Effects of tamoxifen in patients with myeloproliferatIve disorders

ISRCTN	ISRCTN65011803
DOI	https://doi.org/10.1186/ISRCTN65011803
Clinical Trials Information System (CTIS)	2015-005497-38
Protocol serial number	30849
Sponsor	University of Birmingham
Funder	Bloodwise TAP

Submission date: 13/06/2016
Registration date: 20/06/2016
Last edited: 29/10/2024

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-looking-at-tamoxifen-for-people-with-myeloproliferative-disorders-tamarin

Contact information

Mrs Sonia Fox
Public

Cancer Research UK Clinical Trials Unit
Centre for Clinical Haematology
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom

Study information

Primary study design	Interventional
Study design	Non-randomised; Interventional; Design type: Treatment, Drug
Secondary study design	Non randomised study
Study type	Participant information sheet
Scientific title	Effects of TAMoxifen on the Mutant Allele Burden and Disease Course in Patients with MyeloprolifeRatIve Neoplasms
Study acronym	TAMARIN
Study objectives	The aim of this study is to assess whether giving 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.
Ethics approval(s)	East Midlands – Derby Research Ethics Committee, 24/05/2016, ref: 16/EM/0181
Health condition(s) or problem(s) studied	MyeloproliferatIve neoplasms
Intervention	Patients who consent to participate in the study will need to attend hospital at baseline to receive a medical exam (including palpation of the liver and spleen), blood tests (including a full fasting lipid profile), an abdominal ultrasound if they have PV or ET and a blood sample taken for central review at Cambridge Blood and Stem Cell Biobank to ensure that they are eligible for the trial and that it is safe for them to enter the trial. Patients will also be asked to complete a short Quality of Life questionnaire which has been developed specifically for patients with MPNs. Once registered to the study, patients will have a minimum of 24 weeks of treatment with tamoxifen at 20mg od as an oral tablet. Patients will be seen 2 weeks after starting treatment for blood tests and a medical exam and then again at weeks 4, 8, 12, 18 and 24. At weeks 12 and 24 they will also have a blood sample taken for central review at Cambridge and a full fasting lipid profile. At week 24, the patient will also be asked to have a bone marrow aspirate and trephine biopsy and complete the same Quality of Life Questionnaire they completed at baseline. If the patient had an enlarged spleen on the baseline ultrasound, an ultrasound may be repeated at any point during the 24 weeks if the blood counts suggest the patient is in Complete Response. If the patient continues trial therapy beyond 24 weeks, they will be seen a minimum of 12 weekly for blood tests and a medical exam. Patients will also be required to attend their local hospital 28 days after the final dose of tamoxifen for blood tests and a medical exam.
Intervention type	Drug
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Tamoxifen
Primary outcome measure(s)	Primary outcome measures as of 19/11/2018: Reduction in the peripheral blood JAK2V617F, CALR 5bp insertion (exon 9) or CALR 52bp deletion (exon 9) mutant allele burden of ≥50% at 24 weeks measured using validated assays for JAK2 and CALR. Primary outcomes as of 27/06/2017: Reduction in the peripheral blood JAK2V617F, CALR 5bp insertion (exon 9) or CALR 52bp deletion (exon 9) mutant allele burden of ≥50% is measured using validated assays for JAK2 and CALR respectively at baseline and 24 weeks. Previous primary outcomes: Peripheral blood JAK2V617F or CALR mutant allele burden is measured using validated assays for JAK2V617F and CALR respectively at baseline and 24 weeks.
Key secondary outcome measure(s)	Secondary outcome measures as of 19/11/2018: 1. Proportion of patients with a reduction in the peripheral blood JAK2-V617F, CALR 5bp insertion (exon 9), or CALR 52bp deletion (exon 9) mutant allele burden of ≥50% at 12 weeks 2. Toxicity measured as the number of grade 3 and 4 adverse events reported. 3. The number of thrombotic events of any grade reported and validated. 4. Duration of haematological response calculated as time from registration to progression for patients who enter the study in response (CR or PR). For patients who enter the trial in stable disease, the time between first recorded response to the date of progression. Progression is defined as loss of response for PV/ET patients and evidence of disease progression for MF patients. PV/ET patients who continue to achieve a response, or MF patients who have no evidence of disease progression at the end of the trial will be censored at date last seen. Haematological response is defined according to 2009 ELN criteria for ET/PV patients [1] and no evidence of disease progression for MF patients according to IWG-MRT response criteria [2] (for criteria see Appendices 5 & 6) 5. Proportion of patients in each response category according to IWG-MRT response criteria [2] for MF patients and 2013 ELN response criteria [3] for ET/PV patients at 24 weeks of treatment 6. Proportion of patients showing an improvement in response category at 24 weeks compared to baseline according to 2009 ELN criteria for ET/PV patients [1] and according to IWG-MRT response criteria [2] for MF patients. Patients who are in a higher category at week 24 compared to baseline will be classed a success. Patients who enter the trial in CR and who maintain a CR will also be classed as a success in this outcome Exploratory Outcome Measures: 1. Change in allele burden between weeks 12, 24 and baseline. 