TAMARIN
Research type
Research Study
Full title
Effects of TAMoxifen on the Mutant Allele Burden and Disease Course in Patients with MyeloprolifeRatIve Neoplasms
IRAS ID
201126
Contact name
Sean Jennings
Contact email
Sponsor organisation
University of Birmingham
Eudract number
2015-005497-38
Duration of Study in the UK
1 years, 7 months, 3 days
Research summary
Research Summary:
Myeloproliferative neoplasms (MPNs) are blood cancers which affect the normal production of blood cells from the bone marrow. They are caused by changes (mutations) in blood stem cells, frequently in the genes that produce proteins called JAK2, CALR or MPL. MPNs have a risk of developing to an acute leukaemia (a more advanced stage of disease) and currently has no effective cure, apart from bone marrow transplantation which is not possible for many patients.
Recent work in mouse studies has suggested that tamoxifen, a drug widely used to treatment breast cancer, may reduce the number of mutated cells by mimicking oestrogen (a female sex hormone) which has a role in the survival and production of new stem cells that give rise to blood cancers. In these studies, tamoxifen prevented the excessive production of blood cells by restoring normal levels of cell death in the mutated cells.
This is a single arm, multicentre phase II trial designed to assess if adding tamoxifen to patients receiving therapy for their MPN reduces the number of mutated cells found in the blood by ≥ 50% after 24 weeks of treatment compared to the start of the study. Collection of blood and bone marrow samples will also allow laboratory researchers to study the biological effects of tamoxifen and how this correlates with the patient’s disease and response to therapy.
Patients will receive treatment with 20mg once daily (oral tablet) of tamoxifen with their normal therapy for their MPN.
42 patients will be recruited from 13-15 UK centres over 12 months.Summary of Results:
Trial name
TAMARIN- Effects of Tamoxifen on the Mutant Allele Burden and Disease Course in Patients with Myeloproliferative Neoplasms (MPN) Protocol number: RG_15-234 EU Trial number: 2015-005497-38 Abstract Purpose of the study: To see if tamoxifen helps to reduce the number of cells carrying genetic changes (mutations) in patients with myeloproliferative neoplasms (MPN).
What was tested: In this phase 2 study, participants received tamoxifen alongside their usual treatment for MPN to see if adding tamoxifen helped to reduce the number of cells carrying certain mutations (the mutant allele burden). In a phase 2 study, a comparison can be made with a smaller number of patients to see if it’s worthwhile doing a larger trial.
People taking part: 38 adults (27 males and 11 females) with MPN in the United Kingdom took part and were recruited over approximately 118 weeks. The patients had different types of MPN; 14 had Essential Thrombocythaemia (ET), 11 had Polycythaemia Vera (PV) and 13 had Myelofibrosis (MF).
Results: All patients received trial treatment for the expected time of 24 weeks. Adding tamoxifen to these patient’s usual treatment for MPN was successful in reducing the number of cells carrying mutations in 8 patients (more pronouncedly in 3), and was well tolerated. Analysis of patients’ hematopoietic stem and progenitor cells (HSPCs) (the cells that develop into blood cells) prior to their treatment showed differences between patients that responded to tamoxifen and those that didn’t. This suggests that it may be possible to identify MPN patients who are likely to respond to tamoxifen treatment before they start treatment and supports further investigation.
Safety: In this study, researchers found that there were no safety concerns over the use of tamoxifen.
Who sponsored this study?
This study was sponsored by the University of Birmingham. The TAMARIN trials office can be contacted via TAMARIN@trials.bham.ac.uk.General Information about the trial
The study took place in the United Kingdom only. Recruitment began in August 2016 and ended in June 2019. The trial closed in February 2021 when all patients had stopped trial treatment and all data had been collected.The main objective of the study was to test if taking tamoxifen alongside the usual treatment for MPN would reduce the mutant allele burden after 24 weeks. Many people with MPNs have mutations to certain genes found in cells responsible for blood cells generation (hematopoietic stem and progenitor cells, known as HSPC). These are the JAK2 gene and the CALR gene. The JAK 2 gene makes a protein that controls how many blood cells are made, and the CALR gene produces a protein which influences what other proteins are made in the blood cell.
Most treatments for MPN aim to control the number of blood cells in the blood. This reduces the risk of blood clots and bleeding and helps with symptoms such as pain. However, previous laboratory studies have shown that tamoxifen can also reduce numbers of abnormal blood cells by inhibiting their uncontrolled production in the bone marrow (especially those with JAK2 and CALR mutations).
The TAMARIN trial aimed to see whether tamoxifen (which is a relatively cheap, widely available drug, with well-documented safety information) added to current therapies could be a suitable treatment to reduce numbers of abnormal cells associated with the disease and reduce risks of blood clots (thrombosis) and bleeding (haemorrhage).What patients were included in this study?
