AVAIL-T - Avelumab in relapsed/refractory T-cell Lymphoma
Research type
Research Study
Full title
AVAIL-T: A Phase 2a trial of Avelumab, an anti-PDL1 antibody, in relapsed and refractory peripheral T-cell lymphoma (PTCL)
IRAS ID
222665
Contact name
Simon Wagner
Contact email
Sponsor organisation
University of Birmingham
Eudract number
2016-004879-46
Clinicaltrials.gov Identifier
Clinicaltrials.gov Identifier
222665, IRAS; WI210984, Pfizer Ref ; ERN_16-0867, Ethics self assessment number; NH2004, CAS
Duration of Study in the UK
4 years, 0 months, 1 days
Research summary
AVAIL-T Lay Summary of Study Results
Name of Chief Investigator: Professor Simon Wagner Chief Investigator ORCID ID: 0000-0002-8914-0370 IRAS ID: 222665 Name of the Research Ethics Committee that issued a Favourable Opinion for the study: NRES Committee East Midlands – Leicester South
Sponsor Organisation Name: University of Birmingham Study start date: 14th Nov 2017 Study end date: 27th July 2022 Funder's reference number: 16026 Name of Registry: EudraCT Study Registration Number/Identifier: 2016-004879-46 Is the study protocol publicly available? Yes, Clinicaltrials.gov. Registration number NCT03046953 Trial name
AVAIL-T: A Phase IIa trial of Avelumab, an anti-PD-L1 antibody, in relapsed and refractory peripheral T-cell lymphoma (PTCL)Protocol number: RG_16-123
Acknowledgment
The research team would like to thank the participating patients and families, whose support and time is gratefully acknowledged.Abstract
Purpose of the study: To find out the effectiveness of avelumab in treating patients with relapsed or refractory peripheral T-cell lymphoma (rrPTCL). Avelumab is a monoclonal antibody that blocks lymphoma cells from interacting with T cells via a protein on their surface called PD-L1, and this then allows your immune system to recognise and kill the lymphoma cells.
In total, 35 adults with rrPTCL were recruited to the trial over a 2 year period and 32 of these started treatment.
It was planned that all patients received avelumab at a dose of 10mg/kg by intravenous infusion once every 2 weeks for 8 cycles of 28 days, but many patients (23 of the total 35 patients) stopped treatment early due to disease progression. Patients were able to continue treatment past 8 cycles if there was evidence of clinical benefit to them.
Results: More than 50% of the patients on the trial were unable to remain on treatment up to the first evaluation point due to their disease progression, and for those patients that did reach this evaluation point, the avelumab treatment was found to not be effective.
Safety: Those patients that did receive avelumab had relatively mild side effects and did not have autoimmune reactions, which are common side effects for this type of treatment.Who sponsored this study?
This study was sponsored by the University of Birmingham. The AVAIL-T trials office can be contacted via AVAIL-T@trials.bham.ac.ukGeneral Information about the trial
The study took place in the United Kingdom only. Recruitment began in November 2017 and ended in November 2019. The trial closed in July 2021 when all patients had stopped trial treatment and all data had been collected.
The main objective of the study was to determine the response of patients to avelumab over 8 cycles of treatment. In addition to this, key secondary outcomes included determining the toxicity of the drug for patients as well as its effectiveness against rrPTCL in terms of survival and disease improvement.
A safe and well-tolerated dose of avelumab was established in a previous clinical trial for solid tumours, and this dose was used within the AVAIL-T trial on the assumption that it would also be safe for patients with blood cancers.What patients were included in this study?
This trial included only patients with PTCL that had relapsed (their cancer had returned) or was refractory (their previous treatment didn’t work). Although the trial was open to all adults, the average age of the patients entering the trial was 62 years. More men than women took part (83% compared to 17%).Patients needed to have adequate liver and kidney function to participate, disease that could be measured using a CT scan and be fit and able to attend hospital to receive treatment. They also needed to be able to provide informed consent to participate.
Patients were not able to participate in the trial if they had active lymphoma in their brain or spinal cord, evidence of T-cell lymphoma in their liver, evidence of HIV, Hepatitis B or Hepatitis C infection, active autoimmune disease, known allergy or intolerance to drugs similar to avelumab or active cardiovascular disease. Patients, both male and female, needed to agree to use effective contraception during the trial and female patients could not be pregnant or lactating at trial entry.
Which medicines were studied?
Patients received avelumab which is a type of immunotherapy called a checkpoint inhibitor. It is a monoclonal antibody that targets and blocks a protein called PD-L1 on the surface of some immune cells, this activates the immune cells to find and kill cancer cells.
What were the side effects?
