Author: Helen Leask
The trial focuses on patients who require high-flow oxygenation or intubation. Four drugs are in its sights: cenicriviroc, icatibant (Firazyr); apremilast (Otezla),and razuprotafib. All patients will receive remdesivir and dexamethasone or its equivalent as backbone therapy.
Up to 15% of patients with COVID-19 develop ARDS,and approximately half the patients who need ventilation don't survive.
By the time patients reach the ICU, said Esserman,it's no longer about the virus, it's more "the biology of who is doing badly." She said the task at this point is to "try to figure out how we are going to blunt that response to keep this pandemic ― or any pandemic ―from paralyzing the nation."
Cenicriviroc, icatibant, and apremilast were selected for their potential to mitigate the damaging immune response of severe COVID-19. The hope is that apremilast will suppress inflammation, icatibant will ameliorate bradykinin-driven pulmonary edema, and cenicriviroc will block monocyte trafficking, all features of ARDS. Razuprotafib has shown promise for stabilizing pulmonary vasculature.
The primary outcome of the trial is time to recovery, a reasonable endpoint, explained Esserman, given that any agent that reduces time on ventilation would "be really big" for patients and the overloaded critical care system. Mortality is a secondary endpoint.
The I-SPY trials use an adaptive randomization approach based on a Bayesian predictive model. As patient data come in, the software provides real-time updates of the likelihood that the experimental drug will be effective. Each treatment arm in I-SPY COVID will have 50 to 125 patients, depending on how quickly a treatment effect, or lack thereof, is seen.
This fast-track filtering of therapies for patients in peril is ideal for a disease such as COVID-19, said Esserman.
"You screen, then look for a big signal, then move those things on," said Esserman. "There's a lot of noise, but we think something is obviously likely to be a big win, we'll see."
As each institution signed on for the COVID-19 study, the original I-SPY 2 breast cancer trial investigators jumped in to train their ICU colleagues through formal online meetings and informally at the bedside.
"The whole I-SPY network is about the platform trial, but it's also about a way of working together," said Esserman. "You're putting in systems that are efficient and collaborative. You'd think that would be scalable, and in fact it was very rapidly scalable."
As strange as the oncologist-ARDS partnership may seem, Barker believes that oncologists are uniquely positioned to advise colleagues fighting COVID-19. "We in cancer are so accustomed to dealing with complex disease...so we've been forced to push the envelope in all areas.I think that's benefited us in terms of responding to COVID, and the cancer community has really stepped up to do that," Barker said.
The successful ramp-up of I-SPY COVID finally gives adaptive platform trials the credit they deserve, added Barker: "There are so many real advantages to these kinds of trials that it's really inspirational to me to see them finally getting the attention they've needed," she said.
"What we've shown is what I've long suspected:that all the principles that we've put into place for I-SPY are applicable to any serious disease," added Esserman. "Why start over every time you want to test a new agent? That's just foolish."
Whether you're facing a pandemic or the family of a patient with metastatic breast cancer, you don't have time to waste, said Esserman. "You should be having multiple shots at goal and be working harder and faster to figure out how to help the people who have the worst outcomes."
Esserman still marvels over the magic. "Everyone came together with a common purpose to solve a problem, to make things better,to experiment to try new approaches that would make it better for patients," she said. "That was wonderful to watch."
Oncologists in the long-running I-SPY 2 platform trial are training physicians from across the United States who treat acute respiratory distress syndrome (ARDS) on how to run a trial similar to I-SPY 2 but involving patients with severe COVID-19. The high level of energetic goodwill displayed by these overworked oncologists is remarkable, say the two cancer trialists involved.
"People have united around the fact that their lives and their livelihood are on the line here," said principal investigator Laura Esserman, MD, a breast cancer surgeon and director of the University of California, San Francisco (UCSF) Breast Care Center. "What gratified me was how quickly and how intently people worked together," she said.
"It's probably one of the most interesting and inspirational things I've seen," said Anna Barker, PhD, co-chair of the Project Oversight Group of I-SPY 2 and a former principal deputy director of the National Cancer Institute. "We had all of these breast cancer docs willing to work with their colleagues in the ICUs to get this trial underway."
The I-SPY 2 trial of neoadjuvant treatment for locally advanced breast cancer is, according to its website, "widely regarded as the pioneer for the platform trial." Now at 10 years, it is one of the longest running.
It uses an adaptive multiagent design that allows rapid evaluation of up to five treatments or treatment combinations at a time.
Since 2010, almost 20 high-profile breast cancer innovations have run the I-SPY gauntlet, including pertuzumab (Perjeta)and pembrolizumab (Keytruda).Forty-two journal articles have documented the platform's progress, along with more than 60 meeting presentations.
Esserman and colleagues established a charitable foundation, Quantum Leap Healthcare Collaborative, to run I-SPY 2 and its spin-off trials.
The idea of using I-SPY methodology for ARDS patients was tested in November 2019, said Esserman, when she and Carolyn Calfee, MD, a professor of medicine and anesthesia at UCSF, ran the concept by the National Heart, Lung, and Blood Institute. The institute turned it down.
In March this year, Esserman texted Calfee: "Now would be a good time."
Calfee's colleagues quickly signed up, and the idea snowballed. Said Esserman: "We basically took the 2 to 3 years of work it took to get I-SPY together and [created the COVID study] in 3 months."
I-SPY COVID (Investigation of Serial Studies to Predict Your COVID Therapeutic Response With Biomarker Integration and Adaptive Learning) clinical trial will shortly be underway at 10 centers, from Yale Cancer Center in New Haven, Connecticut, to the University of California, Los Angeles.
It's a collaboration between Quantum Leap, the US Food and Drug Administration, and the COVID R&D Alliance, a group of 23 global pharmaceutical companies.
Esserman and Barker have disclosed no relevant financial relationships.
Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.