Condition category
Cancer
Date applied
17/11/2020
Date assigned
17/11/2020
Last edited
17/11/2020
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Myelofibrosis (MF) is a cancer of the bone marrow that disrupts the production of blood cells. Symptoms of MF include anaemia (low red cell levels), weakness, tiredness and often an enlarged spleen. Standard treatment can involve chemotherapy, radiotherapy, a stem cell transplant or treatment with a drug called ruxolitinib. Ruxolitinib targets the specific cells that play a part
in the development of MF, and is the only drug licenced to treat MF. Previous research has shown that ruxolitinib is good at reducing symptoms of MF and decreasing the size of the spleen. However, the majority of patients do not show a complete response to ruxolitinib, meaning that another treatment needs to be added to ruxolitinib to improve the outcome for patients. This study will test whether combining ruxolitinib with another drug called a bromodomain and extra terminal inhibitor (BETi) is safe for MF. Research has suggested that combining these two drugs will have a clinical benefit to patients. The main aims of the study are to find a suitable dose of PLX2853 when combined with ruxolitinib, and investigate the safety by looking at the side effects of treatment, and to see how well the combination treats MF.

Who can participate?
The PROMise trial is for patients diagnosed with intermediate-2 or high risk myelofibrosis currently being treated with ruxolitinib, who may benefit from a new drug, PLX2853, being added to their ruxolitinib.

What does the study involve?
Patients will then take both drugs in oral tablet form (PLX2853 and ruxolitinib) every day for up to 8 cycles of treatment, each cycle lasting 21 days. If at the end of 8 cycles the study doctor feels it is helping the patient and they are not experiencing any major side effects, it will be possible to continue with further cycles of treatment. The patient will visit the hospital for blood tests, physical assessments and a further bone marrow biopsy throughout the trial. More detail of these assessments can be found in the Patient Information Sheet.

What are the possible benefits and risks of participating?
The possible benefit is that adding PLX2853 to ruxolitinib could further reduce the size of the patient’s spleen and modify the natural history of the myelofibrosis. PLX2853 is not chemotherapy, but works by targeting specific cells that are involved in the development and progression of myelofibrosis. PLX2853 works by targeting and slowing down certain activities within cells that promote tumour growth. By inhibiting these activities, PLX2853 may help to stabilise or reduce the growth of tumour cells.
Patients will have to have bone marrow aspirate and biopsy procedures performed whether or not they enter the PROMise trial. This may be painful, uncomfortable afterwards and may cause a small amount of bleeding.
Having blood samples taken may cause some discomfort, bleeding or bruising where the needle enters the body and, in rare cases, light-headedness and fainting.
There are possible side effects from both PLX2853 and ruxolitinib, which are documented in the Patient Information Sheet. There may be risks or side effects of the study drugs that are unknown at this time.

Where is the study run from?
The University of Birmingham (UK)

When is the study starting and how long is it expected to run for?
May 2019 to January 2025

Who is funding the study?
Cancer Research UK

Who is the main contact?
Helen Coulthard (public), H.C.Coulthard@bham.ac.uk
Prof. Adam Mead (scientific), adam.mead@imm.ox.ac.uk

Trial website

Contact information

Type

Public

Primary contact

Mrs Helen Coulthard

ORCID ID

http://orcid.org/0000-0003-1495-8001

Contact details

Centre for Clinical Haematology
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom
+44 (0)121 371 7865
h.c.coulthard@bham.ac.uk

Type

Scientific

Additional contact

Prof Adam Mead

ORCID ID

Contact details

Weatherall Institute for Molecular Medicine
John Radcliffe Hospital
Oxford
OX3 9DS
United Kingdom
+44 (0)1865 222 489
adam.mead@imm.ox.ac.uk

Additional identifiers

EudraCT number

2019-000916-27

ClinicalTrials.gov number

Nil known

Protocol/serial number

CPMS 46423, IRAS 261523

Study information

Scientific title

Investigation into the combination of PLX2853 with ruxolitinib in patients with intermediate-2 or high risk myelofibrosis not receiving an adequate response with ruxolitinib alone

Acronym

PROMise

Study hypothesis

PROMise is a phase I multicentre trial which aims to determine the recommended phase II dose (RP2D) of PLX2853 in combination with ruxolitinib using a continual reassessment method (CRM) design

Ethics approval

Approved 03/11/2020, East Midlands – Leicester Central REC (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, UK; +44(0)207 104 8388; leicestercentral.rec@hra.nhs.uk), ref: 20/EM/0235

Study design

Non-randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Non randomised study

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet.

Condition

Myelofibrosis

Intervention

This is a multicentre phase I dose finding study for PLX2853 when administered in combination with ruxolitinib in patients with high risk or Intermediate-2 myelofibrosis.
Patients who consent to participate will have a screening period of up to 28 days before trial registration for the following assessments to take place. The patient will have a clinical and physical exam (including vital signs, height and weight), blood tests, an ECG, palpation and ultrasound of the spleen, and bone marrow aspirate. Patients will also be asked to complete a few optional Quality of Life questionnaires.

