PHAZAR
Research type
Research Study
Full title
A phase Ib study to assess the safety and tolerability of oral Ruxolitinib in combination with 5-azacitidine in patients with advanced phase myeloproliferative neoplasms (MPN), including myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) arising from MPN.
IRAS ID
163072
Contact name
Mark Drummond
Contact email
Eudract number
2014-002563-16
Clinicaltrials.gov Identifier
CAS Number, HM1025
Duration of Study in the UK
3 years, 0 months, 0 days
Research summary
Research Summary
Myeloproliferative Neoplasms (MPNs) are uncommon diseases that in some cases will progress to an acute leukaemia which is very difficult to treat. As this often happens to older people, most patients are unsuitable for intensive chemotherapy or the potentially curative treatment option of a bone marrow transplant. Therefore, there are limited treatment options for these patients and survival is only around 6 months.
This trial will combine a treatment (ruxolitinib) that is effective at symptom control and may confer a survival advantage in myelofibrosis (an MPN) when given with azacitidine, a treatment that has proven activity in patients with some types of myelodysplastic syndrome and acute myeloid leukaemia. As these two treatments have not been used together before, the trial will consist of a dose finding component, followed by the recruitment of an additional 10 patients at the maximum dose that is found to be safe and tolerable.
Side-effects are anticipated to be similar to those experienced with these treatments used alone. In particular, low blood counts and infections are potential risks although measures to reduce these risks will be taken.
In addition to patients recruited to receive trial treatment, the study will also recruit patients with these diseases who do not want to receive the trial treatment and monitor them for outcome.
Summary of Results
Purpose of the study: To establish the maximum tolerated dose (MTD) of the combination of two drugs called azacitidine and ruxolitinib in patients with accelerated phase (AP) or blast phase (BP) myeloproliferative neoplasms (MPNs). The study also investigated the clinical activity of the combination and collected data on outcome and treatment in a separate group of patients who did not receive trial treatment (an observational component).
What was tested: All patients in the interventional component received ruxolitinib and azacitidine. However the dose of ruxolitinib increased as the study progressed and safety data (adverse events) could be evaluated. Each patient’s response to treatment was also assessed during the study by looking at their bone marrow samples every 3 cycles of treatment.People taking part: 58 patients took part in this trial, recruited between February 2016 and August 2020. This included 34 patients in the interventional component and 24 patients in the observational component.
Results: This trial found that the highest dose ruxolitinib (25mg twice daily) tested in combination with azacitidine could be safely given to patients with accelerated or blast phase MPNs. Clinically meaningful responses were seen but unfortunately most patients did not experience prolonged survival.
Safety: In this study, researchers did not find any new safety concerns with the use of the trial drugs. Patients receiving ruxolitinib and azacitidine were however more likely to experience infections and changes in the number of their blood cells.
Who sponsored this study?
This study was sponsored by the University of Birmingham. The PHAZAR trials office can be contacted via phazar@trials.bham.ac.uk.General Information about the trial
The study took place in the United Kingdom only. Recruitment began in February 2016 and ended in August 2020. The trial closed on 18th August 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 assess the safety of ruxolitinib in combination with azacitidine and investigate the clinical activity of this drug combination (the interventional component). The trial also recruited an observational group of patients who did not receive the trial treatment with the aim of understanding what treatment they did receive, their outcomes and quality of life.
The main trial outcome for the interventional component was to find the MTD of ruxolitinib when combined with azacitidine. This was achieved by monitoring the patients for certain side effects during their first cycle of treatment. The study also investigated if patients’ disease improved by looking at how many patients achieved a complete or partial response following 3 or 6 cycles of treatment. Patients receiving a clinical benefit after 6 cycles of treatment had the option to continue trial treatment for as long as this benefit was maintained.
The trial also investigated changes in the patients requirement for red blood cell or platelet transfusions, changes in the size of the patient’s spleen or liver, how long any responses patients achieved lasted for, how long patients remained on treatment, improvements in blood counts, quality of life and overall and progression free survival.What patients were included in this study?
This trial included patients with a prior diagnosis of myelofibrosis, Polycythaemia Vera or Essential Thrombocythemia (all MPNs) whose disease had progressed to a more aggressive blood cancer similar to myelodysplastic syndrome (MPN-AP) and acute myeloid leukaemia (MPN-BP).
The trial was open to men and women aged 16 or over.In addition, for the interventional component, 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 interventional component if they had certain heart conditions or other co-morbidities that could affect their participation or if they had an active infection needing treatment. They were also not able to participate if they had already received treatment for MDS or AML or if they had taken certain therapies within 1-4 weeks of registration. Patients also could not have received any prior treatment with ruxolitinib or azacitidine.
