CLARITY
Research type
Research Study
Full title
CLARITY: Assessment of VenetoCLAx (ABT-199) in combination with IbRutInib in relapsed/refracTory Chronic LymphocYtic Leukaemia
IRAS ID
188095
Contact name
Sean Jennings
Contact email
Sponsor organisation
University of Birmingham
Eudract number
2015-003422-14
Duration of Study in the UK
5 years, 0 months, 1 days
Research summary
Research Summary
Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in the western world. Current treatments are relatively effective in inducing remissions in the majority of patients, however these therapies are not curative and patients inevitably relapse, with additional toxicity problems for these patients. However, the availability of targeted therapies such as ibrutinib, venetoclax, idelalisib and obinutuzumab has demonstrated that prolonged remission can be achieved, particularly with regard to Minimal Residual Disease (MRD) eradication which has been shown to be an indicator of remission time.
Although ibrutinib has been shown to improve progression free and overall survival in relapsed refractory CLL patients, very few, if any patients will achieve MRD eradication and therefore the aim of this trial is to increase the effectiveness of ibrutinib by using it in combination with venetoclax and assess if this is the ideal combination of drug to use to provide the most effective remission for the patient. We wish to assess the combination of drugs to see if this combination will provide lower toxicity than standard treatments.
This study builds on previous studies that have been performed by our group and we hope that the findings of the study will inform the future care of patients with CLL.
Summary of Results
Trial name CLARITY: Assessment of Venetoclax (ABT-199) in combination with Ibrutinib in relapsed/refractory Chronic Lymphocytic Leukaemia (CLL) Protocol Number: RG_15-156 EudraCT number: 2015-003422-14
ISRCTN13751862Abstract
Purpose of the study: To study how a drug called ibrutinib and a drug called venetoclax affect the rate of growth and lifespan of leukaemia cells in patients with Chronic Lymphocytic Leukaemia (CLL) and to see how patients respond biologically to these drugs.
What was tested: In this study, patients were given a combination of ibrutinib and venetoclax. Each patient’s response to treatment was assessed during this phase 2 trial by looking at their blood and bone marrow samples.
People taking part: 54 patients took part in this trial, recruited between June 2016 and November 2017.
Results: Overall the study team found that after 12 months of combined ibrutinib and venetoclax treatment, 29/50 (58%) patients achieved a complete remission and 20/50 (40%) patients achieved MRD negative remission (the amount of CLL in the blood was almost undetectable after treatment). After 3 years of treatment 26/50 (52%) patients of patients achieved complete remission and 21/50 (42%) of patients achieved MRD negative remission.
Safety: In this study, researchers did not find any new safety concerns with the use of ibrutinib and venetoclax.Who sponsored this study?
This study was sponsored by the University of Birmingham. The CLARITY trials office can be contacted via clarity@trials.bham.ac.ukGeneral Information about the trial
The study took place in the United Kingdom only. Recruitment began in June 2016 and ended in November 2017. The trial closed on 29 October 2022 when all patients had stopped trial treatment and had been followed up. The follow up period for all patients was from the start of trial treatment for up to 5 years, to see if the patient progressed (their disease got worse) or passed away.
Chronic Lymphocytic Leukaemia (CLL) is a cancer that affects the white blood cells called lymphocytes. It is the most common type of leukaemia in adults. CLL is a type of cancer where the bone marrow makes too many white blood cells that are not fully developed, these abnormal white blood cells do not work properly and grow too fast.The main purpose of the CLARITY study was to see what the CLL patients’ biological response to ibrutinib and venetoclax was, how well they responded to treatment, and if there were any side effects to the treatment.
Biological Response: The primary outcome measure of the trial was to find out how many patients achieved MRD (minimal residual disease) negativity (where the amount of CLL in the blood is almost undetectable, less than 0.01%) after a year of combined treatment. A secondary outcome measure of the trial looked at how many patients achieved MRD negativity after 6 months, 2 years, and 3 years of combined treatment.
Patients stopped treatment if results from blood tests taken 3 months apart and a final bone marrow sample confirmed that there were less than 0.01% CLL cells in the samples. Patients who did not reach MRD negativity continued treatment, and all patients were followed up for 5 years.