This trial included patients with a confirmed diagnosis of MPN for 6 months or more. To enter the study, patients had to have certain mutations (JAK2-V617F, CALR 5bp insertion (exon 9) or CALR 52bp deletion (exon 9)) in at least 20% of their peripheral blood granulocyte DNA (the DNA from a type of white blood cell in the blood that circulates through the body). The number of cells carrying these mutations is called the mutant allele burden. Patients must had had stable disease when having cytoreductive therapy (treatment to reduce the risk of haemorrhage/ bleeding).
The trial was open to men and women aged 60 years or more. Of the patients who took part in the study 71% were male and 29% were female.All patients had to have adequate liver and kidney function and be able to give informed consent to participate. They also needed to agree to use effective contraception during the trial.
Patients were excluded from participation if they had had any new treatments for their MPN within 6 months of joining the trial; similarly patients with MF were excluded if the disease had progressed in the past 6 months.
Patients with any history of thrombotic events, hypertriglyceridemia above grade 1, endometrial cancer, hyperplasia, polyps, any malignancy within the past 5 years or any other serious underlying medical condition were also unable to participate. Patients who had a known allergy to tamoxifen or were taking any other drug that should not be taken with tamoxifen were also excluded from the trial.
Female patients had to be post-menopausal at trial entry and were excluded if they were receiving hormone replacement therapy.Which medicines were studied?
Patients continuously received a dose of tamoxifen once a day for the duration of the trial. Tamoxifen is a type of drug called a nonsteroidal agent. It is a selective oestrogen receptor modulator (SERM) that binds to oestrogen receptors. In breast cancer, the prolonged binding of tamoxifen to these receptors blocks oestrogen from attaching to them to stop the cancer cells growing and dividing. In laboratory studies, tamoxifen selectively killed mutated HSPCs but not normal HSPCs, which reduced the number of abnormal blood cells.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. 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 are classes as an SAE. 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.
Four SAEs were reported: one unrelated Grade 3 urinary tract infection, one unrelated Grade 1 intracranial haemorrhage and two vascular disorders, both potentially related to tamoxifen treatment (one superficial thrombophlebitis and one thromboembolic event). These two thrombotic events occurred patients that didn’t respond to tamoxifen treatment (non-responders). There were no deaths reported.
The 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. Pre-existing symptoms present prior to commencing trial treatment were only be reported as an AE if they increase in grade. Grades increase from 1 (least) to 4 (most) to measure seriousness of the event.Throughout the trial there were 205 AEs. Of these there were 162 grade 1 events, 41 grade 2 events, and two grade 3 events. 66 of these events were potentially related to tamoxifen.
What were the overall results of the study?
Overall, this study found that adding tamoxifen to the patient’s usual treatment for MPN was successful in reducing the mutant allele burden (number of cells carrying JAK2V617F or CALR mutations) in a subset of patients, and supports further investigation.
Most drugs currently used in MPN have a limited effect on mutant allele burden. For this reason, a 50% reduction in JAK2V617F or CALR mutated peripheral blood cells was investigated for the TAMARIN study.
For three patients in the TAMARIN trial, adding tamoxifen to their usual MPN treatment reduced the mutant allele burden by 50% or more, achieving the response needed for success. Five additional patients’ mutant allele burden was reduced by 25% or more, which further suggests that tamoxifen can reduce the number of mutated HSPCs in some MPN patients. One patient had a reduced allele burden by 50% or more after 12 weeks on Tamoxifen, but this was not continued at 24 weeks. A total of six patients remained on trial treatment beyond 48 weeks as they were thought to be experiencing a benefit from the treatment.
Analysis was carried out on patients’ HSPCs collected before they started treatment to compare patients who showed a reduction in allele burden after having tamoxifen treatment (responders) and those who didn’t (non-responders). A clear difference in molecular events was discovered in HSPCs from responders and non-responders. Therefore, researchers found it may be possible to predict which patients would be responders, and who would not respond to tamoxifen treatment, based on this analysis. This opens up the possibility of screening patients prior to their treatment to see if they are likely to respond before they begin treatment.
Using peripheral blood samples collected from patients on the TAMARIN study and cell lines (cells with JAK2 mutation that can be propagated in a laboratory), researchers studied the mechanism of action of tamoxifen in selectively reducing mutant allele burden. They discovered that tamoxifen may be able to regulate stress responses in cells and reduce mitochondrial respiration (the process within cells where energy from oxygen and nutrients is converted to form called ATP that can be used by the cell) to cause mutant-only cell death. They also discovered that tamoxifen inhibits a type of signalling pathway (JAK-STAT signalling) that protects mutant HSPCs from cell death. This signalling pathway is highly active in mutant HSPCs of MPN patients. Through a variety of analysis and experiments on HSPCs collected from TAMARIN participants and from cell lines, researchers concluded that tamoxifen is able to selectively target mutant HSPCs with highly active JAK-STAT signalling by inhibiting energy (in the form of ATP) in these cells causing the cell to die, which may explain why patients with very active JAK-STAT signalling pathways in their HSPCs responded well to tamoxifen treatment.
