Check out this great report from CBS News.

Fighting glioblastoma with recombinant poliovirus

A look at this Phase 1 trial design

A study published recently in the New England Journal of Medicine shows that patients with recurrent glioblastoma who were infused with a modified poliovirus at Duke University were more likely to be alive 3 years later compared to similar patients who did not receive the treatment. The publication gained the attention of several media outlets, including the Washington Post, NPR News, and CBS News, who has reported on the study’s progress and profiled several patients over the past few years (see here and here).

I’ve followed this study with great interest. For several semesters now, I’ve showcased this trial in my course on Global Health Research Methods during our introduction to research and clinical trials. Now that the results are published, I decided to write a teaching note that breaks down the article and explores interesting concepts that we discuss throughout the semester. I encourage you to read the manuscript and supplemental materials for yourself.

Let’s take a closer look at the design and implementation of this amazing Phase 1 trial.

Poliovirus in the brain. “What the hell?”, NCT01491893.

The poliovirus Phase 1 trial is registered on (NCT01491893) as the “PVSRIPO for Recurrent Glioblastoma” study. PVSRIPO is the name of the modified poliovirus created by Dr. Matthias Gromeier in the 1990s when he was a postdoc (shoutout to all you postdocs out there!). When Gromeier came to Duke, he was reportedly eager to explore how PVSRIPO might work against brain tumors.

That’s right. His idea was to modify the virus that causes poliomyelitis—yeah, that poliomyelitis—and inject it into the brain.

This wonderful profile of Gromeier by Barry Yeoman captures just how nuts this idea seemed at the time:

‘Poliovirus is the virus that’s most capable of causing the most damage in the brain,’ [Gromeier] says. It invades the central nervous system and can paralyze the muscles we need to walk, swallow, and even breathe. ‘It may sound counterintuitive,’ he says, ‘but I saw this as a sign that it might be a good agent to be used in the brain.’

‘Counterintuitive’ was an understatement. To some experts, it was outrageous. “Early on, when we first heard about it, it was ‘What the hell?’ ” says Mayo Clinic’s Russell.

If you want to learn more about how the modified virus and the body team up to give GBM a run for its money, check out this 2017 paper by Gromeier and colleagues published in Science Translational Medicine.

Clinical trial phases

The road from crazy ideas to approved medical treatments is long, and most drug candidates don’t make it. The results of the initial poliovirus trial published in the NEJM this week have been more than 20 years in the making, and the science is just taking shape. This is because new drugs must go through several phases of research prior to becoming a new medical treatment. (I focus here on drugs, but the same can be same about medical devices and procedures. There are also clinical trials of behavioral interventions, but the process looks a bit different.)

Great overview of clinical trial phases from Brains For The Cure.

Preclinical and Phase 0

Human trials are often preceded by preclinical research in test tubes or cell cultures (in vitro) or in animals (in vivo) to determine whether the treatment is a good candidate to become an investigational treatment. A Phase 0 study might follow with a handful of human participants who get a very low, ‘subclinical’ dose of the medication or treatment, just to give investigators an early look at what happens to a drug in the body (pharmacokinetics).

From Bench to Bedside

Because Phase 0 studies are relatively uncommon, Phase 1 trials are typically the point at which a drug jumps from basic research to clinical (applied) research—from bench to bedside.

The main goal of a Phase 1 trial is typically to evaluate safety and determine an optimal dose to put forward for future trials. These initial trials are often small (up to a few dozen patients) and have the shortest timeline of all clinical trial phases.

Contrary to what people often think, the word ‘trial’ does not mean ‘randomized’. In a Phase 1 trial, everyone typically gets the investigational treatment, though the dose may vary. In the poliovirus trial, for instance, participants received different doses, but everyone was treated with a clinical dose of the modified virus.

At this early stage, the focus is safety, so investigators keep detailed records of side effects and adverse events. They track clinical outcomes too, but it’s not typically expected that a Phase 1 trial will demonstrate a drug’s efficacy. That usually comes in Phases 2 and 3 with larger studies and random assignment to treatment arms.

NIH video about clinical trial phases.

Poliovirus Phase 1 trial design

This was a single group, open label study in which all 61 participants received the experimental treatment. ‘Open label’ just means that every patient knew that he or she was treated. No one was blind to the treatment assignment because everyone was assigned to the treatment.

