March 2020: Colorectal cancer trial updates

Final patient joins MODULATE

The final patient participating in the MODULATE clinical trial has now joined, meaning that all 90 participants who have previously failed all available treatment options, are enrolled in the study.

MODULATE is a phase II clinical trial testing whether it is possible to reverse the resistance of most colorectal cancers to immunotherapy treatments. The trial is evaluating a new combination treatment for ‘microsatellite stable’ colorectal cancer, which makes up about 80-85% of colorectal cancers. These cancers do not respond to immunotherapy, treatment that triggers the immune system to attack cancer, because the tumours exist in an environment that suppresses the immune system.

Participants in MODULATE are treated with nivolumab, a form of immunotherapy known as a ‘PD1 inhibitor’. Some cancer cells have high levels of the protein level PD1, which plays a role in helping them to hide from the immune system. Nivolumab inhibits the effect of PD1, meaning that the immune system can recognise and attack cancers. In addition, participants also received one of two other drugs, believed to facilitate white blood cells in reaching cancers.

The safety and well-being of our participants, other patients, family members, researchers and other clinical and support staff is paramount, therefore, several measures will be implemented to minimise participant exposure to COVID-19 including reduced clinic visits through use of telehealth to perform assessments where possible and blood collection at local facilities with arrangements made for the trial site to obtain the results. In the event a participant is diagnosed with COVID-19 during study treatment, this would be reported as an adverse event and usual procedures for SAE and SUSAR reporting would apply.

Finding new treatments for colorectal cancer

The AGITG currently has a total of 10 trials open to recruitment or in activation investigating colon and rectal cancer. Five open trials are accessible across Australia and New Zealand, and one trial, ASCOLT, is open internationally.

March is Colorectal Cancer Awareness Month. AGITG’s clinical trials for patients with colorectal cancer offer new treatment options that could provide benefits in their outcomes and quality of life.

Open Trials

Please note that recruitment to some trial sites may be on hold due to COVID-19.


Low-dose aspirin could play an important role in reducing the recurrence of colorectal cancer. The ASCOLT study is an international phase III trial that aims to discover whether taking a daily 200mg dose of aspirin for three years could help to prevent colorectal cancer returning in people who have already been successfully treated.

ASCOLT is led by Dr Mark Jeffrey, who says the trial is “A great example of a trial re-examining the potential effectiveness of a well-known common medication (aspirin in this case) which may have a significant effect on survival in colorectal cancer.”

“The survival rates in early colorectal cancer have plateaued in recent years and a positive result from this trial would have very broad and enduring impact.”


Circulating Tumour DNA (ctDNA) is shed from tumour cells into the circulatory system. By using new technology to measure the presence of ctDNA in the bloodstreams of people with colorectal cancer, researchers believe that more accurate decisions can be made about their treatment.

The DYNAMIC-III and DYNAMIC-Rectal studies both use ctDNA tests to inform the treatment of patients who have undergone curative intent surgery.

Both studies will now also be including a sub-study that is examining the impact of ctDNA results, which either increase or decrease the prior estimates of cancer recurrence risk, on measures of fear of cancer recurrence. Fear of recurrence is a significant issue for cancer patients, more than 70% of people who have had undergone curative intent cancer surgery reporting that they have experienced this at some stage.[i] For the majority of patients on the DYNAMIC studies who have a negative ctDNA result, markedly reducing the estimates of recurrence risk, it is hoped that there will be a parallel reduction in fear of recurrence.

DYNAMIC-III, co-chaired by Professor Peter Gibbs and Associate Professor Jeanne Tie , aims to determine whether a chemotherapy decision based on the presence or absence of circulating tumour DNA after surgery for stage III colorectal cancer, will be more effective than standard of care treatment as measured by how many patients remain cancer free at 3 years.

DYNAMIC-Rectal, co-chaired Professor Peter Gibbs and Associate Professor Jeanne Tie, aims to demonstrate that by incorporating ctDNA results in addition to a standard assessment of the pathologic risk of the tumour, that the number of patients receiving adjuvant chemotherapy will be reduced.


In the SPAR trial, researchers are investigating whether taking a statin drug (usually used to regulate cholesterol levels) could boost chemoradiotherapy treatment for people with rectal cancer.

“A positive outcome in the SPAR trial, either through improved tumour response or reduced toxicity from chemoradiation, would lead to a phase III trial to confirm the findings and look at long-term outcomes,” says one of the trial’s Principal Investigators, Associate Professor Michael Jameson. “This could change the worldwide standard treatment for rectal cancer to giving a statin with chemoradiation.”