Once registered to the study, patients will receive up to 8 cycles of ruxolitinib and PLX2853 combination therapy orally daily, with each cycle lasting 21 days. At the end of 8 cycles, patients experiencing clinical benefit may continue on trial treatment.

Patients will be seen on the day 1 of cycles 1-8 for a clinical and physical assessment, as well as for blood tests, spleen palpation and quality of life questionnaires. On day 8 and day 15 of cycle 1, and day 15 of cycle 2-4 there will be additional blood tests, with an ECG done on day 15 of cycle 4 if clinically indicated. On day 1 of cycle 5 there will be an ultrasound of the spleen and a disease response assessment, in addition to the assessments previously mentioned. On day 15 of cycle 8 there will be an ECG (if clinically indicated), as well as blood tests, ultrasound and palpation of the
spleen, disease response assessment, bone marrow aspirate and trephine and MF-SAF questionnaire.

If the patient continues treatment after 8 cycles, they will be assessed every 4 cycles with a clinical and physical assessment, blood tests and quality of life questionnaires. With an ultrasound and palpation of the spleen, and disease response assessment done every 8 cycles.

Once the patient has completed treatment they will have a visit 28 days after this. This visit will include clinical and physical assessment and blood tests. After this they will be followed up annually, this will include a clinical and physical assessment, blood tests, palpation of the spleen, quality of life questionnaires, and an optional bone marrow aspirate.

Intervention type

Drug

Phase

Phase I

Drug names

PLX2853, ruxolitinib

Primary outcome measure

1. The RP2D of PLX2853 administered in combination with ruxolitinib that is safe and tolerable is measured using the occurrence of a dose limiting toxicity (DLT) in the first cycle (21 days)
2. The efficacy of the combination of PLX2853 and ruxolitinib for reduction in spleen size is measured using a reduction in palpable spleen length of >50% from screening to end of 8 cycles of treatment

Secondary outcome measures

1. The safety of the combination of PLX2853 and ruxolitinib is measured using the incidence of adverse events (recorded using Common Terminology Criteria for Adverse Events (CTCAE) v4.0, from commencement of protocol treatment to 28 days post treatment discontinuation
2. The effect of the combination of PLX2853 and ruxolitinib on myelofibrosis-associated symptoms is measured using the proportion of patients whose ruxolitinib dose was adjusted following administration of PLX2853 and total symptom score assessed by the Myelofibrosis Symptom Assessment Form (MFSAF) after 4 and 8 cycles
3. The effect of the combination of PLX2853 and ruxolitinib on bone marrow fibrosis is measured using the bone marrow fibrosis assessed via bone marrow samples after 8 cycles
4. Overall haematological response is measured using the overall response after 8 cycles of treatment assessed using International Working Group (IWG) Criteria, where response includes Complete Response (CR) and Partial Response (PR). Anaemia response using International Working Group (IWG) Criteria and rate of red blood cell (RBC) transfusion
5. Overall survival time is measured using the overall survival time defined as the time from date of registration to date of death from any cause
6. Leukaemia-free time is measured using the leukaemia free survival time, defined as the time from date of registration to earliest of date of death or date of progression to leukaemia
7. Progression free survival is measured using the progression-free survival time, defined as the time from date of registration to the earlier of the date of death from any cause or disease progression by the IWG Criteria

Overall trial start date

01/05/2019

Overall trial end date

31/01/2025

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Age >=16 years
2. Primary or secondary myelofibrosis OR Dynamic International Prognostic Scoring System (DIPSS) defined risk groups intermediate-2 or high risk
3. Treated with >=24 weeks of ruxolitinib with ongoing residual splenomegaly >5cm from costal margin
4. Platelets >75x109/L
5. Neutrophils >1.0x109/L
6. <10% blasts in peripheral blood and/or bone marrow
7. Coagulation (INR or PT) and Activated partial thromboplastin time <=1.5 x ULN
8. Albumin >3.0 g/dL
9. Stable dose of ruxolitinib (no dose modifications) established for 4 weeks prior to trial entry
10. Except as specified above for organ function, all drug-related toxicity from previous therapy for myelofibrosis must be resolved (to Grade <=1 or baseline per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [NCI CTCAE v4.0]) prior to study treatment administration (Grade 2: alopecia, hot flashes, decreased libido, or neuropathy is allowed)
11. Able to provide written informed consent
12. Able to comply with trial treatment and follow-up
13. Serum total bilirubin < = 2.0 × ULN OR Direct bilirubin <=ULN for patients with total bilirubin >2.0 × ULN
13.1. Exception for elevated total bilirubin secondary to Gilbert’s disease, in which case it must be <=3 x ULN
14. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.0 × ULN

