Calibre
Research type
Research Study
Full title
CALiBRe: Assessment of the Mechanism of Action of idelalisib (CAL-101) in B-cell Receptor Pathway Inhibition in CLL
IRAS ID
164086
Contact name
Peter Hillmen
Contact email
Eudract number
2012-003631-36
Duration of Study in the UK
4 years, 11 months, 31 days
Research summary
Research Summary
Chronic Lymphocytic Leukaemia (CLL) is the most common blood cancer in Britain. Some patients with CLL never need treatment and live a normal life but many become unwell and die prematurely due to CLL. At the moment bone marrow transplantation is the only cure for CLL but this is usually not possible because the disease mainly affects older people. Many treatments for CLL involve chemotherapy which, although effective, can have serious side effects especially in older people. Also patients inevitably relapse and sooner or later become resistant to treatment. The experimental drug, idelalisib (CAL-101), appears to be a major advance in CLL treatment.
We aim to assess how the drug idelalisib acts within the body in two groups of CLL patients (those that have recived other treatments for their condition previously and those in which this is their first treatment), by studying this mechanism of action we hope to gain enough information to inform us which other drugs could be
used in combination with idelalisib and how best to do this in order that to increase its efficacy safely. We also wish to assess the safety of this drug in these patients and if it can effectively be used to treat them with lower toxicity than standard treatments.Summary of Results
CALiBRe: Assessment of the Mechanism of Action of idelalisib (CAL-101) in B-cell Receptor Pathway Inhibition in CLL Protocol Number: RG_12-124 EudraCT number: 2012-003631-36
ISRCTN52057158
Chief Investigator: Professor Peter Hillmen Abstract Purpose of the study: To study how a drug called idelalisib affects the rate of growth and lifespan of leukaemia cells in patients with Chronic Lymphocytic Leukaemia (CLL), and to see how patients respond biologically to idelalisib What was tested: In this study, patients received treatment with idelalisib from registration until their disease got worse, or no disease was detected. Each patient’s response to treatment was assessed by blood samples and bone marrow samples that were taken regularly over a 6 month period.
People taking part: 23 patients with CLL were registered to this trial. 11 of these patients had not had treatment for CLL before, and 12 did have treatment previously but this had stopped working or their disease had come back.
Results: The study aimed to recruit 40 patients; however, in March 2016 recruitment was put on hold because of an idelalisib safety alert from other trials. The trial re-opened in May 2017 with an amended protocol, after a safety analysis determined that only patients who previously had treatment for their CLL could be recruited into the trial. The trial did not recruit any more patients following re-opening, as other new treatments were available for patients who may have been eligible for the trial, and the decision was made to close recruitment in March 2018. The 23 patients who were recruited to the study were followed up for 5 years.
No patients in this study achieved a response where their disease could longer be detected or achieved a complete response to the idelalisib treatment. Most of the patient responses were partial responses, or a partial response but a type of the patient’s white blood cells called lymphocytes remained high.
There were fewer patients recruited to the study than the original target, and patients received treatment for varied lengths of time, which affected the results of the study. It is therefore difficult to make conclusions from the results.
Safety: As this trial did not fully recruit, the final safety decision criteria could not be assessed.Who sponsored this study?
This study was sponsored by the University of Birmingham. The CALiBRe trials office can be contacted via CALiBRe@trials.bham.ac.uk.
General Information about the trial
The study took place in the United Kingdom only. Recruitment began in August 2015 and ended in March 2018. The trial closed in September 2021 when all patients had stopped trial treatment and had been followed-up for 5 years, as required by the protocol.
The main objectives of the study were to see what the patient’s biological response to idelalisib was, and therefore how well they responded to treatment, and confirm how idelalisib works in patients with CLL . The safety of idelalisib and how well it works had been evaluated in a number of other studies, but there had been no detailed investigation of its mechanism of action. The scientists working on the CALiBRe trial wanted to understand this mechanism in CLL to see what other drugs might be suitable to combine with idelalisib, and how they could be combined to make them most effective.
In March 2016, the CALiBRe research team were told about new important safety information for idelalisib, from the company that made the drug called Gilead. Several Gilead trials using idelalisib had been stopped earlier than planned due to an increase in deaths and an increase in serious side effects related to infections for patients who were taking idelalisib. There was particular concern relating to patients taking idelalisib who had not received any treatment before.
The CALiBRe research team told the hospital sites recruiting the patients about the new safety information, and temporarily halted recruitment to the trial so no new patients could join. Patients already on the trial who had not had treatment before had to stop idelalisib treatment. Patients on the trial who had not had treatment before but were more likely to have a worse outcome from their disease, because of a genetic abnormality called a 17p gene deletion, were given the option to continue taking idelalisib. These patients were told about the new risks before deciding whether to continue. Patients on the trial who had treatment before were told about the new risks and given the option to continue taking idelalisib.
