This story is part of The Cancer Letter’s ongoing coverage of COVID-19’s impact on oncology. A full directory of our coverage is available here.
NCI is finalizing plans to use its clinical trials networks to administer a compassionate use protocol for distribution of tocilizumab, a drug that blocks the inflammatory protein IL-6.
Tocilizumab, an immunosuppressive agent also known by its brand name Actemra, is sponsored by Genentech. Under NCI’s protocol, the drug will be made available to cancer patients at institutions that are not participating in Genentech’s phase III trial of the drug.
The IL-6 inhibitor was approved by FDA for rheumatology indications in 2011, and has been used for mitigation of cytokine release syndrome caused by CAR T-cell therapy.
According to Genentech, the federal government has obtained 10,000 vials of tocilizumab for the U.S. Strategic National Stockpile “for potential future use at the direction of the HHS.”
It is one of three drugs—the other two being sarilumab and siltuximab—that are now being rushed into late-stage clinical trials for assessment of efficacy in treatment of acute respiratory distress syndrome caused by immune response to SARS-CoV-2 infection (The Cancer Letter, March 27, 2020).
“We are going to, in concert with Genentech, run a treatment referral trial for the Genentech Roche IL-6 receptor antibody for COVID-related ARDS,” James Doroshow, deputy director for clinical and translational research at NCI, said April 9 in an emergency virtual joint meeting of the NCI Board of Scientific Advisors and the National Cancer Advisory Board.
“We wrote a trial, I would like to say—just like in the old days—in four days, a trial was put up. It’s been reviewed by Genentech Roche,” said Doroshow, who is also director of NCI’s Division of Cancer Treatment and Diagnosis and head of the Oxidative Signaling and Molecular Therapeutics Group of NCI’s Developmental Therapeutics Branch. “I hope to be able to have a final version of this to the central IRB very quickly.”
NCI’s protocol for tocilizumab is designed to rapidly make the drug available to cancer patients, who face a particularly high fatality risk from severe complications stemming from COVID-19.
“Why do this? Well, because we know that there are multiple randomized trials and multiple institutional trials,” Doroshow said. “There are some folks who simply can’t afford to get this drug, and we wanted to have a very broadly eligible study, eligible even for patients very young in age, which is not addressed by most of the trials that are out there, to try to see whether we can move the needle in terms of decreasing ICU time, ventilator time, time in the hospital.
“We will collect some clinical data. It’ll be a modest set of data,” Doroshow said. “There will be blood obtained for biomarker evaluation.
“We hope to activate this across all of our networks, and all institutions that are not already participating in one of the various phase III randomized trials that are out there for tocilizumab, or any other IL-6-related agent.”
An excerpt of Doroshow’s remarks to BSA and NCAB follow:
I appreciate very much the opportunity to talk to you about what’s gone on over the past three to four weeks, for the NCI to address, what it can do in its clinical trial networks to respond to this terrible crisis.
I’m going to review the modifications to the NCI clinical trial processes that have taken place over the last 10 to 14 days to try to address the ability to do studies in this patient population.
I’m going to discuss a trial that will soon be onboarded for IL-6 receptor antibodies, as a compassionate use trial.
Let me just say what we’re trying to do to adapt to this current situation. While it may be obvious, but now it was clarified in a series of memoranda that came from Meg Mooney in [the Cancer Therapy Evaluation Program] and Worta McCaskill-Stevens in [the Division of Cancer Prevention], to try to address how individual investigators and sites can deal with this problem.
So, of course, it’s clear that patient care can be transferred relatively easily to different participating sites, where, perhaps, the burden of the virus is less. That’s really not as important a degree of change as is required.
What has happened is that we have made it clear that a much broader range of activities can be performed close to home to allow patients not to travel, and to continue on clinical trials with maintaining the oversight for the study by the responsible investigator, but allowing local physicians to provide treatment on study with non-IND drugs, to do physical exams, perform performance assessments, overall assessments, and performance status assessments, to do protocols, assist with the clinical lab tests, to collect, to actually research blood specimens, and to do radiologic imaging studies, EKGs, ultrasound, and the like.
And, all of that to be sent back to the responsible investigator, and done in such a way, if the patient only needs those drugs, to obviate the patient coming to the site where that individual was registered.
