MAJIC
Research type
Research Study
Full title
A RandoMised study of best Available therapy versus JAK Inhibition in patients with high risk Polycythaemia Vera or Essential Thrombocythaemia who are resistant or intolerant to HydroxyCarbamide.
IRAS ID
91259
Contact name
Claire Harrison
Sponsor organisation
University of Birmingham
Eudract number
2011-005279-18
Research summary
Summary of Research
The MAJIC trial aims to evaluate the activity and safety of the drug Ruxolitinib in patients with Polycythaemia vera (PV) and Essential Thrombocythaemia (ET) who have met criteria for resistance or intolerance of hydroxycarbamide (HC) therapy. Both PV and ET are characterised by the over production of blood cells. HC is the standard treatment for these patients and those who are resistant or intolerant have an increased risk of arterial and venous thrombosis, major haemorrhage and, in the longer term, transformation to myelofibrosis and acute leukaemia. More than 9 out of 10 people who have PV and about half of people with ET have a change in the JAK2 gene. The JAK2 gene makes a protein that controls how many blood cells the stem cells make. Ruxolitinib, the drug being tested in this trial, targets the JAK pathway to stop the JAK2 gene signalling to the stem cells to make blood cells. Ruxolitinib appears to help patients with MPNs (Myeloproliferative neoplasms) whether they have the JAK2 mutation or not. 290 patients with high risk PV or ET who meet the eligibility criteria will be recruited from 13 TAP (Trials Acceleration Programme) centres and 12 additional centres in the UK. Patients will be randomised between Ruxolitinib and Best Available Therapy (BAT). All patients will be assessed for complete or partial response during 1 year to obtain the primary endpoint. Patients will attend routine clinic visits at least every 2 weeks for the first 12 weeks and then every 6 weeks up to 1 year. Patients randomised to Ruxolitinib will continue to take the drug for 5 years as long as complete or partial response is maintained. Patients randomised to the BAT arm will continue to receive BAT and be considered a trial patient for 5 years.Summary of Results
MAJIC: A RandoMised study of best Available therapy versus JAK Inhibition in patients with high risk Polycythaemia Vera or Essential Thrombocythaemia who are resistant or intolerant to HydroxyCarbamideProtocol Number: RG_11-164
EudraCT number: 2011-005279-18
ISRCTN: 61925716Abstract
Purpose of the study: To compare the safety and benefit of a drug called ruxolitinib with best available therapy in the treatment of patients with two rare myeloproliferative neoplasms: Polycythaemia Vera (PV), where the bone marrow makes too many red blood cells, and Essential Thrombocythaemia (ET), where the bone marrow makes too many platelets.What was tested: Patients were randomised to receive either ruxolitinib or best available therapy for the treatment of their disease. Each patient’s response to treatment was assessed during this phase 2 trial by looking at their blood counts and effect on their spleen.
People taking part: 306 patients took part in this trial, recruited between August 2012 and August 2016. This included 190 patients with PV and 116 patients with ET.
Results: This trial found that in patients with PV, more patients achieved a complete response within one year of treatment than those who received best available therapy. However, no significant difference in complete responses was seen in patients with ET.
Safety: In this study, researchers did not find any new safety concerns with the use of the trial drug, ruxolitinib. Patients receiving ruxolitinib were more likely to experience infections, changes in the number of their blood cells and skin cancer compared to patients receiving best available therapy.
Who sponsored this study?
This study was sponsored by the University of Birmingham. The MAJIC trials office can be contacted via majic@trials.bham.ac.uk.General Information about the trial
The study took place in the United Kingdom only. Recruitment began in August 2012 and ended in August 2016. The trial closed on 28-March 2022 when all patients had stopped trial treatment and the majority of the data had been collected.The main objectives of the study were to investigate the safety and activity of ruxolitinib in the treatment of patients with Polycythaemia Vera and Essential Thrombocythaemia who were resistant or intolerant to hydroxycarbamide therapy, when compared to the best available therapy chosen by the patient’s doctor. Complete control of blood counts and a normal spleen was considered a Complete Response (CR) and partial control of blood counts in the presence of a normal or enlarged spleen was considered a Partial Response (PR). This is an established method known as European LeukemiaNet criteria.
The main trial outcome was to see how many patients on each treatment achieved a CR within the first year of treatment. The study also looked at how many patients achieved a PR and how long any responses seen lasted. Patients receiving ruxolitinib with a CR or PR at 1 year of treatment continued therapy and were followed up for 5 years. Patients who did not have a CR or PR with ruxolitinib at 1 year stopped trial treatment but were also followed up for 5 years, as were the patients receiving best available therapy.
