Clinical Trials Register

Summary
EudraCT Number:	2015-005497-38
Sponsor's Protocol Code Number:	RG_15-234
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2016-04-28
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2015-005497-38

A.3

Full title of the trial

Effects of TAMoxifen on the Mutant Allele Burden and Disease Course in Patients with MyeloprolifeRatIve Neoplasms

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

The effects of Tamoxifen on the disease course of patients with Myeloproliferative Neoplasms

A.3.2

Name or abbreviated title of the trial where available

TAMARIN

A.4.1

Sponsor's protocol code number

RG_15-234

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN65011803

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University of Birmingham
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Birmingham
B.5.2	Functional name of contact point	Sonia Fox
B.5.3	Address:
B.5.3.1	Street Address	CRCTU, University of Birmingham
B.5.3.2	Town/ city	Birmingham
B.5.3.3	Post code	B15 2TT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01214159181
B.5.5	Fax number	01214146061
B.5.6	E-mail	TAMARIN@trials.bham.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Information not present in EudraCT
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Tamoxifen
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tamoxifen
D.3.9.1	CAS number	10540-29-1
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Myeloproliferative Neoplasms

E.1.1.1

Medical condition in easily understood language

Blood cancers characterised by an overproduction of blood cells.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10028576
E.1.2	Term	Myeloproliferative disorder
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

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.

E.2.3

Trial contains a sub-study

E.3

Principal 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%”.

E.4

Principal 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 <20% at study entry
• Female patients receiving hormone replacement therapy
• Hypertriglyceridemia > 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)

E.5 End points

E.5.1

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

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 24 of the study

E.5.2

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 showing a decrease in JAK2-V617F, CALR 5bp insertion (exon 9), or CALR 52bp deletion (exon 9) allele burden at 12 weeks compared to baseline
9. Proportion of patients showing a decrease in JAK2-V617F, CALR 5bp insertion (exon 9), or CALR 52bp deletion (exon 9) allele burden at 24 weeks compared to baseline
10. Proportion of patients showing a decrease in requirement for cytoreduction at 24 weeks compared to baseline

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Week 12 of the study
2. Toxicity will be measured from the start of treatment until 28 days after the last administration of trial treatment
3. The number of thrombotic events will be measured from the start of treatment until 28 days after the last administration of trial treatment
4. Duration of haematological response will be assessed at baseline and during 24 weeks of treatment
5. Week 24 of the study
6. Week 24 of the study

Exploratory Outcomes
7. Oestrogen receptor signalling studies will compare samples taken at baseline with samples taken at week 24
8. Week 12 of the study
9. Week 24 of the study
10. Week 24 of the study

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The end of trial will be the last patient’s last visit.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1