Which medicines were studied?
Patients on this trial all received the combination of ruxolitinib and azacitidine. 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. Azacitidine is a type of drug called a hypomethylating agent. It works by switching off a protein called DNA methyltransferase. This switches on genes that stop the cancer cells growing and dividing. This reduces the number of abnormal blood cells and helps to control cell growth.
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.
85 SAEs were reported for this study within 30 patients who started trial treatment. Of these events, 4 were reported in 3 patients allocated to receive 10mg bd (twice daily) of ruxolitinib, 5 were reported in 3 patients allocated to receive 15mg bd of ruxolitinib, 14 were reported in 4 patients allocated to receive 20mg bd of ruxolitinib and 62 were reported in 20 patients allocated to receive 25mg bd of ruxolitinib.Of the 85 SAEs, 40 were considered related to trial therapy and 45 were unrelated events.
The highest number of SAEs were reported for febrile neutropenia (17 events in 17 patients). The other most common SAEs (number of events) were sepsis (7 events), fever (6 events), lung infection (3 events) and abdominal pain (3 events).
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 there were 639 AEs reports in the 31 patients who started treatment. Of these events, 27 were reported in 3 patients allocated to 10mg bd of ruxolitinib, 80 were reported in 3 patients allocated to 15mg bd, 79 were reported in 4 patients allocated to 20mg bd and 453 were reported in 21 patients allocated to 25mg bd.
Of the 639 events, 137 (21%) were reported to be grade 3 (severe or medically significant) or above, reported in 26 (84%) of the 31 patients that reported having experienced at least one adverse event.
The highest number of AEs were reported for vomiting, nausea, constipation, dyspnoea, diarrhoea, neutrophil count decreased, injection site reaction, febrile neutropenia and anaemia.
What were the overall results of the study?
The main aim of the trial was to discover the maximum dose of ruxolitinib that could be safely taken with azacitidine in patients with MPN-AP and MPN-BP. The study included groups of patients who took 10 mg bd, 15mg bd, 20mg bd and 25mg bd. The study showed that patients could take 25mg bd alongside azacitidine without an unacceptable level of side effects. It was therefore concluded that 25mg bd is the maximum tolerated dose of ruxolitinib when used in combination with azacitidine in this patient group.
Another key aim of the study was to assess how many patients’ disease improved (responded) with the combination treatment. This was assessed following a bone marrow biopsy at the end of every 3 cycles of treatment. 9/31 patients did not reach this assessment point due to death, disease progression or withdrawal of consent.
Of the patients who were able to reach the end of 3 cycles of treatment and have a bone marrow to assess their disease, 8 patients had some level of response, 9 had stable disease and 3 had disease progression. 2 were not evaluable following assessment.
Following 6 cycles of treatment, 14 patients were able to have a bone marrow assessment. 5 had some level of response, 5 had stable disease, 2 had disease progression and 2 were not evaluable.
The duration of response (this is time from when patients received their first response to treatment to the time the first response was lost) was evaluated. The results showed that the average duration of response (for patients who did achieve a response) was 7.2 months.
The total amount of time patients were on treatment and the numbers that stopped treatment were analysed. The average treatment length was 3.7 months and 20 patients (65%) stopped treatment before the end of 6 cycles.Patients with MPN-AP and MPN-BP often need to have regular transfusions of red blood cells or platelets due to the impact of their disease on the natural production of blood cells. The trial investigated if the treatments helped patients achieve transfusion independence, i.e. not be as reliant on transfusions of red blood cells or platelets compared to when they entered the trial. Unfortunately, very few patients who were transfusion dependant at the start of the trial became transfusion independent.
Patient blood count data was collected frequently during the trial to look for any clinically meaningful improvements in haemoglobin or platelet count. The results showed that both haemoglobin and platelet count decreased over time. This was not unexpected as both the disease and the treatments given cause low blood counts.
Whilst the study did aim to look at changes in the size of patients spleens and livers, as these are often enlarged due to their disease, only a small number of patients had a palpable liver or spleen so the researchers could not draw any conclusions here.
The research team also looked at Progression Free Survival (PFS) and Overall Survival (OS) at 12 months following registration. 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 12 months following registration. As we would expect MPN-AP and MPN-BP to progress at different rates, these two groups were looked at separately. As The PFS at 1 year was 42% for MPN-AP was and 26% for MPN-BP.
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 at 12 months. The results showed that overall survival at 1 year was 42%. The majority of patients died from their disease.
The study also collected information on patient’s quality of life by asking patients to complete questionnaires throughout their time on the trial.