The trial also investigated whether ruxolitinib can lower the risk of thrombotic and haemorrhagic events, how likely patients were to experience a progression of their disease, impact on bone marrow fibrosis and the levels of JAK2 in circulating blood, overall survival and quality of life.
What patients were included in this study?
This trial included patients with PV and ET who were resistant to or intolerant of hydroxycarbamide.
The trial was open to men and women aged 18 or over.All patients had to have adequate liver and kidney function, 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 effective contraception during the trial and could not be pregnant or lactating at trial entry.
Patients were excluded from participation in the trial if they had certain heart conditions, their disease had progressed to myelofibrosis and also if their previous or current platelet count was less than 100 x 109/L or neutrophil count less than 1 x 109/L (where not due to therapy). Patients also could not have received any prior treatment with ruxolitinib.
Which medicines were studied?
Patients on this trial were randomly allocated to best available therapy or ruxolitinib. Ruxolitinib is a type of drug called a Janus kinase inhibitor also known as a JAK inhibitor. It works by blocking the activity of JAK kinase enzymes and interferes with their signalling pathway. This stops the cancer cells from growing and dividing.What were the side effects?
Serious Adverse Events (SAEs) were reported while patients were on trial treatment and for 4 weeks after they finished treatment. SAEs include 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 or cause birth defects. Hospitalisations for protocol treatment, elective procedures (unless brought forward because of worsening symptoms) or for social reasons (e.g. respite care) were not reported as SAEs.345 SAEs were reported for this study of which 65 were considered related to trial therapy, 271 were unrelated and 9 events were unclassified. The most common SAEs reported by PV patients were transformation to myelofibrosis and dyspnea (reported by 6%). The other common SAEs (percentage of PV patients affected overall) were lung infection (5%), squamous cell carcinoma (4%), and abdominal pain (3%).
The most common SAEs reported by ET patients were transformation to myelofibrosis (reported by 9%) and lung infection (reported by 5%). The other common SAEs (percentage of ET patients affected overall) were dyspnea (4%), thromboembolic event (4%), fracture (3%), diarrhea (3%), headache(3%) and small intestinal obstruction(3%).
This trial also collected Adverse Events (AEs). These are medical occurrences that are unfavourable and an unintended sign, symptom or disease temporally associated with the use of a drug. AEs include events both related and unrelated to trial treatment. Throughout the trial 159 patients experienced high grade adverse events of grade 3 (severe or medically significant) and higher.
The most common AEs for patients with PV were, in those treated with BAT, sepsis (affecting 6% of the patients) and thromboembolic events (7%), and for ruxolitinib-treated patients, anemia (affecting 8%). For ET patients, there no adverse events which affected 5% or more of patients in the BAT arm. For those on ruxolitinib the most frequently reported AEs were anemia (affecting 24% of these patients), lung infections (9%), thromboembolic events (7%), dyspnea (5%), falls (5%), headache (5%), hypokalemia (5%) and hypotension (5%).
What were the overall results of the study?
The main aim of the trial was to see how many patients’ disease improved (responded) with ruxolitinib treatment in comparison to best available therapy. This trial found that in patients with PV, more patients achieved a complete response with ruxolitinib (43%) within one year of treatment than those who received best available therapy (26%). However, no significant difference in complete responses were seen in patients with ET (47% and 43% for ruxolitinib and BAT respectively).The study also looked at partial responses within 1 year of treatment for those patients that did not achieve a complete response. For PV patients, 54% of patients treated with ruxolitinib had a partial response and 67% for BAT. In the ET group, 47% of ruxolitinib patients achieved a partial responses compared to 52% who received BAT. Only a small number of patients had no response at all across both diseases and treatments.
The sustained duration of response (this is time from when patients received their first response to treatment to the time the first response was lost) was looked at for both disease types. The results showed that PV patients treated with ruxolitinib had significantly longer lasting responses with the median time until first loss of response not being reached in this group, compared to 0.8 years with BAT. However, for ET patients treated with ruxolitinib, the median duration of response was 0.8 years compared to 2.4 years with BAT.
The starting doses of ruxolitinib for both diseases were collected. The majority of PV patients (84%) had a starting total daily dose of 20mg and the majority of ET patients (97%) had a total daily starting dose of 50mg. These were the starting doses for each disease as specified in the trial protocol. Over 5 years of treatment, patients with PV on average received a dose slightly higher than the starting dose but patients with ET quite quickly needed to reduce the total daily dose from 50mg.