Elderly patients are at a high risk of colorectal cancer, but may not be able to tolerate current chemotherapy treatments. The aim of the MONARCC trial, led by Dr Matt Burge, is to investigate the activity of anti-EGFR monotherapy, or combined with infusional 5FU, in a molecularly selected, elderly patient population with metastatic colorectal cancer.

Patients with metastatic colorectal cancer who are aged 70 years or over may be eligible to participate in MONARCC. The trial is currently open across Australia.


The RENO trial, led by Professor Chris Karapetis, is a non-randomised prospective study analysing the ‘Watch and Wait’ strategy for patients with rectal cancer. This approach means that after chemo-radiotherapy treatment, patients will not immediately go on to have surgery – which can lead to long-term side effects. Instead, they will go through a follow up process referred to as ‘Watch and Wait’, with a close and strict surveillance of their condition for two years to determine whether there is any sign of tumour regrowth.

Where possible, consults are being conducted remotely due to COVID-19. Recruitment is continuing where possible, with additional sites in NSW expected to open shortly.

RENO is the first prospective study of this strategy in Australia and New Zealand. The trial team is evaluating a specified monitoring program which includes MRIs. They will also examine several predictive biomarkers which may help to advise patients on their risk of recurrence. If the study shows positive results, this could be the first step to implementing the Watch and Wait model in Australia.

Currently, 14 patients have been enrolled in the study out of an enrolment target of 250 at Mount Gambier and Flinders Medical Centre, with the former operating as a teletrial site. AGITG encourages availability of trials to patients in regional, rural and remote areas in Australia to improve outcomes for patients with gastro-intestinal cancer.


Trials in Development


Using a robot rather than keyhole surgery could lead to a higher rate of successful surgeries for people with colon cancer. The RoLaCaRT-1 study, led by Professor Craig Lynch and Professor Andrew Stevenson, will investigate this.

“What we’re mainly looking at is the number of times that patients will have successful surgery if it’s done robotically compared to laparoscopically,” says Professor Stevenson. “We suspect that there may be a 15-20% difference between those two groups.”

Three hundred patients with right-sided colon cancer will be treated either with robotic surgery or laparoscopic keyhole surgery, in a trial that will be the first of its kind in the world.

RoLaCaRT-1 is currently in development.


There is a large unmet need for people with metastatic colorectal cancer that have failed standard therapy and remain fit for further treatment. New technology has been developed to grow cancer cells from biopsies of individual patient tumours – researchers can use these ‘organoids’ to pre-test the likely effectiveness of a range of anti-cancer treatments on individual cancers.

The FORECAST-1 study will investigate the feasibility of sensitivity testing of patient-derived tumour organoids (PDTOs) to inform the further treatment of patients with metastatic colorectal cancer who have failed standard chemotherapy treatments.

Professor Peter Gibbs, the Study Chair of FORECAST-1, says, “There are many patients with advanced bowel cancer that get through our standard lines of therapy. They’re still fit, they’re still keen for further treatments, and there isn’t anything for us to offer them. What we’re hoping to do is to open up new treatment opportunities, along with increasing the precision of the treatments we use.”

FORECAST-1 has received ethics approval. Recruitment is likely to commence later in 2020.


Acute neuropathy (pins and needles and pain on touching or swallowing cold objects or fluids) is a common side effect of oxaliplatin, the chemotherapy treatment commonly used in colorectal cancer treatment. It has a major impact on quality of life, functional status and return to daily life, and there is currently no effective prevention or treatment.

OXTOX is a randomised (2:1) phase II study in 90 people to evaluate whether ibudilast decreases the severity of acute neuropathy and enables people with metastatic colorectal cancer to get more oxaliplatin before needing dose modifications for chemotherapy-induced peripheral neuropathy.

“Preliminary data in our small phase one study look promising,” says Janette Vardy, Study Chair of OXTOX. “We hope to be able to reduce the incidence and severity of peripheral neuropathy associated with oxaliplatin.”

OXTOX is currently in development.


Avelumab is a type of immunotherapy that could hold promise for patients with some forms of curatively resected colon cancer, to prevent cancer from returning.

POLEM is a UK-led trial that is currently in development in Australia, where it is led by Dr David Lau. It is investigating the effectiveness of this treatment in patients with stage III dMMR or POLE exonuclease domain mutant colon cancer. Patients with these mutations make up around 13% of colon cancer patients altogether.

In this trial, Fifty people will receive either 3 months of chemotherapy alone (with agents called CAPEOX or capecitabine) or chemotherapy followed by 6 months of immune checkpoint inhibitor called avelumab, to see whether avelumab decreases the disease from coming back at 3 years.