Myelodysplasic Syndromes / Posted 2 years ago

PHAZAR: 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.

Myeloproliferative Neoplasms (MPNs) are uncommon diseases that in some cases will progress to an acute leukaemia which is very difficult to treat. As this often happens to older people, most patients are unsuitable for bone marrow transplant therapy. There are few other treatment options for these patients and survival is only around 6 months.

This trial will combine a treatment (ruxolitinib) that is effective at symptom control and may confer a survival advantage in myelofibrosis (an MPN) with azacitidine, a treatment that has proven activity in patients with some types of myelodysplastic syndrome and acute myeloid leukaemia. As these two treatments have not been used together before, the trial will consist of a dose finding component, followed by the recruitment of an additional 10 patients at the maximum dose that is found to be safe and tolerable.

Side-effects are anticipated to be similar to those experienced with these treatments used alone. In particular, low blood counts and infections are potential risks although measures to reduce these risks will be taken.

In addition to patients recruited to receive trial treatment, the study will also recruit patients with these diseases who do not want to receive the trial treatment and monitor them for outcome.

  • Inclusion Criteria : For the Interventional component:
    • Age ≥16 years old
    • A prior diagnosis of Essential Thrombocythaemia (ET), Polycythaemia Vera (PV) or Myelofibrosis (MF) with one of the following: - 10-19% bone marrow blasts with or without dysplastic changes (MPN-AP) - ≥20% bone marrow blasts (MPN-BP)
    • In need of treatment in the opinion of the investigator
    • Eastern Cooperative Oncology Group (ECOG) performance status 0-3
    • Adequate liver and renal function, defined as: - Liver transaminases ≤3 × ULN (AST/SGOT and ALT/SGPT) - Bilirubin <4 x ULN (Patients with elevated bilirubin due to Gilbert’s syndrome are eligible) - GFR ≥40 ml/min
    • Willingness to undergo and ability to tolerate assessments during the study including bone marrow assessments and symptom assessments using patient reported outcome instruments
    • Able to give valid informed consent For the Observational Component
    • Age ≥16 years old
    • A prior diagnosis of ET, PV or MF with one of the following: - 10-19% bone marrow blasts with or without dysplastic changes (MPN-AP) - ≥20% bone marrow blasts (MPN-BP) - Patients who are unwilling/unable to enter the interventional component and/or fail the interventional component entry criteria. This can include patients previously treated post transformation into MPN-AP/MPN-BP, or entered into studies with more aggressive therapy such as AML 17/19 as well as those receiving palliation only. - Able to give valid informed consent
  • Exclusion Criteria : For the Interventional Component:
    • 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
    • New York Heart Association Class II, III, or IV congestive heart failure
    • 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)
    • Erythropoietic agent within 28 days prior to registration
    • Thrombopoietic agent within 14 days prior to registration
    • CYP3A4 inhibitor within 7 days prior to registration
    • Experimental treatment within 14 days prior to registration
    • Previous treatment for MPN-AP or MPN-BP, including stem cell transplant and low intensity AML chemotherapy
    • Previously received 5-azacitidine. Ruxolitinib can be taken up until study entry at the pre-study dose. Hydroxycarbamide prescribed prior to study entry must be stopped before the first scheduled day of trial treatment
    • Known contraindications to receiving azacitidine or ruxolitinib
    • Known HIV seropositivity
    • Known to have active hepatitis A, B, or C
    • Women who are pregnant or lactating. Patients of childbearing potential must have a negative pregnancy test prior to study entry
    • 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.
  • Study start date : 05/01/2016
  • Study end date : 31/12/2019
  • Wales-Based Study Contact : please speak to your clinician
  • Principal Investigator : Dr Steven Knapper

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