In May 2017, the trial re-opened to recruitment but only to patients who had received previous treatment for their CLL. Patients who had not had any treatment for their CLL before could not be recruited to CALiBRe when it re-opened. After the trial re-opened, no further patients were found who might be able to join the study. It was unlikely that more patients would be recruited because alternatives to idelalisib were available to give to patients who may have been able to join the trial. The trial was closed to recruitment early in March 2018.
What patients were included in this study?
The trial originally recruited patients:
• with CLL who had not previously had treatment with CLL who had relapsed (their disease returned) or were refractory to treatment (the treatment stopped working) • aged 18 or more • with a life expectancy of at least 6 months • able to give informed consent • prepared to undergo the required investigations within the trial (including bone marrow examinations) • who agreed to use appropriate contraception during the trial and for 30 days afterwards, and could not be pregnant or breast-feeding at trial entry Following the amendment for safety reasons the trial was changed to only recruit CLL patients with relapsed disease (their disease had returned) or refractory disease (previous treatment had not worked) who were previously treated with a drug called ibrutinib but this had not worked. CLL patients with relapsed or refractory disease who could not tolerate ibrutinib or were not able to take ibrutinib could also be recruited for the trial. Note that no patients were recruited when the trial reopened.
Patients could not take part in the trial if they:
• had an active infection at the time of registration or a history of chronic or recurrent infection.
• had severe, concurrent diseases (particularly of the heart and lungs) or mental disorders that could interfere with their ability to participate in the study.
• had mantle cell lymphoma
• were known HIV positive, had active or prior hepatitis B or C, • had another active cancer (except some skin cancers), • had persistent severe low levels of blood cells or active breakdown of red blood cells that was not controlled with medication.
• received any prior treatment with idelalisib, or other very similar drugs, and could not join the trial if they were known be sensitive to idelalisib or any of the ingredients used to make idelalisib into tablets.
Of the patients who took part in the study, 20 were male and 3 were female.
Which medicines were studied?
Patients received continuous treatment with idelalisib by taking a tablet twice a day from when they entered the trial until their disease got worse, or no disease was detected. Idelalisib works by blocking a protein called PI3K inside cancer cells, which tell the cancer to grow. Some leukaemia cells have too much PI3K, so by blocking this protein, idelalisib may shrink the cancer or stop it growing for some time. Idelalisib is also called a PI3K inhibitor.
What were the side effects?
Of the 23 patients registered to the trial, 22 started treatment. One patient was due to start treatment after the safety alert was issued and therefore did not start.
Serious Adverse Events (SAEs) were reported while patients were on trial treatment and for 30 days after they finished treatment. SAEs included any 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, cause birth defects, is a new primary cancer, or is otherwise considered medically significant by the doctor. Hospitalisations for protocol treatment, elective procedures (unless brought forward because of worsening symptoms) or for social reasons (e.g. respite care) were excluded from SAE reporting.
In total, 27 SAEs were reported involving 14/22 (64%) patients. Three SAEs resulted in death; colitis deemed definitely related to trial treatment, pulmonary infarction deemed unlikely to be related to trial treatment and febrile neutropenia deemed definitely related to treatment.
The trial also collected Adverse Events (AEs). These are medical occurrences that are unfavourable and an unintended sign, symptom or disease that occur while a patient is on trial treatment. AEs include effects both related and unrelated to trial treatment. An abnormal laboratory value was only considered to be an AE if this resulted in early discontinuation of idelalisib or meant that the dose of idelalisib had to be reduced or temporarily stopped, or also that another medication was needed to treat the problem caused because it was significant. Any symptoms or illnesses present before starting idelalisib were only reported as an AE if they got worse, which meant it increased in grade. Grades increase from 1 (least) to 5 (most) to measure seriousness of the event. A grade 5 event is a fatal event.
In total 245 adverse events were reported involving 21/22 (95%) patients. Of these, 24 were adverse events related to the patient’s blood affecting 4/22 (18%) patients. The remaining 221adverse events were not related to the patient’s blood and were experienced by 21/22 (95%) patients. 20 adverse events grade 3 or higher were experienced by 9/22 (41%) patients that were considered to be possibly, probably or definitely related to trial treatment.
In the cohort of patients who had not previously had treatment for their CLL, 55 adverse events were reported involving 9/10 (90%) patients. All 55 adverse events were non-haematological. Two adverse events were grade 3 or higher and were considered to be possibly, probably or definitely related to trial treatment. Both of these events were grade 3 lung infections deemed probably related to idelalisib. Two (20%) patients experienced this type of event. No grade 5 adverse events were reported in this cohort.
