Myeloproliferative Neoplasms MedDRA version: 20.0 Level: LLT Classification code 10028576 Term: Myeloproliferative disorder System Organ Class: 100000004864
Conditions
Interventions
Product Name: Tamoxifen
Pharmaceutical Form: Tablet
INN or Proposed INN: Tamoxifen
CAS Number: 10540-29-1
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 10-20
Sponsors
University of Birmingham
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Age = 60 years (men aged between 50-59 may also be considered following discussion with the Chief Investigator) • Women must be post-menopausal (defined as amenorrhoeic for at least 12 consecutive months following cessation of all exogenous hormonal treatments) • Confirmed diagnosis of JAK2-V617F or 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 • JAK2-V617F or 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) • WHO performance status 0-2 • For patients with PV or ET, maintenance of platelet count =600 x 10^9/L, WBC =25 x 10^9/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 • 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. • Patients receiving cytoreductive therapy (with the exception of interferon alpha or investigational agents) for their MPN (not solely aspirin or venesection) • Adequate hepatic function, defined as: o bilirubin = 1.5 x upper limit of normal (ULN) (patients with elevated bilirubin due to Gilbert’s syndrome are eligible) o AST/ALT/ALP = 2.5 x ULN • Adequate renal function (creatinine clearance >30 mL/min) • Male patients must agree to use effective contraception during participation in the trial and for 2 months after the last dose of trial treatment • 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%”. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 10 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 32
Exclusion criteria
Exclusion criteria: • Leukaemic transformation (>20% blasts in blood, marrow or extramedullary site). • Accelerated phase of disease as indicated by >10% blasts in the peripheral blood • 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) • Any of the following previous thrombotic events at any time: o Portal or other splanchnic venous thrombosis o Vascular access complication o Ischemia cerebrovascular o Stroke o Transient Ischaemic attack o Superficial thrombophlebitis o Venous Thromboembolic events including pulmonary embolism (PE) and deep vein thrombosis (DVT) o Peripheral vascular ischemia o Visceral arterial ischemia o Acute coronary syndrome o Myocardial infarction • Previous malignancy within 5 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer • Previous endometrial cancer, hyperplasia or polyps • Prior treatment with hematopoietic stem cell transplantation • Patients who do not carry JAK2V617F, CALR 5bp insertion (exon 9) or CALR 52bp deletion (exon 9) mutations, or whose allele burden is grade 1 • 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) • Known hypersensitivity to tamoxifen or hypersensitivity to any other component of tamoxifen • Concomitant drugs contraindicated for use with the trial drug according to the Summary of Product Characteristics • Known planned scheduled elective surgery during study with the exception of dental and low risk eye surgery (e.g. cataracts)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To investigate the activity of tamoxifen in reducing the molecular markers of disease burden in MPN (the number of mutated cells) by greater than or equal to 50% after 24 weeks of treatment. ;Secondary Objective: The study will also look at how many patients have received certain reductions in allele burden (the number of mutated cells)at different timepoints including: - Proportion of patients showing a reduction in the peripheral blood mutant allele burden of =50% at 12 weeks - Proportion of patients showing any reduction in the peripheral blood mutant allele burden at 24 weeks - Proportion of patients showing any reduction in the peripheral blood mutant allele burden at 12 weeks Safety of tamoxifen in this patient population. Number of thrombotic events that occur Maintenance of stable disease Achievement of disease response Look at oestrogen receptor signalling in stem cells from peripheral blood and bone marrow before (peripheral blood only) and after tamoxifen treatment. ;Primary end point(s): 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;Timepoint(s) of evaluation of this end point: Week 24 of the study | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 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 and no evidence of disease progression for MF patients according to IWG-MRT response criteria 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 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 and according to IWG-MRT response criteria 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 Outcomes 7. 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. 8. Proportion of patients showi | — |
Countries
United Kingdom
Contacts
Public ContactSonia Fox
University of Birmingham
Outcome results
None listed