ASTFOX
Research type
Research Study
Full title
ASTFOX : A Phase I study of IAP antagonist, ASTX660 (tolinapant), in combination with standard of care FOLFOX chemotherapy in metastatic colorectal cancer
IRAS ID
1004428
Contact name
Victoria Coyle
Contact email
Sponsor organisation
Greater Glasgow Health Board
Eudract number
2021-006411-28
ISRCTN Number
ISRCTN11197711
Research summary
Research Summary
In this study, its investigating whether a new drug called ASTX660 can be combined with FOLFOX chemotherapy, a combination of two chemotherapy drugs (oxaliplatin and 5-fluorouracil) routinely used in treatment of advanced bowel cancer. ASTX660 is an “IAP antagonist”, in other words, it combats IAPs. IAPs (Inhibitors of apoptosis proteins) are proteins that can block cells from dying by a process called apoptosis. This cell death helps to maintain the balance of cells in the body and is used to remove cells that are old or damaged. When cancer cells are damaged by chemotherapy they can die by this process, however some cancer cells have the ability to avoid apoptosis and can survive despite chemotherapy treatment. Therefore stopping the IAPs from blocking apoptosis could increase the likelihood of damaged cancer cells dying. We have shown this in laboratory tests in bowel cancer cells. It's also been shown this type of drug causes changes in the types of cells and chemical signals in the tumour and surrounding tissue which could trigger cell death by activating the patient’s immune system. ASTX660 is a new drug that's not licensed for treatment of cancer. It has been tested on its own in clinical trials and has shown to be safe and well tolerated by patients with a range of cancer types but has not been tested in combination with FOLFOX chemotherapy. The purpose of this study is to find the dose of ASTX660 that can be given with FOLFOX chemotherapy, without producing side effects that are serious or detrimental to patients’ day-to-day life. At least three patients at a time will receive treatment, with stepwise increases in the dose of ASTX660, provided the side effects seen in treated patients are acceptable. The dose of ASTX660 with the most acceptable side effect profile will be recommended as the dose to be given in combination with FOLFOX chemotherapy for further studies. Up to 30 patients will be treated in the study from 3 hospital sites in the UK.Summary of Results
Background and Study Aims
In patients with advanced colorectal (bowel) cancer, chemotherapy damages cancer cells causing them to 'self-destruct' by a process known as apoptosis. Unfortunately, cancer cells can find ways to 'switch off' apoptosis and therefore become resistant to chemotherapy. This can lead to growth or spread of the cancer. In the laboratory it has been shown that ASTX660 (tolinapant) can 'switch on' apoptosis so that colorectal cancer cells die in response to FOLFOX chemotherapy. Additional laboratory tests suggest that this combination treatment could lead to cancer cell death by other processes, not just apoptosis.ASTX660 (tolinapant) is an experimental unlicensed drug. It has been tested on its own in clinical trials and has shown to be safe and well tolerated but has not been tested in combination with FOLFOX chemotherapy. This study was investigating whether ASTX660 (tolinapant) could be safely combined with FOLFOX chemotherapy, a combination of two chemotherapy drugs (oxaliplatin and 5-fluorouracil) that are routinely used in the treatment of advanced bowel cancer. The dose of ASTX660/ (tolinapant) with the most acceptable side effect profile would be recommended as the dose to be given in combination with FOLFOX chemotherapy for further studies. It was planned that up to 30 participants would be treated within this study.
The study also planned to look at how the body processes the ASTX660 (tolinapant) drug when given alongside chemotherapy and how this drug changes cells and proteins in participants' tumours and blood. Participants enrolled on the study would have a tumour biopsy or sample taken before and during treatment to investigate how the cancer cells and immune cells in the tumour and surrounding tissue change with treatment. Blood samples would also be taken to help us look at the effect of the drug on cancer and other cells in the blood.
The primary aim of the study was to show that the combination of ASTX660 (tolinapant) and FOLFOX chemotherapy is safe and tolerable for patients with advanced bowel cancer. A secondary aim of the study is to measure participants response to treatment based on changes in tumour size on CT scan. However, the study was not designed to show that combination treatment is more effective than chemotherapy alone and a future larger study would be needed to do this.
Who carried out the research?