We’ve also, in concert with the FDA and with the NCI Central IRB, begun a process in which we can ship oral IND agents—I underscore, IND agents—directly to patients and to sites, so that the sites can then subsequently submit, send those drugs on to patients—and in fact, even multiple cycles of drugs—so that we can, again, limit the amount of time, the amount of travel that the patients need to do, and keep them on study.
There are only a few exceptions to this rule. There are about a half dozen drugs, I can’t tell you why, but the U.S. Department of Transportation lists those drugs as dangerous goods. Why they are specifically dangerous versus many other anticancer drugs, I can’t tell you, but those drugs cannot easily be shipped. And, happily, those drugs make up a really small minority of the drugs used in the vast range of our clinical trials.
Now, again, it’s probably not a surprise to people who are listening to this talk that FDA regulations require that injectable IND agents must be administered at the registered site, and this is not something that we at the NCI can do differently.
What we can do, however, is to make sure that the current situation does not lead to an enormous compromise, either in the safety or the integrity of the studies, by racking up huge amounts of deviations to trials that will cause havoc in the eventual evaluation of the data.
So, basically, if minor deviations occur because of travel restrictions—the exact time for study visits is not exactly on schedule, or if those study visits are done by telemedicine rather than in person, if lab tests or imaging trial studies are done slightly off the mark, in terms of the timing required, if there are minimal treatment delays, if there are delays in biospecimen collections—all those will be viewed as minor deviations, and no institution participating in NCI-designated and supported trials will get significant hits for those kinds of things.
We understand that this is a really remarkable time in our history. We want to be able to get the big-picture understanding of the outcomes for our trials that have involved so many patients, without compromising those trials, but, at the same time, without compromising the ability of institutions to do their studies and not be affected by changes in practice that are unavoidable.
And, I’d like to say a specific word about acknowledging that major deviations to studies are clearly going to be unavoidable. We want those to be reported to the central IRB, but again, those things we have to be flexible,and understand the conditions in which we’re trying to carry out clinical research for the population of institutions and patients who are still appropriate for entering on a clinical trial.
And so, again, I can give you my word that we will take into consideration the times, rather than the strict issues related to these deviations, as trials are reported out.
All of that we’ve talked at great length about, and we have weekly meetings with the NCTN group chairs, and all of the auditing visits for all of the major groups have been rescheduled. No face-to-face auditing will be done. All of the auditing will be done remotely until it’s safe to be able to do that.
A major change that has been negotiated with the NCI Central IRB, where they have specifically, and in writing, supported remote informed consents, telephone discussions in conjunction with patient signatures, and return of written documents by fax or PDF are now viewed as appropriate and consistent with good clinical practice. I think this will help us not to require patients to come in multiple times for an informed consent visit versus a visit to get their initial treatment, if that is required.
Let me move on to a subject that represents something that I would love to be able to see. I think that we should understand that, if we’re going to be flexible in this specific context, we ought to learn something about the entire process that we use for doing clinical trials, how that could be changed to make them more nimble.
And so, some of you remember the treatment referral protocols that the NCI ran. It started with distribution of Taxol. It went on to distribution of bevacizumab and other agents, but before they became available commercially.
We are going to, in concert with Genentech, run a treatment referral trial for the Genentech Roche IL-6 receptor antibody for COVID-related [Acute Respiratory Distress Syndrome].
There are some folks who simply can’t afford to get this drug, and we wanted to have a very broadly eligible study, eligible even for patients very young in age, which is not addressed by most of the trials that are out there.
James Doroshow
We wrote a trial, I would like to say—just like in the old days—in four days, a trial was put up. It’s been reviewed by Genentech Roche. I hope to be able to have a final version of this to the central IRB very quickly.
Why do this? Well, because we know that there are multiple randomized trials and multiple institutional trials. There are some folks who simply can’t afford to get this drug, and we wanted to have a very broadly eligible study, eligible even for patients very young in age, which is not addressed by most of the trials that are out there, to try to see whether we can move the needle in terms of decreasing ICU time, ventilator time, time in the hospital.
We will collect some clinical data. It’ll be a modest set of data. There will be blood obtained for biomarker evaluation.
So, we hope to activate this across all of our networks, and all institutions that are not already participating in one of the various phase III randomized trials that are out there for tocilizumab, or any other IL-6-related agent.