In total 190 adverse events were reported involving all 12 (100%) relapsed/refractory patients. Of these, 24 were haematological adverse events affecting 4/12 (33%) patients. The remaining 166 adverse events were non-haematological and were experienced by all relapsed/refractory (100%) patients. 18 adverse events were grade 3 or higher and were considered to be possibly, probably or definitely related to trial treatment. Seven (58%) relapsed/refractory patients experienced this type of event. One grade 5 adverse event was reported, diarrhoea deemed definitely related to treatment. The patient died 16 days later of idelalisib-induced colitis.
What were the overall results of the study?
The urgent safety measure, which resulted in changes to the protocol, affected the overall results of the study, as the recruitment target was not met and some patients had to stop treatment early.
No patients in this study achieved a response where their disease could longer be detected or achieved a complete response to idelalisib treatment.
The research team looked at the best disease response the patients had in the study. The definition of disease response in the trial protocol was: achieving complete remission, complete remission but with an incomplete recovery of the bone marrow or partial remission, within the first 6 months of the trial treatment. The response was assessed according to published criteria, called International Workshop on CLL (IWCLL) response criteria.
By the 6 month assessment, 13 out of 23 (57%) patients had achieved a response; there were 9 (39%) partial remissions, 4 (17%) partial remissions with a type of the patient’s white blood cells called lymphocytes remaining high. For the other 10 patients (53%), 7 (30%) had stable diseases, 3 patients could not be assessed (13%).
The research team also looked at the amount of time from when the patients were registered to the trial, to when their disease got worse or when they died from any cause. This was called progression-free survival. 16 patients in the trial progressed, and 4 patients died without experiencing progression. The progression-free survival at 1 year was 59% and at 2 years was 36%. This was the proportion of patients who had not progressed or died at 1 year and 2 years, from all the patients on the study. Median progression-free survival was reached at 1.3 years. This was the amount of time from when the patients started the trial, to when 50% had died from or their disease had got worse.
The research team looked at the amount of time from when the patients were registered to the trial to when they died from any cause. This was called overall survival. There were 7 deaths in total in the trial. Overall survival at 1 year was 86% and at 5 years was 67%.
How has this study helped patients and researchers?
Unfortunately, CALiBRe was seriously impacted by the halt in recruitment and did not recruit enough patients give conclusive results. However, we have shown that idelalisib treatment resulted in responses consistent with those reported previously, so the patients taking part received appropriate treatment for their CLL. Blood and bone marrow samples were taken for further research into how the drug works within the body and have also been stored in the UKCLL Biobank for use by other researchers in the future.
Are there plans for further studies?
No. Due to the safety issue with idelalisib, we are not aware of any further studies that are currently planned with this drug. Also, new drugs with fewer/better side effects are now available for CLL and trials are often set up to look at combinations of these instead.
Where can I find more information about this study?
To learn about this study, you can find more detailed information on the ISRCTN registry.
https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbZKm4C0TeSkP8lYcMVEmwG5YgbuJ2IrBmA7aYFZ0WnaGtC9f_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIiCUNci9FwpcIQPg6kqgbpiilk-2BL9KaDgPhOsqMsC9zjNsFbtUazjVxfWtA1DtoshX-2B3RpF7e9I743VnwDjot-2FEGQweb0nCB8LEIXaSNA0F2LGZg5-2BMdV6rwnr2OUBi7s22Wgw2eAu2G6mtXLtATOdlJp6fiteekLYXe6KeiAn5g-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C34fa49acd8a24db4748e08da9d6b7400%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637995382076386463%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=2oskEEisvsnxVjjAL1s0sD1hqILF4eqbDs0Ujspsqt4%3D&reserved=0
A summary is also provided on the Cancer Research UK website.
https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbZ0oYz60WoglvPkqIfU1HPHTUfauCq2ZPvNtWjz0kGXSOCiSOfyPyipJY7AGHLby83CxCKkzl39Br4eiOAMc6C5Ci37wubE-2F5FqCUgDsT1l4snl9ClNd49mcmL5NpMDSmM52CxGI1jRjtZBs0fnu0oZT-2FQGyaW3STmuQ3-2Fst729184kIWjvwiKU1YstKwI-2FXpl4PWAZEBP1T-2Bcn3G3Onsps-3D7sup_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIiCUNci9FwpcIQPg6kqgbpS9APcefWUO9ejq2TyLRN6yX7gcBQHoUnBxUO906w1jmxiKEUX0et8fVpRNRkOUJka8RLp7yCXxcM8yNI-2F1-2BFmzQTNeRpBL-2FzIkny9HyCCs1irR1jrT-2FnH4Ygba0qoQ-2BrvKBLfg7SJJlh-2FeL62nV1LA-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C34fa49acd8a24db4748e08da9d6b7400%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637995382076386463%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=OpH9m3uX23k4vZm%2Bd7SHis7pbL0A3QNO3SDCvOWdBpk%3D&reserved=0REC name
Yorkshire & The Humber - Leeds West Research Ethics Committee
REC reference
15/YH/0020
Date of REC Opinion
22 Jan 2015
REC opinion
Favourable Opinion