2. Proportion of patients showing a decrease in requirement for cytoreduction at 24 weeks compared to baseline 3. Proportion of patients showing a decrease in allele burden of ≥50% at 36 and 48 weeks compared to baseline 4. Duration of reduction in the mutant allele burden, defined as time from first observed reduction of ≥50% until reduction from baseline becomes <25% or patients death. 5. Expression (RNAseq), DNA-protein interaction (ChipSeq) and methylation studies focused on oestrogen receptor signalling in haematopoietic progenitors obtained from peripheral blood and bone marrow before (peripheral blood only) and after tamoxifen treatment Secondary outcome measures as of 27/06/2017: 1. Proportion of patients with a reduction in the peripheral blood JAK2-V617F, CALR 5bp insertion (exon 9), or CALR 52bp deletion (exon 9) mutant allele burden of ≥50% is measured using validated assays for JAK2 and CALR respectively at baseline and 12 weeks 2. Toxicity measured as the number of grade 3 and 4 adverse events reported according to CTCAE for the duration of treatment and including 4 weeks after the last administration of trial treatment. 3. The number of thrombotic events of any grade reported and validated, according to CTCAE for the duration of treatment and including 4 weeks after the last administration of trial treatment 4. Duration of haematological response will be assessed by the local investigator at baseline and after two, four, eight, 12, 18 and 24 weeks of treatment according to 2009 ELN criteria for ET/PV patients and to IWG-MRT response criteria for MF patients 5. Proportion of patients in each response category according to IWG-MRT response criteria for MF patients and 2013 ELN response criteria for ET/PV patients is assessed by the local investigator after 24 weeks of treatment 6. Proportion of patients showing an improvement in response category at 24 weeks compared to baseline according to 2009 ELN criteria for ET/PV patients and according to IWG-MRT response criteria for MF patients is assessed by the local investigator after 24 weeks of treatment compared to baseline Exploratory outcome measures: 1. Proportion of patients showing a decrease in JAK2-V617F, CALR 5bp insertion (exon 9), or CALR 52bp deletion (exon 9) allele burden is measured using validated assays for JAK2 and CALR respectively at baseline and 12 weeks 2. Proportion of patients showing a decrease in JAK2-V617F, CALR 5bp insertion (exon 9), or CALR 52bp deletion (exon 9) allele burden is measured using validated assays for JAK2 and CALR respectively at baseline and 24 weeks 3. Proportion of patients showing a decrease in requirement for cytoreduction as reported by the local investigator at baseline and 24 weeks 4. The expression (RNAseq), DNA-protein interaction (CHIP-Seq) and methylation studies focused on oestrogen receptor signalling in haematopoietic progenitors will be performed in the lab of Dr Mendez-Ferrer at the University of Cambridge following the collection of peripheral blood (baseline and 24 weeks) and bone marrow aspirate samples (24 weeks only) Previous secondary outcome measures: 1. Peripheral blood JAK2V617F or CALR mutant allele burden is measured using validated assays for JAK2V617F and CALR respectively at baseline and 12 weeks 2. Peripheral blood JAK2V617F or CALR mutant allele burden is measured using validated assays for JAK2V617F and CALR respectively at baseline and 24 weeks 3. Peripheral blood JAK2V617F or CALR mutant allele burden is measured using validated assays for JAK2V617F and CALR respectively at baseline and 12 weeks 4. Toxicity measured as the number of grade 3 and 4 adverse events reported according to CTCAE for the duration of treatment (and including 4 weeks after the last administration of trial treatment). 5. Thrombotic events of any grade reported according to CTCAE for the duration of treatment (and including 4 weeks after the last administration of trial treatment) 6. Duration of haematological response calculated as time from registration to loss of response for PV/ET patients or evidence of disease progression for MF patients. PV/ET patients who continue to achieve a response, or MF patients who have no evidence of disease progression at the end of the trial will be censored at date last seen 7. Response according to IWG-MRT response criteria for MF and 2013 ELN response for ET/PV measured at 24 weeks
Completion date	17/02/2021

