘this isn’t working,’” she explains.

About the Study

The chemotherapy regimens GA and mFFX remain standard treatment options, but so far these agents do not have biomarkers to predict response. PASS-01 will, for the first time, explore progression-free survival differences in the two standard backbone regimens used in the advanced pancreatic cancer setting. Biomarker- driven strategies in pancreatic cancer are lacking, perhaps accounting for a large number of failed phase II and III studies.

This study will not only evaluate two standard of care chemotherapy regimens, but will also explore whether researchers can choose the better one for a particular patient from the start by evaluating tumor molecular profiling, chemotherapy sensitivity signatures, GATA6 expression, and other putative biomarkers as predictors of response to chemotherapy. In addition, the use of patient-derived organoid models for personalized medicine will continue to develop within this study.

Patients diagnosed with untreated metastatic pancreatic cancer will be randomized to either the GA or mFFX arm. Given that both regimens are standard of care, study treatment will be administered as per standard of care at each institution, including a maintenance therapy approach which is encouraged in both arms. Dose modifications, antiemetics, supportive medications, and use of growth factors will follow institutional guidelines.

The primary outcome measure is to determine progression-free survival in GA and mFFX arms with secondary outcome measures, which include overall response rate by RECIST 1.1 and duration of response in patients receiving GA or mFFX. RECIST stands for “response evaluation criteria in solid tumors.” It is a set of published rules that define when tumors in cancer patients improve (“respond”), stay the same (“stabilize”), or worsen (“progress”) during treatment. Secondary outcome measures will also include overall survival associated with GA or mFFX profiles, signatures and pharmacotyping, GATA6 as a biomarker of response to GA or mFFX, and concordance between organoid and patient transcriptomic profiles.

“This trial does have a huge translational component, and that’s what pancreatic cancer patients desperately need,” says Jaffee. “It all sounds complicated, but we have incredible technologies now that we didn’t even have a few years ago. Those technologies allow us to move things forward much more quickly. Translational research really just means taking the knowledge and information we gain from basic biology and clinical trials to techniques that can help meet very critical needs in patient care. It’s really geared to improving outcomes for patients. And we know that pancreatic cancer patients absolutely need new pathways for better treatment. Hopefully, identifying certain biomarkers will help us get to the point where outcomes are improved.”

A Step Closer to Personalized Treatment

As part of the trial, one area of focus will be on a tiny protein called GATA6. Research is ongoing to see if measurement of GATA6 as a potential biomarker is able to help separate pancreatic cancer tumor types into groups, helping researchers learn how patients would respond to different treatment paths based on the tumors’ subtype. Research has identified two general subtypes of pancreas adenocarcinoma: basal-like and classical-like.

“Our research shows the basal-like cohort, or GATA6-low, may be particularly resistant to mFFX, and may do better on a GA-based chemotherapy,” says Dr. Knox. “This is pilot data from our COMPASS trial that needs further confirmation in randomized trials. GATA6 can be easily measured in a few days from a patient’s biopsy and could turn out to be a predictive tool in clinical decision-making. If we know we are choosing the more active regimen and avoiding one that doesn’t work, our patients could benefit more from the first-line chemo, avoid the side effects of an ineffective regimen and perhaps still be well enough to try other treatments.”

“There is significant work being done internationally to validate certain biomarkers as well as to find new ones,” says Jaffee. “Take that work and couple it with the organoid work being done by (Dr. David) Tuveson and others and what becomes clear is that we are clearly onto something.”

Organoids are tiny 3-D structures that are grown in vitro. The technology has led to the development of many novel human cancer models, including pancreatic cancer. Research is showing that patient-derived organoids may quickly and accurately predict how patients with pancreatic cancer respond to a variety of treatments, facilitating a precision-medicine approach to treat the disease.

“As PDOs (patient-derived organoids) have the potential to act as patient avatars, it is crucial to validate that they can reliably predict the drug responses in the patient and do it quickly in advance of the patient’s full exposure to drugs,” says Knox. “PASS-01 hopes to validate pancreatic cancer PDOs’ chemotherapy signatures and also test other drug options that patients might wish to try with their doctors. If successful we should see patients living longer with these more scientifically informed drug decisions.”

That, indeed, is the goal, says Jaffee. “All of this work is geared to personalizing treatment for each patient we see,” she adds. “I am very excited about this trial but I don’t, however, think it’s going to be a home run. I do think it’s going to get us to a better place in which we can get that home run sooner rather than later. Every trial we do gets us one step closer to that goal.”

Patients in PASS-01 “will be exposed to as much personalized treatment as we can deliver,” Knox says. “PASS-01 is a very innovative strategy to learn as much as we can from each patient’s tumor and that hasn’t been attempted before in a randomized trial. Its success could be a huge influence on the next studies planned and therefore get us much closer to moving that needle in a meaningful way for our pancreatic cancer patients.”