Let’s step through the Methods section to learn more about the design. You’ll probably want to reference three additional documents:

  1. The study registration on (NCT01491893)
  2. The study protocol
  3. The authors’ Supplemental Appendix

Studies like this are very complex, and 3000–6000 words is often not enough space to give enough detail for curious readers to evaluate your claims, let alone attempt to replicate your study. Lots of good stuff lives in supplemental files!

Study objectives

Desjardins et al. (2018). Recurrent glioblastoma treated with recombinant poliovirus. NEJM. DOI: 10.1056/NEJMoa1716435.

As a Phase 1 trial, the primary objective was to evaluate safety and determine the optimal dose for a Phase 2 study. This means that the study was designed first and foremost to answer this question. Estimating survival relative to a historical control group was a secondary objective. The authors also identified two exploratory or hypothesis-generating (rather than -testing) objectives: (a) characterize changes observed in MRI scans during the course of treatment and (b) identify potential biomarkers—in this case, something measurable in tumors—that could predict which patients will have a positive response to the treatment. As we’ll see, the data from this Phase 1 study shows that some people respond big time, but this is not universal.

Patient recruitment

Every trial must define inclusion and exclusion criteria. What are the essential characteristics patients must have to enroll, and what conditions rule people out? In an early stage trial like this one, these criteria help to ensure that researchers enroll the appropriate patients and limit exposing more at-risk groups to potential harm (e.g., no pregnant women or breastfeeding mothers).

In later trials that aim to evaluate efficacy in routine clinical practice—pragmatic trials—the list of inclusion and exclusion criteria might be shorter to maximize generalizability. To take a silly example, only enrolling left-handed red-heads named Sally might limit the extent to which the results apply to the target population of all women.

In the poliovirus trial, the key inclusion criteria were:

The full set of inclusion and exclusion criteria are listed in Table S1 of the Supplemental Appendix.

Table S1 from the Supplemental Appendix.

Historical controls

While the primary objective of the trial was to evaluate safety and largest practical dose, the researchers also wanted to get an initial look at “the efficacy of PVSRIPO administered at the optimal dose” in terms of overall survival.

Since this was a single group study in which all participants were treated, the researchers constructed a “historical” control group for comparison. These were patients previously treated at Duke who, based on medical record data, would have met the criteria for enrollment had the trial been recruiting back then. In the Supplement, the authors note two reasons for taking this specific approach:

  1. They felt that a sham infusion would have been unethical (presumably because the experimental treatment was not combined with another standard treatment in this trial; therefore, a sham infusion would have meant no treatment at all).
  2. They believed that comparing survival rates among trial participants to published results of other treatments would also be flawed because the studies had different inclusion and exclusion criteria.
Explanation from the Supplemental Appendix.

Historical cohorts are not perfect comparisons. For instance, this study compares two cohorts of patients treated over two different time periods. It’s also likely that some patients from the historical cohort would not have chosen to participate in the trial had they had the opportunity. This means it’s possible that the patients who volunteered to be part of the poliovirus trial could be different in some unobserved ways from the some segment of the historical cohort.

But nothing is perfect. I think the use of a historical cohort was a nice addition to this Phase 1 design. Table 1 in the main paper suggests that the groups were mostly similar on observed characteristics.

As reported in the Washington Post, Deepa Subramaniam of the Georgetown Lombardi Comprehensive Cancer Center is quoted as saying that this approach is “suboptimal”, which is true in general, but it’s not clear to me that a randomized design would have been optimal for this Phase 1 study. (Protip: use the word “suboptimal” and you will probably be right more than you are wrong.)

Snapshot of Table 1 from Desjardins et al. (2018). Recurrent glioblastoma treated with recombinant poliovirus. NEJM. DOI: 10.1056/NEJMoa1716435.

Dose escalation and dose expansion

Dose level for the first 16 patients.

Patients in this trial received 1 of 7 doses of PVSRIPO. A patient’s dose was determined by his or her order of enrollment in the trial and by a set of rules. The first person received dose level 1, the second dose level 2, etc, until reaching dose level 5.

According to the Supplement: “The starting dose was “1 x 10⁸ tissue culture infectious dose (TCID50), which is 1/10th of the highest non-toxic dose in non-human primates…and 1/50th of the highest non-toxic dose in NHPs in the dose range-finding toxicology study.”