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 60; UK Sample Size: 60

Participant exclusion criteria

1. Prior exposure to a bromodomain inhibitor such as OTX-015 or CPI-0610
2. Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to trial entry)
3. Patients and partners of childbearing potential (pre-menopausal female capable of becoming pregnant) not willing to use effective contraception from the time of negative pregnancy test during screening to 90 days after the last dose of study drug
4. Women of non-child-bearing potential may be included if they are either surgically sterile or have been postmenopausal for >=1 year
5. Ongoing systemic infection requiring treatment with antibiotic, antiviral, or antifungal treatment
6. ECOG Performance Status Score >= 3
7. Clinically significant cardiac disease, defined as any of the following:
7.1. Clinically significant cardiac arrhythmias including bradyarrhythmias and/or patients who require anti-arrhythmic therapy (excluding beta blockers or digoxin). Patients with controlled atrial fibrillation are not excluded
7.2. Congenital long QT syndrome or patients taking concomitant medications known to prolong the QT interval (drugs with a low risk of QTc prolongation that are needed for infection control or nausea may be permitted with approval from the Clinical Coordinator)
7.3. QT interval corrected for heart rate using the Fridericia method (QTcF) > = 450 msec males or QTcF > = 470 msec (females) at Screening
7.4. History of clinically significant cardiac disease or congestive heart failure > New York Heart Association Class II. Patients must not have unstable angina (anginal symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months
7.5. Uncontrolled hypertension, defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg which has been confirmed by 2 successive measurements despite optimal medical management
7.6. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within the 3 months before start of study medication (except for adequately treated catheter-related venous thrombosis occurring > 1 month before the start of study medication)
8. Inadequate renal function as defined by eGFR or CrCl <=30 mls/min
9. Current active viral hepatitis including hepatitis A (hepatitis A virus immunoglobulin M positive), hepatitis B (hepatitis B virus [HBV] surface antigen positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Patients with HCV with undetectable virus after treatment are eligible. Patients with a prior history of HBV are eligible if quantitative PCR for HBV DNA is negative. Note that elevated levels of biotin may interfere with viral serology testing
10. Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 μg (NIH 2020) (Note: Patients who switch from a high dose to a dose of 30 μg/day or less are eligible for study entry.)
11. Known or suspected allergy to the investigational agent or any agent given in association with this study
12. Inability to take oral medication or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the Investigator, would preclude adequate absorption
13. Patient is participating in any other therapeutic clinical study (observational or registry studies are allowed)

Recruitment start date

15/11/2020

Recruitment end date

31/01/2023

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Cardiff and Vale University Health Board
Cardiff and Vale UHB Headquarters University Hospital of Wales (UHW) Heath Park Cardiff
Cardiff
CF14 4XW
United Kingdom

Trial participating centre

Southampton General Hospital
University of Southampton and University Hospital Southampton NHS Foundation Trust Tremona Road
Southampton
SO16 6YD
United Kingdom

Trial participating centre

St Thomas's Hospital
Guy's and St Thomas' NHS Foundation Trust 249 Westminster Bridge Road
London
SE1 7EH
United Kingdom

Trial participating centre

Cambridge Biomedical Campus
Cambridge University Hospitals NHS Foundation Trust Hills Road
Cambridge
CB2 0QQ
United Kingdom

Trial participating centre

Belfast Health & Social Care Trust
Knockbracken Healthcare Park Saintfield Road
Belfast
BT8 8BH
United Kingdom

Trial participating centre

The Christie Hospital
The Christie NHS Foundation Trust Wilmslow Road Withington
Manchester
M20 4BX
United Kingdom

Trial participating centre

St Mary's Hospital
Imperial College Healthcare NHS Trust South Wharf Road
London
W2 1BL
United Kingdom

Trial participating centre

Freeman Hospital
Newcastle Upon Tyne Hospital Trust Freeman Road High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom

Trial participating centre

Leicester Royal Infirmary
Infirmary Square
Leicester
LE1 5WW
United Kingdom

Trial participating centre

University College Hospitals
250 Euston Road 1st Floor Central
London
NW1 2PG
United Kingdom

Trial participating centre

John Radcliffe Hopsital
Headley Way
Oxford
OX3 9DU
United Kingdom

Trial participating centre

Nottingham University Hospitals NHS Trust Headquarters
QMC Campus Derby Road
Nottingham
NG7 2UH
United Kingdom

Trial participating centre

University Hospitals Birmingham NHS Foundation Trust
Mindelsohn Way Edgbaston
Birmingham
B15 2GW
United Kingdom

Trial participating centre

Northern General Hospital
Sheffield Teaching Hospitals NHS Foundation Trust Herries Road
Sheffield
S5 7AU
United Kingdom

Trial participating centre

St James University Hospital
Leeds Teaching Hospitals NHS Trust Beckett Street
Leeds
LS9 7TF
United Kingdom

Sponsor information

Organisation

University of Birmingham

Sponsor details

Research Support Group
Aston Webb Building
Edgbaston
Birmingham
B15 2TT
United Kingdom
+44 (0)121 4142644
researchgovernance@contacts.bham.ac.uk

Sponsor type

University/education

Website

http://www.uab.edu/

Funders

Funder type

Charity

Funder name

Cancer Research UK; Grant Codes: C42639/A27723,PLEXXIKON INC

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

Other non-profit organizations

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer-reviewed journal.

IPD sharing statement:
The current data sharing plans for this study are unknown and will be available at a later date.

Intention to publish date

31/01/2026

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

17/11/2020: Trial’s existence confirmed by National Institute for Health Research (NIHR)