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Tackling a public health crisis

Tackling a public health crisis

If Betty Draper, one of the female leads in the retro TV series Mad Men, had been diagnosed with lung cancer today rather than in 1970, her projected life expectancy would be almost the same. Despite dramatic advances in the treatment of other types of cancer over the past JK years, there have been no such breakthroughs for people suffering from lung cancer: its mortality rate remains higher than breast, prostate and colorectal cancers combined. An international research team aims to change that.

[cancer cell]
Shutterstock image

A 3D rendered close-up of a cancer cell

Staring perplexed at her computer screen in a back office of the Canadian Cancer Trials Group (CCTG) behind Botterell Hall, Carolyn Wilson felt a growing sense of frustration. As the study coordinator responsible for data management on what should have been an enticing new lung cancer study, she couldn’t understand why so few people were enrolling.

After all, the trial was testing an exciting and potentially life-saving new treatment for a devastating disease that kills more Canadians each year than any other type of cancer. But the intake figures that she reviewed daily were disappointingly low. Ms. Wilson knew that if the trial wasn’t completed in a reasonable amount of time, medical science might move elsewhere and an opportunity to provide the best treatment to patients who desperately needed it would be lost. What could possibly be wrong, she wondered?

A “big, heavy truck” of an international trial

That question concerned other members of Ms. Wilson’s team, too. Although they never meet the patients who enrol in clinical trials, Ms. Wilson and her behind-the-scenes colleagues are committed to providing top technical and administrative support for the CCTG’s front-line clinicians and investigators seeking new ways to fight cancer. “Science and research are my passions, and I’ve always wanted to help improve the quality of patients’ lives,” says Ms. Wilson, who received her MSc in biochemistry from Queen’s in 2004. “This job gives me a great opportunity to do both.”

[Chris O’Callaghan and Carolyn Wilson]
Chris O’Callaghan and Carolyn Wilson

In the end it was Chris O’Callaghan, the senior investigator for the study, who devised an innovative yet simple solution to their problem. Ensuring that enrolment figures stay on target is just one of many challenges he faces on a daily basis – particularly at the beginning of a large study such as this, when treatment centres from countries around the world are coming on board, many with their own unique requirements. “It’s a bit like starting a big, heavy truck,” he notes wryly. “A lot of things need to be set in motion initially, but once you’ve got momentum it doesn’t take long to build up speed!”

Deciding which direction that truck should go, and ensuring there will be enough fuel to reach its destination, require timely input and collaboration from a number of key people. University of Ottawa oncologist Glen Goss wrote the initial proposal for the current trial, negotiated with global biopharmaceutical company AstraZeneca for support, and acts as principal investigator for all participating centres worldwide, as well as leading his institution’s participation in Canada. Dr. O’Callaghan is the “point person” responsible for everything related to the study’s day-to-day operation and the tracking of results. Other key contributors include CCTG Director Janet Dancey; Lesley Seymour, Director of the CCTG's Investigational New Drug Program; and CCTG senior biostatistician Keyue Ding.

Building on the work of 30 previous trials

Cancer stats
  • 539: on average, the # of Canadians who will be diagnosed with cancer every day.
  • 214: on average, the # of Canadians who will die from cancer every day.
  • Between 1992–1994 and 2006–2008, survival rates increased from 56% to 63% for all cancers combined.

Source: Canadian Cancer Society, 2015

Called BR.31 – because it’s the 31st CCTG trial in the “bronchus” (lung) category – this study builds on the findings of its |30predecessors. Before 2004, people whose tumours had been surgically removed continued to be monitored but received no further treatment. Most saw a recurrence of their disease, and the majority did not survive five years. Positive results from the BR.10 trial, also conducted by the CCTG and published that year, showed that the addition of chemotherapy following surgery reduced patients’ risk of death by30 per cent. Almost overnight, post-surgical chemo became standard practice in the treatment of early-onset lung cancer.

But investigators wanted to move the survival rates even higher. They continued to test other promising leads, including targeted drugs that they hoped would prevent lung cancer cells from growing. Unfortunately, this method didn’t benefit the study’s focus group: early-stage patients whose cancer hadn’t spread and who had been treated with both surgery and chemotherapy.

In 2014, Queen’s and the Canadian Cancer Trials Group launched BR.31 to test a new type of immunotherapy drug designed to help the body’s own immune system recognize and attack cancer cells. The role of the immune system in fighting diseases, including cancer, has been known for decades. Only recently, however, have researchers identified specific immune mechanisms to target lung cancer cells.