The total amount of time patients were on treatment and the numbers that stopped treatment was looked at for both ET and PV patients. The median treatment (either ruxolitinib or BAT) length for PV patients was 1681 days and for ET patients this was much lower at 1235 days. Overall 54 out of 180 PV patients (30%) and 60 out of 118 ET patients (51%) stopped treatment during the course of the trial. Whilst this was similar across treatments for PV (33% vs 26% for ruxolitinib and BAT respectively), the percentage of ET patients who stopped treatment with ruxolitinib was much higher than those who stopped BAT (71% vs 24%).
The research team also looked at Progression Free Survival (PFS) and Overall Survival (OS). PFS is the time between the patient being registered to the trial to when their disease changes to a more aggressive blood cancer or the patient dies from any cause. This can be displayed as the percentage of patients who are alive and progression free at specific timepoints in the trial. The PFS for PV patients at 1 year of receiving ruxolitinib treatment was 96%, 84% at 3 years and 76% after 5 years on the trial. For PV patients receiving BAT, PFS was 95% at 1 year, 75% at 3 years and 64% at 5 years. The PFS for ET patients who were randomised to ruxolitinib at 1 year was 91%, 78% at 3 years and 55% at 5 years. For ET patients randomised to BAT, PFS was 98% at 1 year on study, 90% at 3 years and 81% at 5 years.
Overall survival was measured in the trial. Overall survival is the time between patients entering the trial and dying from any cause. Again this can be presented as the number of patients alive as specific timepoints. The results showed for PV patients treated with ruxolitinib that overall survival at 1 year was 100%, 88% at 3 years and 83% at 5 years. For BAT it was 99% at 1 year, 87% at 3 years and 75% at 5 years of treatment. Whereas ET patients treated with ruxolitinib, overall survival at 1 year was 98%, 89% at 2 years and 64% at 5 years compared to those treated with BAT where overall survival was 98% at 1 year, 96% at 2 years and 87% at 5 years.
The study collected information on patient’s quality of life by asking patients to complete questionnaires throughout their time on the trial.
For PV patients, the quality of life results showed that the baseline symptom scores for both treatments arms were quite similar. However, there was an improved total symptom score (TSS) seen in PV patients treated with ruxolitinib over BAT and significant symptom reductions were seen for fatigue, early satiety, night sweats, itching, bone pain and weight loss.
For ET patients, the overall symptom response rate during the first 12 months of treatment didn’t show much difference between the two treatment arms. However, the results did show that the average total symptom score (TSS) and specifically the score for pruritus were significantly lower for patients treated with ruxolitinib over BAT and other benefits were also seen in those treated with ruxolitinib such as improved concentration, lower anxiety / depression and better ability to perform usual activities.
The number of patients experiencing a thromboembolic or haemorrhagic event during the trial was collected as this is a significant clinical complication of the disease. A review of these events showed that for the PV patients that received ruxolitinib treatment, 12% had a haemorrhagic event and 10% had a thromboembolic event. Whereas for PV patients that received BAT, 16% of patients had a haemorrhagic event and 17% had a thromboembolic event. For patients with ET, the results showed that for those receiving ruxolitinib, 5% of patients had a haemorrhagic event and 17% had a thromboembolic event. Of ET patients that received BAT, 13% of patients had a haemorrhagic event and 13% had a thromboembolic event. The study also showed that controlling blood counts, including white cells, haematocrit and platelets in PV patients, improved event free survival (time to a thromboembolic or haemorrhagic event, disease progression of death from any cause).
In addition laboratory researchers looked at blood and bone marrow samples from patients that took part in the trial. Specific genetic changes (mutations) associated with these diseases were looked at. 95% of patients with PV and 50% of patients with ET have the JAK2V617F mutation. A further 20-25% of ET patients will have the CALR mutation. A high JAK2V617F mutant allele burden (number of cells carrying this mutation) can be related to poorer disease outcomes. The trial looked to see if treatment with ruxolitinib or BAT reduced the mutant allele burden in PV and ET patients. If the mutation became undetectable, this would be considered a complete molecular response.
The results showed that the overall mean allele burden for any mutation did not change much for ET patients receiving ruxolitinib or BAT treatment. Although 1 complete molecular response and one partial molecular response were seen for ET patients that had a JAK2V61F mutation receiving ruxolitinib treatment and 2 complete molecular responses and one partial molecular response were seen for ruxolitinib treated ET patients that had a CALR mutation.
For PV patients, the molecular results showed that patients treated with ruxolitinib had more frequent partial molecular responses, which meant that giving ruxolitinib treatment reduced the mutant allele burden by 50% or more. This was associated with important clinical benefits including achieving a complete haematological response, improved event free, progression free and overall survival and clearance of MPN stem cells. Laboratory analysis also showed that patients with additional mutations were more likely to experience events, in particular if they have a mutation called ASXL1.
