Clinical trials take innovative approach

It is a simple concept: bench investigators who identify potential cancer therapies, and clinicians who evaluate experimental drugs in patient trials, sitting down together to figure out how each can make the others’ work more effective. And yet, until just the past few years, the two groups often worked separately from one another at many institutions. The thought process at the bench seldom extended to therapeutic practice, and clinical trial physicians developed their protocols with limited input from the basic scientists who made the initial discoveries.

Because of that, Ranjit S. Bindra, M.D., Ph.D., associate professor of therapeutic radiology, says extraordinary lab work frequently went unnoticed. “There are so many great discoveries in journals like Science Translational Medicine, Science, and Nature, from many institutions, where the clinical implications are so profound, and yet they never made it into the clinic.” Some work, Bindra says, was just not translatable, but in other instances, he says, “they probably also just never had a feasible mechanism to drive them into the clinic.”

Such a mechanism is now the organizing principle of the Phase I Program at Yale Cancer Center (YCC), one of the few academic programs in the country where regular contact between bench scientists and clinicians is standard practice.

“There is a special drug development seminar once a month,” says Joseph Paul Eder, M.D., professor of medicine (medical oncology) and clinical leader of the Phase I Research Group. “There’s another that’s called clinical cancer colloquium, where basic scientists from Science Hill come talk to us, or we go to them, and say, ‘Here are great targets.’ What is special about Yale is that the clinicians and translational scientists talk almost daily. The clinicians attend the science lectures, we pass each other in the hall, and I hope that every scientist knows our doors are always open and our cell phones are always on.”

One project enhanced by these frequent interactions was a paper published in February 2017, whose senior authors were Bindra and Peter M. Glazer, M.D., Ph.D., chair and Robert E. Hunter Professor of Therapeutic Radiology and professor of genetics.

Their research, in Science Translational Medicine, demonstrated the sensitivity of tumor cells with mutations in two metabolism genes, IDH1 and IDH2, to targeted drugs called PARP inhibitors. In the discussion section of the manuscript, the authors wrote that their findings could form “the basis for a possible therapeutic strategy.” They could say that confidently because before the paper was even published, Bindra began a series of discussions about how to translate this discovery directly into the clinic with Patricia M. LoRusso, D.O., director of the early therapeutics clinical trials program and associate center director of experimental therapeutics at YCC, who leads the Phase I Program’s Disease Aligned Research Team.

Bindra recalls, “She raised her hand in a research seminar and said ‘I’m not impressed with your animal data. You’re showing these curves that are barely separating in a flank model, you’re not going to be able to convince clinicians to bring this into the clinic.’” Bindra went back to the lab to “look at the different PARP inhibitors and to find one that had the biggest difference.” They ended up selecting an FDA-approved PARP inhibitor, olaparib, which demonstrated marked activity in vivo.

That choice is helping patients already. Eder quickly plugged the findings into an existing protocol designed to thwart cancer cells’ ability to repair their own disease-promoting DNA. “Yale had set up a clinical trial to be reactive to potentially important new information in the area of DNA repair,” says Eder. “Yale investigators took that basic information and brought it immediately into the clinic. Yale enrolled IDH1/2-mutant patients into the study, and already months later we know at least in some patients this really works.”

LoRusso and Bindra have even more ambitious plans. “Pat and I are writing a series of trials together, really testing [the findings] in rigorous Phase II studies,” says Bindra. LoRusso says trialists will go a step beyond standard safety-related protocols and send samples obtained from their patients back to the bench scientists, “to try to understand why it’s working or why it’s not working and in what patients it’s working.”

“You can’t often do that by just looking at the patients,” she adds. “You need to take the tumor and the patient information and go back into the lab. That’s one of the beauties of having the science and the clinic here.”

Another development seen as beautiful by those involved is the clinic itself, a dedicated trial facility significantly funded by Yale New Haven Hospital that opened in 2016. “Instead of being a sort of designated corner of a general medical oncology unit,” says Eder, “it’s now a specified place.” LoRusso says the new facility has accelerated the Phase I Program, which served roughly 25 patients per year when she came to Yale three years ago, and now is on target to enroll at least 150 patients in 2018. “I think it’s done wonders,” she says, “There’s nothing like working in an extremely pleasant environment. It’s a state-of-the-art facility.”

Those comforts matter to patients who struggle to follow the strict protocols of a clinical trial, according to Joseph W. Kim, M.D., assistant professor of medicine (medical oncology). Kim designs many of the trials. His role also includes explaining both the pros and cons of trial participation to his Yale Medicine patients. “These trials are quite involved with research blood draws and biopsies,” Kim says. “The patients need a lot of attention.” While cautioning against false hope, Kim can also describe the encouraging longevity certain patients have enjoyed thanks to recent research advances. “We have patients from 2014 who remain on treatment without any evidence of disease,” he notes. “An average life expectancy of patients coming to the Phase I clinic is 3 to 6 months. So, they are well beyond life expectancy. It’s amazing.”

Kim has adapted other work by Glazer and Bindra for a current trial to treat patients with advanced prostate cancer. “We sat down and talked about how hypoxia could suppress DNA repair,” Bindra says. “He clearly looked at the papers and was thinking deeply about it.” Their close cooperation mirrors that of many other bench researchers and clinicians at Yale.

For Eder, the program puts Yale in a place where it wants to be. “I don’t think you can find any of the original papers on immuno-oncology drugs like ipilimumab and nivolumab where Yale investigators were not first or last authors on those papers.”

Now, he says, investigators have the optimal outlet for their work. “It’s not just great scientists at the bench. It’s not just great docs in the clinic. We can bring these two things together and bridge that for a clinical trial that will benefit [patients] now.” And, he enthusiastically tells patients, “You can be among the first.”