Response to Treatment: Further secondary outcome measures evaluated how well patients responded to treatment at 6 months, 1 year, 2 years, and 3 years, how long their responses lasted, and the best response at any point. Response was assessed using the IWCLL criteria (this is internationally agreed criteria that involves a list of different assessments including a CT scan, physical examination and blood tests, that are carried out to work out a response to treatment).
Survival: Other secondary outcomes for the trial included progression free survival, defined as time from date of registration to date of progression or death from any cause, and overall survival, defined as time from date of registration to date of death from any cause.
Side Effects: Data on the toxicity (side effects) of combination therapy were collected and evaluated.What patients were included in this study?
This trial included patients with CLL who had relapsed disease (their cancer had returned) or had refractory disease (previous treatment stopped working). The trial was open to men and women aged 18 or more.
All patients had to have adequate liver and kidney function and adequate bone marrow function (there were specific ranges for the tests in the protocol to assess this), patients had to be able to give informed consent and be able to attend hospital to receive treatment as an out-patient to participate. Patients needed to agree to use appropriate contraception during the trial and could not be pregnant or breast feeding.
Patients could not take part in the trial if they had certain heart conditions, if their disease had progressed to an aggressive form and if they had major surgery within 30 days prior to registration. Patients also could not have received any prior treatment with ibrutinib, venetoclax or any drugs of similar types.
The average age of patients was 64, the youngest patient was 31 and the eldest was 83. 37 patients (69%) were men and 17 patients (31%) were women. All patients had had some treatment for their CLL before enrolling in CLARITY, this was between 1 and 6 courses of treatment, with an average of 1 prior treatment per patient.Which medicines were studied?
Patients on this trial received venetoclax in combination with ibrutinib. Patients took venetoclax and ibrutinib tablets every day.
Ibrutinib is a type of drug called a BTK inhibitor. This is a targeted treatment drug that works by blocking the signals that CLL cells use to grow and divide. Venetoclax is a type of drug called a BCL-2 inhibitor. This is a targeted treatment drug that works by binding to and blocking the BCL-2 protein found in CLL cells, this causes the cancer cells to die.
The purpose of using ibrutinib in the trial was stop the CLL cells growing and dividing, and reduce the level of CLL in the body. Venetoclax was given to block further growth of and to cause the death of remaining CLL cancer cells.
Ibrutinib was first given alone (420mg per day) for 8 weeks before the patients started venetoclax. Venetoclax was started on a low dose (10mg or 20mg per day) and the dose increased over 5 weeks to a maximum total of 400mg per day. This was to help prevent a known side effect called ‘tumour lysis syndrome’. Ibrutinib was given at the same time as venetoclax was increased, and then after this 13 week period both ibrutinib and venetoclax continued at the maximum dose. Ibrutinib was given for up to 5 years, while venetoclax could be given for a maximum of 3 years.What were the side effects?
This trial collected Adverse Events (AEs) while patients were on trial treatment and for 4 weeks after they finished treatment. These are medical problems such as symptoms or illnesses that occur while a patient is on trial treatment. AEs can be related (a ‘side effect’) or unrelated to trial treatment. Blood tests that were not in the ‘normal’ range were considered to be an AE if they resulted in the patient discontinuing treatment or if their treatment had to be changed in any way because of it. AEs are assigned grades from 1 to 5 to measure seriousness of the event.
If an AE was considered ‘serious’ it was reported as a Serious Adverse Events (SAEs) within 24 hours of the hospital team becoming aware of it. These were medical occurrences that resulted in patients being admitted to hospital, were life threatening, resulted in death, caused long term or significant disability or incapacity or caused birth defects.
48 SAEs were reported in 26 out of 54 patients. 30 were considered related to the trial treatment and 18 were unrelated. The most common SAEs were 13 reports of lung infection (10 patients experienced this at least once) and 4 reports of fever (3 patients experienced this at least once). Two SAEs were reported for Covid-19 infection in two different patients. Most SAEs (36/48) were grade 3 (severe events where patients may have been admitted to hospital or had medical treatment), and only 1/48 reports were for a more severe grade 4 event. No SAEs resulted in death (grade 5 events).