This study was co-sponsored by NHS Greater Glasgow and Clyde and University of Glasgow. It was funded by Cancer Research UK and Taiho Oncology Inc (formerly Astex Pharmaceuticals Inc). The study was co-ordinated by the Cancer Research UK Glasgow Clinical Trials Unit.
The Chief Investigator is Professor Victoria Coyle, Professor of Medical Oncology and Consultant in Medical Oncology, Queens University Belfast.What public involvement was there in the study (how many people, what their relevant lived experience was, and what they did) The study had public involvement from the very beginning of the research. Patients and the public provided support for the trial concept due to the unmet need for better treatments for patients with advanced bowel cancer. The research team included members of the public that that had lived experience of bowel cancer as a patient and/or carer. Their opinion was requested particularly when considering the chemotherapy treatment and the burden that attending for treatment and investigations would have on participants. They regularly joined meetings discussing the management of the study and also reviewed all documentation that was provided to participants.
The Patient and Public Involvement in this study was commended by the REC, the Umbrella Trial Steering Committee and by the study funder.Where and when the study took place
The plan was for the study to take place in 3-6 cancer centres throughout the UK. The study opened in July 2024 and closed in July 2025. At the time of closure had been opened in 2 cancer centres.Who participated in the study?
Participants aged 16 or over with metastatic colorectal cancer in whom second line palliative FOLFOX chemotherapy was an appropriate treatment option.What treatments or interventions did the participants take/receive?
All participants would receive both ASTX660 (tolinapant) and FOLFOX chemotherapy. Treatment would be given every 2 weeks for up to 12 cycles in total (24 weeks or approximately 6 months total duration) depending on side effects and how the cancer responded to treatment. FOLFOX is a chemotherapy treatment. ASTX660 (tolinapant) is a capsule taken by mouth once a day on a 7 days on/7 days off schedule. Participants would start taking the capsules on the day chemotherapy started for 7 days and then stop for the next 7 days.There were additional blood tests to check for side effects of the drug and to check the levels of the drug in the blood at different times after it is taken. These blood tests were additional to the blood tests that are taken as part of routine care. There were additional tests on the heart to check the heart rhythm (up to 4 electrocardiograms) and the pumping of the heart (one echocardiogram or MUGA). There were CT or MRI scans to check how the cancer was responding to treatment. These were done every 6 weeks during treatment, which may or may not be more frequent than scans done during standard care treatment, meaning it was possible participants would have 1 or 2 extra scans over the course of treatment. It was planned that some participants would have a biopsy or sample of tumour taken before and during treatment to help investigate findings in the tumour, but this did not happen since the study ended early.
What medical problems (adverse reactions) did the participants have?
No serious medical problems (adverse reactions) were reported during the study.What were the results of the study?
Unfortunately the study finished early due to a change in the agreement for supply of the study drug (ASTX660/tolinapant) which meant this drug was no longer available for new patients to take part in the study. Recruiting new patients to the study was halted in April 2025 following a request from the pharmaceutical company - Taiho Oncology Inc (formerly Astex Pharmaceuticals Inc) to the Chief Investigator for the study to close. A decision had been made by the company to stop external studies such as ASTFOX This was a commercial decision; there were no safety concerns to consider. Alternative options were considered but none of these were deemed feasible to pursue and so an early termination End of Trial declaration was therefore submitted to the regulatory authorities.Details of any further research planned:
At this moment in time there are no plans for further research.Where can I learn more about this study?
Information regarding the study is also available on the clinical trial register:
https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fwww.isrctn.com%252FISRCTN11197711%2FNBTI%2F__vHAQ%2FAQ%2F76dff95c-13aa-454f-92d6-55115653a1b8%2F2%2F0ZHbrzeWUb&data=05%7C02%7Cwales.rec1%40wales.nhs.uk%7C75e7e7aa933c4911592908df0da79096%7Cbb5628b8e3284082a856433c9edc8fae%7C0%7C0%7C639244685474925559%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=TTLsGahjtENKY%2FfV2eSS7yyvmU1beEHEcG1ogoPmoKE%3D&reserved=0We would like to thank the participants and their families that took part in this research. We would also thank all the study investigators and staff from participating hospitals, the study team and study Co-Sponsor.
REC name
Wales REC 1
REC reference
23/WA/0173
Date of REC Opinion
5 Sep 2023
REC opinion
Further Information Favourable Opinion