For patients in the interventional component, the quality of life results showed a slight trend to improvement over time. However, the number of patients completing questionnaires decreased during the course of the trial due to patients dropping out as a result of death or disease progression.
In the observational component, the study collected information on what treatments patients received and their outcomes as well as quality of life.
Patients received a range of treatments including high intensity chemotherapy, stem cell transplant and lower intensity treatments. The study confirmed the approach to treating MPN-AP and MPN-BP is highly variable.
5 patients experienced a response to standard treatment, 8 were non-responders and an evaluation of response was not available for 11 patients.
Patient reported quality of life scores remained very similar over the course of the trial.
How has this study helped patients and researchers?
PHAZAR showed that ruxolitinib and azacitidine can be safely given to patients with MPN-AP and MPN-BP. Some patients did see an improvement in their disease but this effect was not long term and did not increase their survival. The results did suggest that treating earlier in the disease course, i.e. before the leukaemia is too advanced, when patients were in ‘accelerated phase’, increased the chance of achieving a response. Not all patients could receive the treatment as planned as a complication of giving these two treatments together is the effect on the patients’ blood counts, which are already low due to their disease, and in some cases this delayed or prevented the treatment being given.The associated biological sample collection provided novel insights into the biology of these conditions. A pattern of genetic mutations was found that can help predict if patients are more likely to have a worse outcome. This could help put future patients into risk groups and develop targeted treatments.
Collecting data from the observational component has given researchers more information about how these patients are treated and will support the planning of future trials.
Overall the trial results have helped researchers understand these conditions better and will help determine the best way to treat them with the therapies available.
Are there plans for further studies?
Yes, the trial Sponsor is actively seeking funding for a follow-on study. Whilst the drug combination used in PHAZAR was found to be safe with clinically meaningful responses, most patients died within the first year of the study and treatment administration was hampered due to drug induced low blood counts alongside disease progression. The follow-on study will use a next generation JAK inhibitor which does not induce the same level of reductions in blood counts, and an oral hypomethylating agent making this study potentially more attractive to patients and easier to deliver. This future study will also include patients slightly earlier in their disease course than PHAZAR to see if this can improve their outcomes.
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-2B3M71ppf7N9agbZKm4C0TeSkP8lYcMVEmwG7rKY0DMPXiXpLn9c7xtQM0DOmG_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIYgs8iA-2FTLJ2pVnglRlBQs34oagKI-2FhZ02uWXrH2xTZxKCc-2BHgrY3psEfzSezFLtozh0Q9A-2FQYXSUSWroRoqnktH0DgbWUU9tgMdNbz-2BYiypDISIu34wtNb2Am9PxKsO9OPTqIwYlRUKly9DLMnouEMcwnzGlW0Iff-2By2nzuxwmQ-3D-3D&data=05%7C01%7Cedgbaston.rec%40hra.nhs.uk%7C5639aaf4d8d24962a3a808db9f2c65f9%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638278785256843729%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=1AiuBSVR8dxGjdWUfAOGuTwCC9o1HaEDmqr3Y9N4ocA%3D&reserved=0
A 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-2B3M71ppf7N9agbZ0oYz60WoglvPkqIfU1HPHTUfauCq2ZPvNtWjz0kGXSOCiSOfyPyipJY7AGHLby83CxCKkzl39Br4eiOAMc6C7xAZli6pF3DZPCsh2wt7mh2ENmfiql5r8WHIiUtZ-2Bp4VRyCt1uZgcqGQikBxtcus6gRa1OOOnf85L5-2BOYbT2Lh2NEIZqQ7fsKMAdnOB6uiDLKmULCZ-2FfHE7THJziBbXKA-3D1ZO__E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIYgs8iA-2FTLJ2pVnglRlBQsU8-2FnK9J7XCDIH23JEHi3sSReAsDos77mcoEFSwlWj79nJqiP32p6J4-2FHhzKyA3fH8VSFsTeQ9ByO0y5lAecvXU0Z22ppStC-2F1f3d9t5i9ulNnyys7vT9VB-2FZzEKWOLq2dOv7Q0SzHbXefNgqpwfQGQ-3D-3D&data=05%7C01%7Cedgbaston.rec%40hra.nhs.uk%7C5639aaf4d8d24962a3a808db9f2c65f9%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638278785256843729%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=%2B6hEMJC4IaG9eEz5tcgfeFiMIAEPC0ijAzNklHtd%2Bj0%3D&reserved=0REC name
West Midlands - Edgbaston Research Ethics Committee
REC reference
14/WM/1260
Date of REC Opinion
19 Jan 2015
REC opinion
Further Information Favourable Opinion