The plan was for 21 patients to be administered dose level 5, but only 4 patients actually received this dose. As described in the paper, the last patient to receive dose level 5 suffered a “dose-limiting toxic event”¹: a grade 4 intracranial hemorrhage following catheter removal. This was unexpected as “preclinical data suggested that dose-limiting toxicity (DLT) would not occur at any of the five DLs evaluated”. However, the team had a clear plan for making decisions about how to proceed with dosing. Since 1 of the 4 patients who received dose level 5 experienced a dose-limiting toxic event (25%), they changed plans:

This trial is an example of dose-escalation and dose-expansion. Iasonos O’Quigley explain these phases in this article published in Nature Reviews Clinical Oncology:

Phase I trial designs increasingly go beyond their former focus on safety, and aim to identify the most-promising agents by adding dose-expansion cohorts, before moving to phase II testing. Such phase I trials now frequently include a dose-escalation phase that determines the maximum tolerated dose (MTD), followed by a dose-expansion phase to determine the recommended dose.

The dose-expansion phase included 52 of the 61 patients in the trial:

  • 6 patients received dose level 2
  • 24 patients received dose level -1
  • 15 patients received dose level -2
  • the final 7 patients went back up to dose level -1

The authors explain this deescalation pattern as follows:

…imaging changes that were suggestive of localized inflammation were managed with glucocorticoids if they were associated with neurologic symptoms. Given the protracted course of such peritumoral inflammation before tumor contraction, symptomatic patients had to continue taking glucocorticoids for extended periods, which exposed them to substantial side effects. To mitigate peritumoral inflammation, the PVSRIPO dose was deescalated gradually to dose level 2 and then to dose levels −1 and −2.

The results

With respect to the primary objective of studying safety and finding an optimal dose, the authors note in the abstract that “dose level −1 was identified as the phase 2 dose”.

But it was the secondary objective that grabbed widespread media attention this week.

The overall survival rate among the trial cohort was 21% (95% CI, 11 to 33) 3 years after infusion compared to 4% (95% CI, 1 to 9) among the historical control group. As of March 20, 2018, 3 patients had survived more than 57 months! (See the three tick marks at the far right of the PVSRIPO line indicating censored data.)

Overall Survival among Patients Who Received PVSRIPO and Historical Controls. Tick marks indicate censored data. PVSRIPO denotes recombinant nonpathogenic polio–rhinovirus chimera. Source: A Desjardins et al. N Engl J Med 2018. DOI: 10.1056/NEJMoa1716435.

You might be wondering “where are the p-values?”. First, can’t you just appreciate the estimates and confidence intervals? Geez. Second:

It is too early to evaluate our statistical hypothesis of survival at 24 months, because only 20 of the 31 patients at dose level −1 were treated with PVSRIPO more than 24 months before the data-cutoff date of March 20, 2018…the analyses presented in this article are descriptive and do not include formal statistical tests

Check back for what promises to be a very interesting analysis. By my reading of Table S4 in the Supplement, 9 of the 31 patients who received dose level −1 were still alive as of the data-cutoff date (29%).

My takeaway

This study represents a potential breakthrough in the treatment of glioblastoma, a ray of hope against a disease that has proven very difficult to treat. A 3-year survival rate of 21% is a significant accomplishment.

Of course 21% is not 100%—44 patients have died. Not everyone responds to the treatment, but those who do have the potential to watch as this treatment goes through Phase 2, 3, and hopefully Phase 4 trials one day.

But the science is just getting started. In the Phase 2 trial that is underway at Duke (NCT02986178), 62 patients will be randomly assigned to receive PVSRIPO alone or in combination with lomustine, a chemotherapy drug. The estimated study completion date is 2023, so you’ll have a while to wait for the next installment.

Joining the Phase 2 study

“To learn more about [the Phase 2 study], you or your doctor may contact the study research staff using the contact information provided by the sponsor [].”


[1] Defined in the paper as “as any toxic effects of grade 3 or 4 that were not reversible within 2 weeks or any death that was considered by the investigators to be related to treatment”.



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Eric Green

Eric Green


I'm a psychologist and professor at Duke University who studies health and technology. I'm also a Co-Founder of Nivi, a digital health company (Boston/Kenya).