Serious Adverse Events (SAEs) were reported whilst patients were on trial treatment and for 4 weeks after they finished treatment. SAEs include untoward medical occurrences that result in patients being admitted to hospital, are life threatening, result in death, cause long term or significant disability or incapacity or cause birth defects.
Hospitalisations for supportive treatment due to the patient’s cancer getting worse or death from their PTCL were not reported as SAEs. Unfortunately, this was expected for this patient group and would not be considered related to trial treatment.
Twenty seven SAEs were experienced by 18 patients, of which 12 events in 10 patients were judged to be at least possibly related to avelumab. For the treatment-related serious adverse reactions, there was one death due to liver failure, one infusion-related reaction, one excess fluid on the lungs, one immune-mediated colitis (inflammation of the bowel due to overactive immune cells), one gastric perforation, 4 infections of varying type, and 3 fevers.
The trial also collected Adverse Events (AEs) from grade 1 to grade 5, which are medical occurrences that are considered mild, moderate, severe or medically significant but not immediately life threatening, life-threatening or death. Grade one AEs are mild events where intervention is not needed. Grade 2 AEs are moderate events where minimal, local or non-invasive intervention is required, and Grade 3 AEs are severe or medically significant events that are not immediately life-threatening. Grade 4 AEs are life-threatening needing urgent intervention and Grade 5 are death-related. These AEs include events both related and unrelated to trial treatment.
In total 244 AEs were reported among 31 patients; 41 (17%) were grade 3 or above, reported in 16 of the 31 patients. The most common AEs were fevers and infections.During the trial, there were 26 deaths reported. 22 were due to the patients’ disease, and one patient death was treatment-related (due to treatment they had after stopping this trial, so non-trial related). The other 3 deaths were as follows: one had an unknown cause, one was heart disease with underlying lymphoma, and one was liver failure.
What were the overall results of the study?
Avelumab did not meet the criteria for effectiveness which were set before the trial started: there needed to be 11 responses to treatment in 30 patients treated in order to show effectiveness of the drug, and we found that only 5 patients responded. For those patients who did respond there was a meaningful duration of response: 3 of the 5 patients who responded had a response lasting 12 months.
Of the 35 patients registered to the trial, 32 patients started treatment. Two patients did not start treatment, one due to progression and one due to death between the time of registration and the planned start of treatment. One patient did not start treatment as they were found to be ineligible shortly after registration.
The research team looked at how many patients’ PTCL improved with treatment. In this trial, a response was recorded if the patient had a Complete Response (CR) or a Partial Response (PR) to treatment. The patients’ responses were determined by using published criteria (called Cheson criteria) to assess any change in the total size of their tumours by comparing their CT scans after 8 cycles of treatment with the scan they had at the start of the study.
19 of the 35 patients (54%) did not have a CT scan done during the first 8 cycles of treatment so did not have a response reported and we were not able to include them in the results. The reasons for this were progressive disease (12 patients), death (3 patients), ineligible (1 patient) and withdrawal of consent (2 patients). The final patient did have a CT scan that was inconclusive at cycle 3, with progression later confirmed during cycle 4.
16 of the 35 patients did have CT scan done during the first 8 cycles of treatment and were evaluated for response to avelumab. 5 patients responded to treatment (14%) all achieving PR within the first 8 cycles of treatment. Four patients (11%) had stable disease (SD) and 7 progressed (20%).
For the 16/35 (46%) patients who were evaluable, only 13 patients had CT scans containing measurements for the target lesions reported at screening, and these showed only a modest reduction in tumour size during treatment, with a median (middle value in the range) reduction of 4.3%.
The research team also looked at duration of response for those patients who had a response to avelumab. All these patients had a response lasting at least 6 months, and 3/5 (60%) had a response lasting 12 months.
The research team also looked at how long people lived without disease progression after treatment with avelumab. They found that 21% of the 35 patients survived without progression for 6 months and 17% survived without progression for 12 months. Of the 5 patients who achieved a response to avelumab, 100% survived without progression for 6 months and 60% survived without progression at 12 months. Two patients survived without progression until the end of the trial and continued compassionate use of the drug after the trial ended.
Looking at overall survival of the 35 patients, the median overall survival was 10 months, with 66% of patients surviving 6 months and 33% surviving 12 months.How has this study helped patients and researchers?
The study examined the potential of a newly available treatment in advanced I.e. refractory and relapsed PTCL. It was found that it was not an effective treatment for the majority of patients with this condition, but we cannot exclude it being useful in subgroups or as an adjunct to other treatments.Are there plans for further studies?
No
Where can I find more information about this study?
To learn about this study, you can find more detailed information on the website Clinicaltrials.gov A summary is also provided on the Cancer Research UK website.
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East Midlands - Leicester South Research Ethics Committee
REC reference
17/EM/0166
Date of REC Opinion
24 May 2017
REC opinion
Further Information Favourable Opinion