All three patients who had a 50% or more reduction and three further patients who had a 25% or more reduction in allele burden at 24 weeks had the JAK2V617F mutation (which results in high expression of JAK-STAT signalling). Two other patients who had a 25% or more reduction at 24 weeks had CALR mutations. These mutations also require increased JAK-STAT signalling in order to cause disease.To conclude, the study demonstrated the safety and activity of tamoxifen in reducing the mutant allele burden in a subset of MPN patients who could potentially be identified by a blood test (to screen for certain mutations in their HSPCs) before receiving the treatment. This test could serve to select the type of treatment and provide SERMs, such as tamoxifen, only to patients who are likely to respond (=reduce their tumour size). In addition, the study highlights a possible role for other SERMs in autoimmune diseases that are also dependant on JAK-STAT signalling.
How has this study helped patients and researchers?
The trial met its primary outcome and has confirmed that tamoxifen is able to reduce mutant allele burden in a certain subset of MPN patients. It also identified that patients with specific mutations were more likely to respond to the drug.The trial found that tamoxifen administration was safe and non-toxic. Two thrombotic events were experienced in the study which were possibly related to the treatment and so caution is advised when weighing up the possible benefit of reducing the mutant allele burden against the risk of thrombosis. Thrombotic events only occurred in non-responders, therefore the selection of prospective responders based on their genes might help reduce the risk of thrombosis in future studies.
Are there plans for further studies?
These results advocate for future clinical studies to test the effects of other SERMs in MPN, with careful consideration of thrombotic risk. Additionally, the results of this study could be used to inform approaches for other diseases where JAK-STAT signalling is involved.Where can I find more information about this study?
To learn about this study, you can find more detailed information on the EU database.https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Furl6570.hra.nhs.uk%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agba4yu73OCS9U-2BkKS40W1kfatiYvtk1-2B2gi1K6vKImualuEvGXLTaqyGguvvPB7GX2G-2BOvKylFDvjfYqf-2BPhUNUs-3DjKpV_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YJcCX1ddBTsVpnJn7XD5DfP4E33rE2CIYaQoHHIID2It6iRaCmAtdOY34mmmt9SaSW4TSbAVR94ZsJhWMSZELa81RfJJmq-2FGg53iNOFXa-2BHqnLizkmPWfOaqr-2BQfRHxX020eQXIJStPzhz8NelhyAn8HM1t4q5jEvPboBx-2FPGFFGg-3D-3D&data=04%7C01%7Capprovals%40hra.nhs.uk%7Cc5a554dfea5a4816397e08d9f09382d7%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637805338659108942%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=iXHg3J9UzGdQcjmlN%2BEgTC3Cv0A8dxXZePpfKKDd6Ns%3D&reserved=0
A summary is also provided on the Cancer Research UK website.
https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Furl6570.hra.nhs.uk%2Fls%2Fclick%3Fupn%3DouFFm-2FZqrUn2jjUD5TieZEUmTPTEIQDKfOR7z73qrtHZ-2FrBXIgBav0pNlbbn3XznTSPh5uYukRqenp0pRCAz1SeTry2UAzEo4cWqJF9PL6bcuvxyMpvv9CquCkSDgvK6rC57X5rCW-2Bw-2FfwpwLt-2Bpz358y-2FDMn02X5xoGQjzU1bOhRMXpxzHH3emSAiiV59uIsLXloXDtm7u7663wEUKqHg-3D-3DCK-R_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YJcCX1ddBTsVpnJn7XD5DfPG1GSMvst-2Foabj6tHODR-2Fq-2FDTRLLvWEkEhB2F18uNUMMhDA6ghbx-2F3gFSisZ3VgZhHLYJjNmE-2FHSjYcR2lVwmfK6S-2F0rbEnrDnnIp9xs1lSiI-2FR60zWqg9lia-2F4CmrGuiyJjOYfz2fi5PNl5uuLEcQA-3D-3D&data=04%7C01%7Capprovals%40hra.nhs.uk%7Cc5a554dfea5a4816397e08d9f09382d7%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637805338659108942%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=aQRAD3UbeNvxeiRUbtri9oBh9wOgkZEuEyhLKs9Ua3E%3D&reserved=0
REC name
East Midlands - Derby Research Ethics Committee
REC reference
16/EM/0181
Date of REC Opinion
24 May 2016
REC opinion
Further Information Favourable Opinion