Assessing the safety and tolerability of oral ruxolitinib in combination with 5-azacitidine in patients with advanced phase myeloproliferative neoplasms (MPN), including myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) arising from MPN.

• Register: ISRCTN
• Last refreshed on: 28 August 2023
• Main ID: ISRCTN16783472
• Date of registration: 19/03/2015
• Prospective Registration: Yes
• Primary sponsor: The University of Birmingham (UK)
• Public title: Assessing the safety and tolerability of oral ruxolitinib in combination with 5-azacitidine in patients with advanced phase myeloproliferative neoplasms (MPN), including myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) arising from MPN.
• Scientific title: A phase Ib study to assess the safety and tolerability of oral ruxolitinib in combination with 5-azacitidine in patients with advanced phase myeloproliferative neoplasms (MPN), including myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) arising from MPN
• Date of first enrolment: 05/01/2016
• Target sample size: 64
• Recruitment status: Completed
• URL: https://www.isrctn.com/ISRCTN16783472
• Study type: Interventional
• Study design: Non-randomised; Interventional; Design type: Treatment (Treatment)
• Phase: Phase I

Countries of recruitment

England, Northern Ireland, Scotland, United Kingdom, Wales

Contacts

• Name: Sonia Fox

Key inclusion & exclusion criteria

Inclusion criteria: Current participant inclusion criteria as of 01/08/2018:
For the Interventional component:
1. Age = 16 years old
2. A prior diagnosis of Essential Thrombocythaemia (ET), Polycythaemia Vera (PV) or Myelofibrosis (MF) with one of the following:
2.1. = 10% blasts in blood or bone marrow with or without dysplastic changes (MPN-AP) at baseline
2.2. = 20% blasts in blood or bone marrow (MPN-BP) at baseline
3. In need of treatment in the opinion of the investigator
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-3
5. Adequate liver and renal function, defined as:
5.1. Liver transaminases = 3 × ULN (AST/SGOT and ALT/SGPT)
5.2. Bilirubin <4 x ULN (Patients with elevated bilirubin due to Gilbert’s syndrome are eligible)
5.3. GFR = 40 ml/min
6. Willingness to undergo and ability to tolerate assessments during the study including bone marrow assessments and symptom assessments using patient reported outcome instruments
7. Able to give valid informed consent

For the Observational Component
1. Age = 16 years old
2. A prior diagnosis of ET, PV or MF with one of the following:
2.1. Blasts in blood or marrow 10-19%
with or without dysplastic changes (MPN-AP)
2.2 = 20% Blasts (MPN-BP)
2.3. Patients who are unwilling/unable to enter the interventional component and/or fail the interventional component entry criteria. This can include patients entered into studies with more aggressive therapy such as AML 17/19 as well as those receiving palliation only


Previous participant inclusion criteria:
For the Interventional component:
1. Age = 16 years old
2. A prior diagnosis of Essential Thrombocythaemia (ET), Polycythaemia Vera (PV) or Myelofibrosis (MF) with one of the following:
2.1. Blasts in blood or marrow 10-19%
with or without dysplastic changes (MPN-AP)
2.2. = 20% Blasts (MPN-BP)
3. In need of treatment in the opinion of the investigator
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-3
5. Platelet or red blood cell transfusion-dependent
6. Adequate liver and renal function, defined as:
6.1. Liver transaminases = 3 × ULN (AST/SGOT and ALT/SGPT)
6.2. Bilirubin <4 x ULN (Patients with elevated bilirubin due to Gilbert’s syndrome are eligible)
6.3. GFR = 40 ml/min
7. Willingness to undergo and ability to tolerate assessments during the study including bone marrow assessments and symptom assessments using patient reported outcome instruments
8. Able to give valid informed consent

For the Observational Component
1. Age = 16 years old
2. A prior diagnosis of ET, PV or MF with one of the following:
2.1. Blasts in blood or marrow 10-19%
with or without dysplastic changes (MPN-AP)
2.2 = 20% Blasts (MPN-BP)
2.3. Patients who are unwilling/unable to enter the interventional component and/or fail the interventional component entry criteria. This can include patients entered into studies with more aggressive therapy such as AML 17/19 as well as those receiving palliation only
Exclusion criteria: Current participant exclusion criteria as of 01/08/2018:
For the Interventional Component:
1. Any co-morbidity that could limit compliance with the trial or any other condition (including laboratory abnormalities) that in the Investigators opinion will affect the patient’s participation in this trial
2.New York Heart Association Class II, III, or IV congestive heart failure
3. On-going cardiac dysrhythmias of grade 3, QTc prolongation >480 ms, or other factors that increase the risk of QT interval prolongation (e.g. heart failure, hypokalemia defined as serum potassium <3.0 mEq/L, family history of long QT interval syndrome)
4. Erythropoietic agent within 28 days prior to registration
5. Thrombopoietic agent within 14 days prior to registration
6. CYP3A4 inhibitor within 7 days prior to registration
7. Experimental treatment for AML or MPN within 14 days prior to registration (except Ruxolitinib and Hydroxycarbamide which can be taken up until study entry at the prestudy dose. Hydroxycarbamide must be stopped before the first scheduled day of treatment)
8. Previously received 5-azacitidine
9. Known contraindications to receiving azacitidine or ruxolitinib
10. Known HIV seropositivity
11. Known to have active hepatitis A, B, or C
12. Women who are pregnant or lactating. Patients of childbearing potential must have a negative pregnancy test prior to study entry
13. Patients and partners of childbearing potential not willing to use effective contraception for the duration of the study treatment and for three months after the last dose.
14. Active infection = grade 3 (CTCAE criteria) at trial entry