Now, at the initiative of principal investigator Glen Goss, a new class of these “immune regulators” would be brought into play. “We’ve seen dramatic responses with this treatment in advanced lung cancers,” says Dr. Goss. “Our study will be the first one worldwide to use immunotherapy against the cancer in early-stage disease – and we hope to show the same successful results.”

A public health crisis

Arguably the least sympathetic of diseases in terms of public fundraising support, lung cancer is nevertheless the most common cancer worldwide and the leading cancer killer in both men and women. Even when diagnosed early, the chances of recurrence range from 30 to 60 per cent and the “cure rate” (survival after five years) is only 19 per cent.

Each year 26,000 Canadians are diagnosed with lung cancer and the vast majority will die of the disease. It has the highest mortality rate of any cancer, accounting for approximately 30% of all cancer deaths: more than breast, prostate and colorectal cancer combined.

Undoubtedly the connection between smoking and lung cancer, first established in the early 1960s, is at least partly responsible for the disease’s low profile and feeble fundraising appeal. That may also help explain why the nine-month prognosis given in 1970 to heavy smoker Betty Draper, a fictional character in the TV series Mad Men, would not be much longer today.

Glen Goss believes the impact of decreased smoking in the general population will be reflected soon in a falling incidence of lung cancer. (Approximately 85 per cent of current patients with lung cancer are smokers, which correlates with the incidence of smoking by BR.31 trial participants.) But, “We are very concerned about what appears to be a new type of this disease occurring now in young women who have never smoked,” he says.

This is one more reason why Dr. Goss considers lung cancer to be nothing less than a public health crisis – and why he and his fellow researchers are committed to finding better ways to attack it.

CCTG staff]
Principal Daniel Woolf recently toured the CCTG Central Operations and Statistics Office to meet the staff and faculty and learn about their work. There are 100 staff (in trial management, compliance and oversight, administration, finance, strategic partnerships, and information technology) and 12 faculty (medical senior investigators, biostatisticians, scientists) at the CCTG. The Br.31 lung cancer trial is one of 100 clinical trials ongoing at the CCTG. Of those 100, about 40 are open for recruitment for cancer patients. (Photo by: Greg Black)

 

How BR.31 works

So how does the BR.31 drug work? Unlike chemotherapy or targeted drugs, which attack cancer cells directly, immunotherapy is designed to stimulate the body’s own immune system to do the fighting. As Dr. O’Callaghan explains, “It is based on the fundamental treatment premise that you want your immune system to think the cancer is foreign and therefore not part of you.Cancer is very good at hiding from the immune system.”

Cancer is very good at hiding from the immune system.

One way this happens is through PDL receptors on the surface of the cancer cells, which send a “Don’t hurt me!” signal to immune system cells poised to strike. To counteract this manoeuvre, the BR.31 drug, Durvalumab, produces a molecule that sticks to the PDL receptors and blocks their white-flag signal. This enables the body’s own immune system to recognize and attack the cancer cells. Another advantage of the new drug is that it also blocks the body’s feedback loop which would otherwise slow down the immune reaction, thus delivering a “double whammy” to the tumour.

The researchers hope these agents will generate immune memory cells that will enable a person’s immune system to recognize and kill cancer cells if they are re-introduced into the body after treatment has ended. This is the same principle behind vaccinations, such as the one used successfully for measles.

Finally, notes Dr. O’Callaghan, “We know this drug is very safe. Only about three per cent of people taking Durvalumab alone have more serious serious side effects – which compares very favourably to other cancer treatments where adverse reactions can be much higher. If I had lung cancer, I would be first in line to be on this study!”

The enrolment conundrum

Which brings us back to Carolyn Wilson’s original question: Why weren’t more people enrolling?

“Centres would tell us they were screening for patients, but it was difficult to find people who met the eligibility criteria … and of those who did, many were declining,” says Ms. Wilson. “It seemed very odd.”

Each participating cancer centre keeps a screening log that records which studies patients are approached for, as well as a brief explanation if they don’t enrol. The BR.31 team needed to extract information from these logs about why patients weren’t going on their study.

“We tried to keep it as simple as possible and to do it electronically so we could get real-time information,” explains Ms. Wilson, who presented the group’s solution last spring to an international conference.