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	All
Target sample size at registration	42
Total final enrolment	38
Key inclusion criteria	Current inclusion criteria as of 27/06/2017: 1. Age ≥ 60 years (men aged between 50-59 may also be considered following discussion with the Chief Investigator) 2. Women must be post-menopausal (defined as amenorrhoeic for at least 12 consecutive months following cessation of all exogenous hormonal treatments) 3. Confirmed diagnosis of JAK2-V617F,CALR 5bp insertion (exon 9) or CALR 52bp deletion (exon 9) positive Essential Thrombocythaemia (ET), Polycythaemia Vera (PV) or Myelofibrosis (MF) (primary or secondary) for ≥ 6 months 4. JAK2-V617F, CALR 5bp insertion (exon 9) or CALR 52bp deletion (exon 9) mutant allele burden ≥ 20% in peripheral blood granulocyte DNA at study entry (assessed via central review) 5. WHO performance status 0-2 6. For patients with PV or ET, maintenance of platelet count ≤600 x 109/L, WBC ≤25 x 109/L and venesection requirements ≤1 per month for the previous 3 months prior to registration, without introduction of any new therapeutic agents for their MPN for 6 months prior to registration 7. For patients with MF, there must not have been any evidence of disease progression* for the previous 6 months (prior to registration) and no new therapeutic agents for their MPN introduced during this period 8. Patients receiving cytoreductive therapy (with the exception of interferon alpha or investigational agents) for their MPN (not solely aspirin or venesection) 9. Adequate hepatic function, defined as: 9.1. bilirubin ≤ 1.5 x ULN (patients with elevated bilirubin due to Gilbert’s syndrome are eligible) 9.2.AST/ALT/ALP ≤ 2.5 x ULN 10. Adequate renal function (creatinine clearance >30 mL/min) 11. Male patients must agree to use effective contraception during participation in the trial and for 2 months after the last dose of trial treatment 12. Patient must be able to give written informed consent Defined by IWG-MRT ELN criteria. Please note no baseline bone marrow is required to confirm absence of “Leukemic transformation confirmed by a bone marrow blast count of ≥20%”. Previous inclusion criteria: 1. Age ≥ 60 years (men aged between 50-59 may also be considered following discussion with the Chief Investigator) 2. Women must be post-menopausal (defined as amenorrhoeic for at least 12 consecutive months following cessation of all exogenous hormonal treatments) 3. Confirmed diagnosis of JAK2-V617F or CALR positive Essential Thrombocythaemia (ET), Polycythaemia Vera (PV) or Myelofibrosis (MF) (primary or secondary) for ≥ 6 months 4. JAK2-V617F or CALR mutant allele burden ≥ 20% in peripheral blood granulocyte DNA at study entry (assessed via central review) 5. WHO performance status 0-2 6. For patients with PV or ET, maintenance of at least a partial haematological response according to 2009 ELN criteria must have been achieved for the previous 6 months (prior to registration), without introduction of any new therapeutic agents for their MPN 7. For patients with MF, there must not have been any evidence of disease progression for the previous 6 months (prior to registration) and no new therapeutic agents for their MPN introduced during this period. 8. Patients receiving cytoreductive therapy for their MPN (not solely aspirin or venesection) 9. Adequate hepatic function, defined as: 9.1. bilirubin ≤ 1.5 x upper limit of normal (ULN) (patients with elevated bilirubin due to Gilbert’s syndrome are eligible) 9.2. AST/ALT/ALP ≤ 2.5 x ULN 10. Adequate renal function (creatinine clearance > 30 mL/min) 11. Male patients must agree to use effective contraception during participation in the trial and for 2 months after the last dose of trial treatment 12. Patient must be able to give written informed consent *Defined by IWG-MRT ELN criteria (Appendix 6). Please note no baseline bone marrow is required to confirm absence of “Leukemic transformation confirmed by a bone marrow blast count of ≥ 20%”
