Myeloproliferative neoplasm in accelerated phase (MPN-AP) MedDRA version: 20.0 Level: PT Classification code 10077465 Term: Myeloproliferative neoplasm System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Inrebic® 100 mg Hartkapseln
Pharmaceutical Form: Capsule, hard
Trade Name: Onureg® 200 mg Filmtabletten
Onureg® 300 mg Filmtabletten
Pharmaceutical Form: Film-coated tablet
Sponsors
Martin-Luther-Universität Halle-Wittenberg
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Males and females at least 18 years of age at the time of signing the informed consent form - Diagnosis of MPN-AP (defined by a blast count of 10%-19% peripherally or in the bone marrow) at the time of diagnosis or at any time during the course of a known primary myelofibrosis (PMF), post–polycythemia vera (PV) myelofibrosis (MF) or post–essential thrombocythemia (ET) MF - Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of 0, 1 or 2 - Prior to Day 1 of study therapy, any treatment-related toxicities from prior therapy must have resolved to Grade 1 or pretreatment baseline of last therapy - Subject is willing and able to adhere to the study visit schedule and the protocol-specifiec procedures - Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 22 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 20
Exclusion criteria
Exclusion criteria: - Subject with thiamine deficiency, defined as thiamine levels in whole blood below normal range according to institutional standard and not demonstrated to be corrected prior to start of trial treatment - Known or suspected hypersensitivity to azacitidine, mannitol, or its constituents - Subjects who are known not to tolerate a daily dose of 400 mg of fedratinib - The following laboratory values within 14 days prior to first dose: - Platelet count 100 x 109/L - Myeloblasts = 20 % in peripheral blood - Serum creatinine > 2.5 x upper limit of normal (ULN) - Serum amylase or lipase > 1.5 x ULN - Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN - Total bilirubin > 1.5 x ULN, subject’s total bilirubin between 1.5 – 3.0 x ULN are eligible if the direct bilirubin fraction is 10 mg/day prednisone or equivalent. - Subject on treatment with aspirin with doses > 150 mg daily - Subject with diagnosis of active liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis) - Subject with prior malignancy other than the disease under study unless the subject has not required treatment for the malignancy for at least 3 years prior to enrollment. - Significant active cardiac disease within the previous 6 months, including: a. New York Heart Association (NYHA) class IV congestive heart failure; b. Unstable angina or angina requiring surgical or medical intervention; and/or c. Myocardial infarction - Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication - Subject who is unable to swallow capsule - Subject is pregnant or lactating female
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I: To determine the safety and tolerability of the drug fedratinib in combination with CC-486 Phase II: To determine the rate of best response [clinical improvement (CI), partial remission (PR), or complete remission (CR)] of the combination therapy of fedratinib and CC-486;Secondary Objective: - Determine the duration of best response (DOR), percentage of subjects with at least 50% reduction in MF-associated symptoms, durability of symptom response, percentage of subjects with a spleen response, time to spleen response, durability of spleen response, percentage of subjects that demonstrate an anemia response, progression free survival (PFS), overall survival (OS), proportion of subjects who transit to allogeneic SCT. - safety and tolerability of fedratinib in combination with CC-486. - effectiveness of the risk mitigation strategy for gastrointestinal events and Encephalopathy Health-Related Outcomes using specific questionnaires;Primary end point(s): Phase I: - Safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious AEs (SAEs), electrocardiograms (ECGs), and vital signs. - DLTs as defined under “Treatment Details” section will be used to establish the MTD of fedratinib in combination with CC-486. The SRC will determine the RP2D and schedule based on safety data of the combination of fedratinib and CC-486. Phase II: - Best response to the combination therapy at week 24 according to the IWG-MRT and the ELN consensus report. This includes clinical improvement (CI), partial remission (PR), and complete remission (CR) ;Timepoint(s) of evaluation of this end point: Phase I: until Dose Limiting Toxicity is reached Phase II: Week 24 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - duration of response - Change in MF-associated symptoms of the combination treatment from baseline as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) - Time from the first observation of best symptom response to first documented loss of symptom response - Spleen response by palpation as defined by the IWG-MRT and ELN consensus report of the combination treatment as compared to baseline - Time from the first treatment dose to disease progression, relapse or death - proportion of subjects who transit to allogeneic SCT - proportion of subjects that demonstrate an anemia response according to the IWG-MRT and ELN consensus report criteria - Analysis of incidence of subjects with a CTCAE Grade =3 of nausea, diarrhea, vomiting or occurrence of Encephalopathy - Thiamine levels during the study - Change in Health-Related Quality of Life (HRQoL) and Patient-Reported Outcomes (PRO) from baseline by EORTCQLQ-C30 and EQ-5D-5L Questionnaires ;Timepoint(s) of evaluation of this end point: - Time from first observation of response to first documented loss of symptom response, relapse or death - Change in MF-associated symptoms and spleen response by week 24 - Time from the first treatment dose to disease progression, relapse or death - Transition to allogeneic SCT and anemia response max. within 24 months - CTCAE Grade =3 of nausea, diarrhea, or vomiting, or occurrence of Encephalopathy within max. 24 months - Thiamine levels at screening, on Day 1 of the first 3 cycles, every third cycle thereafter, and at the EOT - Change in HRQoL and PRO from baseline measured monthly | — |
Countries
Germany
Contacts
Public ContactCoordinating Investigator
Universitätsklinikum Halle
Outcome results
None listed