For the Observational Component:
No Exclusions planned.

Previous participant exclusion criteria:
For the Interventional Component:
1. Any co-morbidity that could limit compliance with the trial or any other condition (including laboratory abnormalities) that in the Investigators opinion will affect the patient’s participation in this trial
2.New York Heart Association Class II, III, or IV congestive heart failure
3. On-going cardiac dysrhythmias of grade 3, QTc prolongation >480 ms, or other factors that increase the risk of QT interval prolongation (e.g. heart failure, hypokalemia defined as serum potassium <3.0 mEq/L, family history of long QT interval syndrome)
4. Erythropoietic agent within 28 days prior to registration
5. Thrombopoietic agent within 14 days prior to registration
6. CYP3A4 inhibitor within 7 days prior to registration
7. Experimental treatment for AML or MPN within 14 days prior to registration (except Ruxolitinib and Hydroxycarbamide which can be taken up until study entry at the prestudy dose. Hydroxycarbamide must be stopped before the first scheduled day of treatment)
8. Previously received 5-azacitidine
9. Known contraindications to receiving azacitidine or ruxolitinib
10. Known HIV seropositivity
11. Known to have active hepatitis A, B, or C
12. Women who are pregnant or lactating. Patients of childbearing potential must have a negative pregnancy test prior to study entry
13. Patients and partners of childbearing potential not willing to use effective contraception for the duration of the study treatment and for three months after the last dose.

For the Observational Component:
No Exclusions planned.

Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Myeloproliferative neoplasms (MPN), including myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) arising from MPN
Cancer
Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissue

Intervention(s)

All patients registered to the interventional component will receive treatment with a minimum of 6 cycles (each cycle 28 days) of 5-azacitidine in combination with one of 5 doses of ruxolitinib (5mg bd, 10mg bd, 15mg bd, 20mg bd, 25mg bd). 5-azacitidine will be administered on days 1-5 and 8-9 of each cycle via subcutaneous injection at a dose of 75mg/m2. Ruxolitinib will be taken orally, twice daily. If patients are achieving a clinical benefit at the end of 6 cycles, they can continue treatment for as long as they are benefitting at the discretion of the Chief Investigator. Patients will be followed up for a minimum of 1 year following registration.
The observational component will receive standard care and the trial will collect information on their outcome.

Primary Outcome(s)

To determine the MTD of ruxolitinib in combination with 5-azacitidine; Timepoint(s): Within 1 cycle of treatment

Secondary Outcome(s)

1. Best response following 3 and 6 cycles of treatment Assessment will be made according to the following criteria: Proposed criteria for response assessment in patients treated in clinical trials for MPNs in blast phase (MPN-BP): Formal recommendations from the post-MPN acute myeloid leukaemia consortium (for patients with >20% blasts at baseline)
2. International Working Group (IWG) response criteria in myelodysplasia (for patients with <20% blasts at baseline)
3. Change in the proportion of patients who require transfusion of red cells or platelets
4. Achievement of red blood cell (RBC) transfusion independence
5. Achievement of platelet transfusion independence
6. Change in palpable splenomegaly or hepatomegaly
7. Duration of Complete Response (CR) or Partial Response (PR)
8. 12 months Progression-free survival (PFS)
9. 12 months Leukaemia-free survival (LFS)
10. 12 months Overall survival (OS)
11. Duration of treatment
12. Clinical improvement in haemoglobin level
13. Clinical improvement in platelet count
14. Quality of life as measured by the MPN SAF; EQ-5D-5L and EORTC QLQ-C30 (Cycles 1, 2, 4 and 6 for interventional patients; at registration, 3 months and 6 months for observational patients)
15. To determine treatment and outcome of Advanced Phase MPN (MPN-AP) and Blast Phase MPN (MPN-BP) patients who enter the observation component.
16. Change in clonal marker (e.g. JAK2 or CALR allele burden) (to be centrally assessed)

Secondary ID(s)

2014-002563-16

18136

Source(s) of Monetary Support

Bloodwise TAP

Ethics review

Status:
Approval date:
Contact:

Old ethics approval format; NRES Committee West Midlands - Edgbaston,19/01/2015, ref: 14/WM/1260

Results

• Results available: Yes
• Date Completed: 18/08/2022