Myelofibrosis MedDRA version: 20.0 Level: PT Classification code 10028537 Term: Myelofibrosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10028537 Term: Myelofibrosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: PLX2853
Pharmaceutical Form: Tablet
INN or Proposed INN: PLX2853
Current Sponsor code: PLX2853
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Tr
Sponsors
University of Birmingham
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Age=16 years • Primary or secondary myelofibrosis OR Dynamic International Prognostic Scoring System (DIPSS) defined risk groups intermediate-2 or high risk • Treated with =24 weeks of ruxolitinib with ongoing residual splenomegaly >5cm from costal margin • Platelets >75x109/L • Neutrophils >1.0x109/L • 3.0 g/dL • Stable dose of ruxolitinib (no dose modifications) established for 4 weeks prior to trial entry • 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). • Able to provide written informed consent • Able to comply with trial treatment and follow-up • Serum total bilirubin =2.0 × ULN OR Direct bilirubin =ULN for patients with total bilirubin >2.0 × ULN o Exception for elevated total bilirubin secondary to Gilbert’s disease, in which case it must be =3 x ULN. • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =2.0 × ULN Are the trial subjects under 18? yes 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 20 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 40
Exclusion criteria
Exclusion criteria: • Prior exposure to a bromodomain inhibitor such as OTX-015 or CPI-0610 • Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to trial entry) • 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 .Women of non-child-bearing potential may be included if they are either surgically sterile or have been postmenopausal for =1 year. • Ongoing systemic infection requiring treatment with antibiotic, antiviral, or antifungal treatment • ECOG Performance Status Score = 3 • Clinically significant cardiac disease, defined as any of the following: o 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. o 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). o QT interval corrected for heart rate using the Fridericia method (QTcF) =450 msec males or QTcF =470 msec (females) at Screening o 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. o 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 o 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) • Inadequate renal function as defined by eGFR or CrCl =30 mls/min • 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. • 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.) • Known or suspected allergy to the investigational agent or any agent given in association with this study • 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 • Patient is participating in any other therapeutic clinical study (observational or registry studies are allo
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To establish the recommended phase 2 dose and safety of PLX2853 in combination with ruxolitinib and to assess how well the combination of PLX2853 and ruxolitinib reduces spleen size in patients with intermediate-2 or high risk myelofibrosis. ;Secondary Objective: •To assess the safety of the combination of PLX2853 and ruxolitinib •To measure the effect of the combination of PLX2853 and ruxolitinib on myelofibrosis-associated symptoms •To assess the effect of the combination of PLX2853 and ruxolitinib on bone marrow fibrosis •To assess overall haematological response •To measure overall survival time •To measure leukaemia-free time •To measure progression free survival ;Primary end point(s): Occurrence of dose limiting toxicity in cycle 1 and reduction in palpable spleen length of >50% from screening to the end of 8 cycles of treatment. ;Timepoint(s) of evaluation of this end point: The timepoint of evaluation for Occurrence of dose limiting toxicity, is the end of cycle 1. The timepoint for reduction in palpable spleen length is at the end of 8 cycles of treatment. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •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. •Proportion of patients whose ruxolitinib dose was adjusted following administration of PLX2853 •Overall response after 8 cycles of treatment assessed using International Working Group (IWG) Criteria, where response includes Complete Response and Partial Response •Anaemia response after 8 cycles of treatment using International Working Group (IWG) Criteria •Rate of red blood cell (RBC) transfusion •Percentage reduction in spleen length assessed using ultrasound from screening to the end of treatment. •Incidence of molecular response after 4 and 8 cycles of treatment assessed using IWG Criteria •Bone marrow fibrosis assessed via bone marrow samples after 8 cycles. •Overall survival time defined as the time from date of registration to date of death from any cause. Alive patients will be censored at the date last known alive. •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. Alive patients without disease progression will be censored at the date last known alive. •Leukaemia free survival time, defined as the time from date of registration to earliest of date of death or date of progression to leukaemia. Alive patients without progression to leukaemia will be censored at the date last known alive. •Total symptom score assessed by the Myelofibrosis Symptom Assessment Form (MFSAF) after 4 and 8 cycles •Quality of Life measured by Quality of Life Questionnaire (EORTC QLQ)-C30 and Patient Global Impression of Change (PGIC) questionnaires. ;Timepoint(s) of evaluation of this end point: AEs will be evaluated until 28 days post treatment discontinuation. An endpoint of last treatment will be used for patients whose ruxolitinib dose was adjus | — |
Countries
United Kingdom
Contacts
Public ContactRebecca Collings
University of Birmingham
Outcome results
None listed