1081 AEs were experienced by 53 out of 54 patients. 23 out of 54 patients experienced at least one grade 3 event (severe). The majority of AEs were low grade and resolved with a treatment break or by giving the patient a lower the dose of the drug. The most common AE experienced by patients was diarrhoea (121 events in 38 patients), infections (lung infection 22 events in 16 patients, upper respiratory infection 15 events in 12 patients, urinary tract infection 24 events in 7 patients, skin infection 12 events in 9 patients, other infection 43 events in 22patients), nausea (74 events in 31 patients), bruising (40 events in 21 patients) skin disorders (38 events in 23 patients), low neutrophil count (decrease in a type of white blood cell) (38 events in 14 patients), fatigue (39 events in 24 patients), and vomiting (35 events in 12 patients). Other AEs that occurred in at least 5% of patients were: headache, indigestion/gastric reflux, muscle or joint ache, cough, other stomach issues, dizziness, rash, back pain, mouth ulcers, dry skin, constipation, palpitations, and fever. Less common was stomach pain, swelling in the arms and legs, high blood pressure, nose bleed, flu-like symptoms, nasal congestion, pins and needles, and insomnia.
Decreased neutrophil count (lack of a type of white blood cell) and gastrointestinal problems (diarrhoea etc.) were the most common reason for patients to need to have a treatment break or reduction in the dose of either or both drugs.What were the overall results of the study?
Researchers measured the amount of CLL (minimal residual disease, MRD) by examining the patients’ blood and bone marrow samples at the various chosen time points for the combined treatment. The MRD data for the study showed by 6 months of combined treatment, 13 out of 50 patients (26%) had achieved MRD negative remission, by 1 year this was 20 out of 50 (40%) patients, by 2 years this was 20 out of 50 (40%) patients and by 3 years, 21 out of 50 (42%) patients who were still being followed up achieved MRD negativity (where the amount of CLL in the blood is almost undetectable, less than 0.01%).
Disease responses for patients were assessed at 6 months, 1 year, 2 years, and 3 years of combined treatment. Responses are categorised as: complete response (CR), complete response with some disease still in bone marrow (CRi), partial response (PR), stable disease (SD), progression or relapse (PD). The responses based on patients on treatment at the time of the assessment were:
* At 6 months, 24/50 (48%) patients had a CR or CRi, 26/50 (52%) patients had a PR
* At 1 year, 27/48 (56%) patients achieved a CR or CRi; 19/48 (40%) patients had a PR; 1 (2%) patient had SD. and 1 response was not known
* At 2 years, 19/33 (58%) patients achieved a CR; 12/33 (36%) patients had a PR; 1 (3%) patient had SD, and 1 response was not known
* At 3 years, 16/20 (80%) patients achieved a CR; 2/20 (10%) patient had a PR; 1/20 (5%) had SD; and 1 response was not known The number of patients assessed at each time point decreased as patients discontinued the study. Patients who achieved a CR with an MRD negative remission stopped treatment at a defined point.
Overall, in terms of best response at any point in the study, 43/50 patients (86%) achieved a CR, 1/50 patients (2%) achieved a CRi, and 6/50 patients (12%) achieved a PR. This means that all patients who received the combination treatment had a response to treatment, and 86% of them responded fully.
Patients were followed up for up to 5 years to see if they maintained their best response or their disease started to get worse again.
The research team looked at progression free survival for this treatment combination. This is 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. The progression free survival is estimated to be: at 1 year, 100%; 3 years 96% and; at 5 years, 73%.
The research team also looked at overall survival, which is the amount of time from when the patients registered to the trial to when they died from any cause. There were 12 deaths in total in the trial. Overall survival is estimated to be: at 1 year, 100%; 3 years, 98% and; 5 years, 88%. The main causes of death were due to CLL progression and other cancers.
The data suggests that the combination treatment of ibrutinib and venetoclax was effective in taking a large proportion of patients into remission and maintaining a disease-free response. There was variation in whether patients became MRD negative with this treatment. MRD monitoring was used to guide when to stop treatment or continue treatment.How has this study helped patients and researchers?