Key exclusion criteria	Current exclusion criteria as of 27/06/2017: 1. Leukaemic transformation (>20% blasts in blood, marrow or extramedullary site). 2. Accelerated phase of disease as indicated by ≥10% blasts in the peripheral blood 3. Treatment of ET, PV or MF with Interferon alpha or other investigational agents for their MPN within 6 months prior to trial entry. JAK inhibitors, such as ruxolitinib, are allowed if taken continuously for ≥6 months prior to registration (dose changes during that period will be allowed) 4. Any of the following previous thrombotic events at any time: 4.1. Portal or other splanchnic venous thrombosis 4.2. Vascular access complication 4.3. Ischemia cerebrovascular 4.4. Stroke 4.5. Transient Ischaemic attack 4.6. Superficial thrombophlebitis 4.7. Venous Thromboembolic events including pulmonary embolism (PE) and deep vein thrombosis (DVT) 4.8. Peripheral vascular ischemia 4.9. Visceral arterial ischemia 4.10. Acute coronary syndrome 4.11. Myocardial infarction 5. Previous malignancy within 5 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer 6. Previous endometrial cancer, hyperplasia or polyps 7. Prior treatment with hematopoietic stem cell transplantation 8. Patients who do not carry JAK-2V617F, CALR 5bp insertion (exon 9) or CALR 52bp deletion (exon 9) mutations, or whose allele burden is <20% at study entry (assessed via central review) 9. Female patients receiving hormone replacement therapy 10. Hypertriglyceridemia > grade 1 11. Any serious underlying medical condition (at the judgment of the Investigator), which could impair the ability of the patient to participate in the trial (e.g. liver disease, active autoimmune disease, uncontrolled diabetes, uncontrolled infection (HIV, Hepatitis B and C), known genetic defect (apart from MPN) relating to venous thromboembolic events, or psychiatric disorder precluding understanding of trial information) 12. Known hypersensitivity to tamoxifen or hypersensitivity to any other component of tamoxifen 13. Concomitant drugs contraindicated for use with the trial drug according to the Summary of Product Characteristics (Appendix 8) 14. Known planned scheduled elective surgery during study with the exception of dental and low risk eye surgery (e.g. cataracts) Previous exclusion criteria: 1. Leukaemic transformation ( > 20% blasts in blood, marrow or extramedullary site). 2. Accelerated phase of disease as indicated by > 5% blasts in the peripheral blood 3. Treatment of ET, PV or MF with Interferon alpha or JAK inhibitors, such as ruxolitinib, or other investigational agents for their MPN within 6 months prior to trial entry 4. Any of the following previous thrombotic events at any time: 4.1. Portal or other splanchnic venous thrombosis 4.2. Vascular access complication 4.3. Ischemia cerebrovascular 4.4. Stroke 4.5. Transient Ischaemic attack 4.6. Superficial thrombophlebitis 4.7. Venous Thromboembolic events including pulmonary embolism (PE) and deep vein thrombosis (DVT) 4.8. Peripheral vascular ischemia 4.9. Visceral arterial ischemia 4.10. Acute coronary syndrome 4.11. Myocardial infarction 5. Previous malignancy within 5 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer 6. Previous endometrial cancer, hyperplasia or polyps 7. Prior treatment with hematopoietic stem cell transplantation 8. Patients who do not carry any mutations in JAK2V617F or CALR or allele burden < 20% 9. Female patients receiving hormone replacement therapy 10. Hypertriglyceridemia > grade 1 11. Any serious underlying medical condition (at the judgment of the Investigator), which could impair the ability of the patient to participate in the trial (e.g. liver disease, active autoimmune disease, uncontrolled diabetes, uncontrolled infection (HIV, Hepatitis B and C), known genetic defect (apart from MPN) relating to venous thromboembolic events, or psychiatric disorder precluding understanding of trial information) 12. Known hypersensitivity to tamoxifen or hypersensitivity to any other component of tamoxifen 13. Concomitant drugs contraindicated for use with the trial drug according to the Summary of Product Characteristics 14. Known planned scheduled elective surgery during study with the exception of dental and low risk eye surgery (e.g. cataracts)
Date of first enrolment	01/08/2016
Date of final enrolment	20/06/2019