How has this study helped patients and researchers?
For PV patients treated with ruxolitinib, the trial has shown for the first time an improvement in thrombosis free and event (thrombosis, haemorrhage, disease progression or death) free survival. Another new finding for PV patients was that a 50% reduction in JAKV617F allele burden occurred more frequently in patients treated with ruxolitinib and this was also associated with improved clinical benefits such as achieving a clinical response, improved progression free survival, event free survival and overall survival. The study also confirmed that ruxolitinib is safe and effective when compared to BAT in terms of haematological response.However, for patients with ET the trial results showed that whilst some symptom responses were superior with ruxolitinib treatment compared to best available therapy, no significant difference was seen in achievement of haematological response, transformation, thrombosis or haemorrhage. ET patients also had a reduced PFS with ruxolitinib compared to BAT and experienced more infections.
Overall the trial results will help researchers understand both conditions better and help determine the best way to treat these with the therapies available. The laboratory research performed in this study has aided the understanding of how ruxolitinib works in these diseases.
Are there plans for further studies?
Ruxolitinib is currently licenced for the treatment of Myelofibrosis, Graft versus Host Disease (GvHD) and second line treatment for Polycythaemia vera (PV). The University of Birmingham currently have a phase 3 trial running called the MITHRIDATE trial. MITHRIDATE will compare ruxolitinib, as a first line treatment, with best available therapy in patients with PV. At present there are no plans for further studies with ruxolitinib for ET patients.Where can I find more information about this study?
To learn about this trial, you can find more detailed information on the EU and ISRCTN registry.https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agba4yu73OCS9U-2BkKS40W1kfatiYvtk1-2B2gi1K6vKImualqfjI4EWGRCq5YsNji0bHvVxtHaMi7LBMR6nG83MXOrs-3DG91G_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YK5DrfOOPIeyRrVSUA-2BA5AFWImVqyyYFaMpWAeyoivOH9JJIFbP7qmt3ICUFmOa9bssO81SEYQdTw7HUYsdgVZEjv21gbcojqnstpoVsgaNTF-2BHYSCADfXXiptqy9-2BYirJHYs594BouFFOh-2F6RpBTmH9V6qptbkimMvgMUApOnDtQ-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C171aff7efa53401cc95708db302534f2%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638156708583002692%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=D1JGvQhXI6Epkg1oxCMiPrPTO9CFBfSd4cQKp5DaQ2A%3D&reserved=0
https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbZKm4C0TeSkP8lYcMVEmwG4YTwaCetk8J-2FDdupAaoC5tx3Mf_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YK5DrfOOPIeyRrVSUA-2BA5AF3PPnFuBWi7ezewevuj4h9D9V7mQxHbRCYtn9HA1SLO7m-2FbgfZl-2BpURc1vWfmTbJDLRG1lF3AF3lKcWHe1ZgHYruAdnFj0IfuolbRC0pfqfxqkM1sujhrilM97-2FZmkB76dH1KzPLXwdUkY0xIoNQq-2Bg-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C171aff7efa53401cc95708db302534f2%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638156708583002692%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=%2FGNGsP6thKUgRKpp8hmahItjPQaUSk3hUq2AR6vKxfg%3D&reserved=0A 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-2B3M71ppf7N9agbZ0oYz60WoglvPkqIfU1HPHTUfauCq2ZPvNtWjz0kGXSOCiSOfyPyipJY7AGHLby83CxCKkzl39Br4eiOAMc6C5-2FmwuCE-2BLHcdEySYVp46uEeCWCtHozDz09GiBHuErKItWDfaHR5jQIuwHXs2xdu6A-2Bj-2FJkZBe3hA5BTB3muto6M7k2uxLftfoXD4-2BqcLuPa-2FRAF31gqZ1SezsXvci05iw-3D_jOh_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YK5DrfOOPIeyRrVSUA-2BA5AFrsnJMaC5fJrDlbNaH5ujaLbxvOrRV4FYu56X4mT588AOebubFyyvuQ7rAyojyj7066brbUTuw7NBZfmkoRSZDzNYhNvocb19Fb7hl-2FeULI7XeWIAM4R0tg4MDbMypsRoi-2FdDNP-2BizeoFwIuZ9P5rSg-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C171aff7efa53401cc95708db302534f2%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638156708583002692%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=FONFI7WvSgLhRTgGJ8Osi9KkI9%2BshYOjsXy6i4gwRfo%3D&reserved=0REC name
North West - Liverpool Central Research Ethics Committee
REC reference
12/NW/0045
Date of REC Opinion
25 Jan 2012
REC opinion
Further Information Favourable Opinion