The overall results of the study have shown that the combination of ibrutinib and venetoclax treatment was well tolerated in patients with relapsed or refractory CLL with a great percentage of patients achieving MRD negative remission. This is the first study to explore using MRD response as an indicator of how long this combination therapy should be given for. Patients had a variation of MRD responses which suggests that there should be an individual approach to how long treatment should be given for, tailored to a patient based on their MRD response.
The results from CLARITY formed the basis of adaptive trial design incorporating ibrutinib and venetoclax combination in the front-line, phase 3 FLAIR study (Sponsored by the University of Leeds, https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbZKm4C0TeSkP8lYcMVEmwG7GsMohR-2B3DWlHoEh9JABvoZXja_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIdPHBlLP6Utfuphj0qRqZN4j-2BBjiHnTtMq-2BX5It6PYsqoZW3qQywoTlqN6RvusYjkPfkpvo79-2FncsIu-2FYokz7lsWuKl-2Ffp4NY7Dvty0U-2F8ptgaXb2e3Wb8C51ktI-2FBWGE5rAUKyjeJPrLmwZMfOF8jRntRGc21Ppxhof2CqQyONw-3D-3D&data=05%7C02%7Cleedseast.rec%40hra.nhs.uk%7Ce0097e7664f54f6085e708dc0d31e760%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638399755184012624%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=qqq7jSVFtsgWYTRMB06HgQ%2FHdSUB16mx7oqluNLwgQc%3D&reserved=0
Blood and bone marrow samples were also taken for further research into how the drug works within the body and have been stored in the UKCLL Biobank for use by other researchers in the future.Are there plans for further studies?
At present there are no plans for further studies with ibrutinib and venetoclax. There are currently new drugs of the same type available with potentially fewer side effects than those investigated during the CLARITY trial.Where can I find more information about this study?
To learn about this trial, you can find more detailed information on the ISRCTN registry.
https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbZKm4C0TeSkP8lYcMVEmwG40YzP5z4yhz-2BHWMfcKFK2TZoOT_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIdPHBlLP6Utfuphj0qRqZNzzMsC84Eunf-2FxfUyKjgbgp8qsO78w-2FF36BPdHEqv8K-2F7w4r-2FtXEGrsBiqJ2Oz6fT36cG-2F0CB-2Fk49DaK7e6BLJFntQq6PnvjhP4tV8NHGM463u4DrHPmnBx3VHa0jWiSWPyAQNMJbWH90aAzNLmUbcA-3D-3D&data=05%7C02%7Cleedseast.rec%40hra.nhs.uk%7Ce0097e7664f54f6085e708dc0d31e760%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638399755184012624%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=27PerX%2B2Y0s4uWgd8GDAHIfnEbY3XLMUfiArXzGLzXo%3D&reserved=0A summary is also provided on the Cancer Research UK website.
https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbZ0oYz60WoglvPkqIfU1HPHTUfauCq2ZPvNtWjz0kGXSOCiSOfyPyipJY7AGHLby89dR2yPuzMUTVenkV1545NB6xOONiAdAbtZdCjVfhHn3oIJKMVpkZvPuw8ESOPDTdsZrFIwYes4pchX03a3Fatj-2Bug6ojO7U8GjOTubSVwvLrKlPpb-2FuO9QNKT1qCEfR0A-3D-3DMLJj_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIdPHBlLP6Utfuphj0qRqZNVgGGLqbLSTk9UhNu7H-2BdU7Xx9Cj4kp6ntoTumpW6jejIPGeGjthLtz45CjqqfCKq4RqtVFYSprD9cH-2BRi9OxTLSp1CnWhMmqT4D5XEUf4o-2BlGCsMmZ4ltOXb1EmAm4SzYq2DIhhHwZuS-2FgDCennwKw-3D-3D&data=05%7C02%7Cleedseast.rec%40hra.nhs.uk%7Ce0097e7664f54f6085e708dc0d31e760%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638399755184012624%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=K26yX4mQts2z76MhOnFuRpUb766ozFF070fNI7A4w8w%3D&reserved=0REC name
Yorkshire & The Humber - Leeds East Research Ethics Committee
REC reference
15/YH/0530
Date of REC Opinion
21 Dec 2015
REC opinion
Further Information Favourable Opinion