Locations

Countries of recruitment

United Kingdom
England
Northern Ireland
Scotland
Wales

Study participating centres

Addenbrooke’s Hospital

Hills Road
Cambridge
CB2 0QQ
United Kingdom

Beatson West of Scotland Cancer Centre

1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Belfast City Hospital

Lisburn Road
Belfast
BT9 7AB
United Kingdom

Birmingham Heartlands Hospital

Bordesley Green East
Birmingham
B9 5SS
United Kingdom

Churchill Hospital

Old Road
Oxford
OX3 7LJ
United Kingdom

Clatterbridge Cancer Centre

Clatterbridge Road Site
Wirral
CH63 4JY
United Kingdom

Good Hope Hospital

Rectory Road
Sutton Coldfield
B75 7RR
United Kingdom

Guy’s Hospital

Great Maze Pond
London
SE1 9RT
United Kingdom

Hammersmith Hospital

Du Cane Road
London
W12 0HS
United Kingdom

Nottingham City Hospital

City Hospital Campus
Nottingham
NG5 1PB
United Kingdom

Royal Devon and Exeter Hospital

Barrack Road
Exeter
EX2 5DW
United Kingdom

Royal Hallamshire Hospital

Glossop Road
Sheffield
S10 2JF
United Kingdom

Royal Stoke University Hospital

Newcastle Road
Stoke-on-Trent
ST4 6QG
United Kingdom

Southampton General Hospital

Tremona Road
Southampton
SO16 6YD
United Kingdom

St James’s University Hospital

Beckett Street
Leeds
LS9 7TF
United Kingdom

The Queen Elizabeth Hospital

Edgbaston
Birmingham
B15 2TH
United Kingdom

University College London Hospital

235 Euston Road
London
NW1 2BU
United Kingdom

University Hospital of Wales

Heath Park
Cardiff
CF14 4XW
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
IPD sharing plan	The data sharing plans for the current study are unknown and will be made available at a later date.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article		25/11/2023	08/08/2024	Yes	No
Abstract results	Presented at ASH	05/11/2020	15/02/2023	No	No
Basic results		15/02/2023	15/02/2023	No	No
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Protocol file	version 4.0	29/10/2018	31/01/2023	No	No

Additional files

32214 TAMARIN_Protocol_v4.0_29Oct2018.pdf: Protocol file
ISRCTN65011803_BasicResults_15Feb2023.pdf: Basic results

Editorial Notes

29/10/2024: Internal review.
08/08/2024: Publication reference added.
15/02/2023: The following changes have been made:
1. An updated basic results summary has been uploaded.
2. Abstract reference added.
14/02/2023: The basic results summary has been removed, pending addition of an updated version.
31/01/2023: Uploaded protocol (not peer-reviewed) as an additional file.
15/02/2022: The basic results have been uploaded as an additional file.
18/01/2022: The overall end date was changed from 31/12/2020 to 17/02/2021.
10/01/2022: The intention to publish date has been changed from 20/06/2021 to 20/02/2022.
18/05/2020: The following changes were made to the trial record:
1. The overall trial end date was changed from 30/04/2020 to 31/12/2020.
2. The intention to publish date was changed from 28/08/2020 to 20/06/2021.
03/07/2019: The total final enrolment was added.
02/07/2019: The recruitment end date was changed from 30/06/2019 to 20/06/2019.
21/05/2019: The recruitment end date was changed from 30/04/2019 to 30/06/2019.
02/04/2019: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Haematological oncology; UKCRC code/ Disease: Cancer/ Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissue" to "MyeloproliferatIve neoplasms" following a request from the NIHR.
15/01/2019: The following changes have been made to the trial record:
1. The recruitment end date has been changed from 31/12/2018 to 30/04/2019.
2. The overall trial end date has been changed from 31/12/2019 to 30/04/2020.
3. The intention to publish date has been changed from 28/04/2020 to 28/08/2020.
19/11/2018: The following changes were made:
1. The contact details were updated.
2. The primary outcome measures were updated.
3. The secondary outcome measures were updated.
4. The overall trial end date was changed from 31/07/2018 to 31/12/2019.
5. The recruitment end date was changed from 31/07/2017 to 31/12/2018.
6. The trial participating centres were updated.
7. The intention to publish date was changed from 01/05/2018 to 28/04/2020.
8. The participant level data was updated.
9. The IPD sharing statement was updated.
27/06/2017: Updated primary and secondary outcome measures. Funder name changed from Leukaemia and Lymphoma Research to Bloodwise. Updated inclusion and exclusion criteria.
22/09/2016: Cancer Help lay summary added.