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Failure as a Route to Success

Credit: photopitu/adobe

Credit: photopitu/adobe

By Lorraine Chantrill

Lorraine Chantrill describes the obstacles that have impeded a clinical trial of genomically guided treatment of an aggressive form of cancer.

Pancreatic cancer is expected to become the second most common cause of cancer death by 2030. This poor outcome is due to a constellation of factors: it is often undetectable when at an early stage and diagnosed late, it is a disease of older people, and it is aggressive, usually leading to death within a few months.

The only treatment that extends life expectancy when the disease is advanced is chemotherapy. Chemotherapy works on the premise that cancer cells are rapidly dividing; it does not exploit any differences between one cancer cell and another.

A key characteristic of pancreatic cancer that has impeded the development of new treatments is that there does not seem to be a common driver of cancer growth. Instead there are small subsets of patients with changes in their tumour genome that could benefit from targeted treatments that we currently use in other cancers.

We designed a trial to see if we could test a different approach to treating pancreatic cancer. Instead of treating all patients the same, we wanted to see if treating the cancer in an individualised way would be better.

This story tells the tale of the challenges we faced along the way and how difficult it is to implement a new way of approaching treatment in a disease that moves so quickly.

The pilot stage of the IMPaCT trial was a randomised trial that was designed to assess the feasibility of acquiring suitable tumour specimens for molecular analysis and returning high quality actionable genomic data within a clinically acceptable timeframe. It screened for three molecular targets. We chose these because the genomic results could be checked with standardised tests and proven treatments were available.

The only problem was that this approach addressed only about 10% of pancreatic cancers, so we had to screen at least ten times the number of cases than we aimed to treat in our study. When we started, we had hoped to enrol only 20 patients for the study.

At the time we designed the study, the technology was very new and there was much scepticism about “genomic medicine” to overcome. The many complex administrative processes and protocols demanded by current clinical trial frameworks had to be observed when setting up the trial at three hospital sites in Sydney, and sequencing of the tumour had to be fast because this cancer kills swiftly once diagnosed. While the sequencing could be performed rapidly, simple logistics such as specimen access from hospital pathology departments resulted in time delays.

After screening almost 100 cases, an eligible genetic target was identified in 22 patients. While we were able to return results within 28 days for 75% of patients, this did not lead to treatment changes for these patients.

Barriers to Enrolment of Eligible Patients

Not a single patient was treated on the IMPaCT study as it was originally designed. Of the patients for whom an eligible genetic signature was identified, many died before results were obtained and others became too sick to receive treatment or decided to proceed with standard chemotherapy before results could be returned. Two people objected to the concept that they may be randomised to receive standard therapy, and they withdrew from the study.

It became very clear to us that patients with advanced pancreatic cancer can’t afford to wait protracted periods of time for sequencing results before they start treatment, and they also don’t want to be randomised and risk being given standard therapy.

We are now particularly aware of the need to have efficient multidisciplinary teams that can work quickly to obtain patient consents, collect high quality tumour samples, analyse them, and return the results within a month or less.

Two amendments have been made to the trial to make it more appealing to patients and their doctors. First, patients will now be able receive chemotherapy while they wait for molecular analysis. Second, we have removed the standard arm from the trial so that no one with an eligible target will be randomised to receive standard treatment from now on.

Hopefully we will also be able to continue to improve on the trial and add more targets so that we can offer targeted treatment to a higher proportion of patients. With the advent of therapies that exploit the immune response to cancer, we hope to make available some treatments for those cancers without an identifiable target as well.

Unfortunately, every time we want to adapt the study we have to submit an amendment to the ethics committee and the individual hospitals. The time taken to approve and implement amendments has been about 3 months, so that has led to delays.

It often feels like two steps forward and one step back, but we have made a good start in mapping out what is necessary and the challenges that we need to overcome. Only by actually running the race and finding the hurdles will we work out how to win.

Lorraine Chantrill is Principal Investigator on the IMPaCT trial, a Staff Specialist Medical Oncologist at The Macarthur Cancer Therapy Centre at Campbelltown Hospital, and a researcher at The Kinghorn Cancer Centre at The Garvan Institute of Medical Research. The IMPaCT study (gicancer.org.au) is a collaborative study run by the Australasian Gastrointestinal Trials Group and the Australasian Pancreas Cancer Genome Initiative with Sydney Catalyst, and is funded by government and charities.