It was Dr. O’Callaghan’s idea to create a simple web-based form – a “screen failure log” – that would generate a spreadsheet to monitor reasons patients were not being enrolled. Surprisingly, they discovered that the most common ineligibility factor related to the surgery patients had had to remove their tumours. It turned out, in some cases, that although the surgery had indeed been done, details that were part of the trial’s written protocol had not been documented, or an extra required step not completed.

“We were able to collect the data quickly and present our findings to the trial’s surgical steering committee,” says Ms. Wilson. “They decided that since this was an immunological rather than a surgical study, they could change the eligibility criteria to better reflect current practice, and allow these patients to participate.”

After the committee agreed to protocol amendments and the changes were implemented, enrolment increased by 53 per cent.

The next most common reason for patients not being enrolled was their decision to decline. The screen failure logs showed this was due to two things: the frequency of required therapy visits and the costs associated with coming for treatment, such as transportation, parking and meals.

AstraZeneca, the company providing Durvalumab for BR.31, came to the rescue on both counts. Their own research showed that administering the drug 13, rather than 19‚, times over the same 12-month period was equally effective. Patients’ treatment schedules have now been changed.

As well, says Ms. Wilson, since participants are often reimbursed for costs associated with study treatment visits, “We presented our data to AstraZeneca and requested additional funding for this purpose. They’ve agreed to help … so we’re hopeful this will be another boost to enrolment. Our bottom line is finding ways to increase patient access to this promising new therapy.”

A worldwide study

In response to the notion that researchers are “in cahoots” with Big Pharma, both Drs. Goss and O’Callaghan describe the relationship between CCTG and their industrial partner as one of mutual interest. “We approached AstraZeneca with the concept of doing this trial in an as-yet untested patient setting, and they agreed to provide both the drugs and funding for us to conduct the trial independently, as well as collecting and analyzing the data,” says Dr. Goss. “If the trial is positive, the company may then present the results to regulatory authorities around the world as the unbiased results of independent academic researchers.”

Since BR.31 will be conducted in 15 countries once all centres are up and running (with Canada, France, Spain, Australia, Japan and Italy the biggest participants), this final step is key to generating global changes in treatment. Having participants from so many different countries not only casts a wider net for recruitment, it also hastens international exposure of the findings, Dr. O’Callaghan points out. “And there are benefits with regulatory bodies, too,” he adds. “For example, both China and Japan will only approve drugs that have been tested within their borders.”

Here at home, positive results from BR.31 would lead to submissions to Health Canada for licensing of Durvalumab to become the standard of care for early-onset lung cancer patients who have had their tumours surgically removed. The Phase III trial is expected to be completed within the next five years.

Another potential breakthrough could come from a second group of trial participants whose tumours have been surgically removed, but who have declined chemotherapy. These patients are being treated and followed with the same protocol as those who chose to receive chemo, says Dr. Goss, and their presence in the trial is “stratified” to ensure that this factor does not affect the overall findings. “If this group does just as well as the group that did receive chemotherapy, we may be able to advise dropping it from standard treatment, and enable patients to move from surgery right to immuno therapy. That possibility has us excited, too!”

Bringing new hope

Imagine you have just been diagnosed with lung cancer. Imagine the doctor tells you that – even though it’s in the early stages and can be surgically removed – the odds of your making a complete recovery are only 50-50. Imagine your excitement when you learn about a clinical trial that is testing a new treatment which uses your own immune system to fight the cancer. Imagine … new hope, for you and your family.

Patients with early-stage lung cancer account for approximately a quarter of all lung cancers today. “These are the people in whom we have the best chance of improving the cure rate,” says Dr. Goss. “This is the group that BR.31 is targeting.” Evidence of an improved cure rate resulting from immunotherapy would translate into a major change in the way this cancer is treated in Canada, the U.S., and internationally. It could push the needle dramatically upward on life expectancy statistics that are now stuck in the 1970s

But whatever the final results of BR.31, the men and women of the Canadian Cancer Trials Group will continue to initiate and coordinate new studies, working with partners around the world to lead the fight against cancer. From back offices and laboratories to the front lines treating patients, it remains an enduring and compelling quest for the CCTG team.

[image of lungs]
In her work Through the Breathing Glass, Julia Krolik shines a warming light on the complexity and stigma of lung cancer. The window represents hope in the form of novel treatments, with bronchioles extending into a multitude of possibilities.
(Illustration: Julia Krolik (MSc'14), Art the Science)

 

[cover of Alumni Review 2016 Issue 3]