Myeloproliferative Neoplasm
Conditions
Keywords
Blast Phase, Fedratinib, Decitabine
Brief summary
The purpose of this research is to study the safety and tolerability and to establish the maximum tolerated dose (MTD) of the combination of two drugs, fedratinib and decitabine, for the treatment of advanced-phase MPNs.
Detailed description
This is a single center phase I dose-escalation trial of Fedratinib in Combination with Decitabine in Patients with Myeloproliferative Neoplasms. The primary objective is to determine the maximum tolerated dose of the combination therapy, using a 3+3 dose escalation algorithm. Fedratinib will be administered at 2 dose levels: 300 mg and 400 mg by mouth, once daily. Fedratinib will be administered concomitantly with decitabine 20 mg/m2 intravenously over 1 hour per day for 5 days in 28-day cycles.
Interventions
DRUGFedratinib Oral Capsule 300 mg
300 mg by mouth, once daily
DRUGDecitabine 20 mg/m2
20 mg/m2 for injection, for intravenous use
DRUGFedratinib Oral Capsule 400 mg
400 mg by mouth, once daily
Sponsors
Bristol-Myers Squibb
Joseph Jurcic
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must have MPN-AP as defined by 10%-19% blasts in the peripheral blood or bone marrow and evidence of dysplastic marrow features with a concomitant diagnosis of essential thrombocythemia (ET), polycythemia vera (PV) or primary myelofibrosis (PMF) or a diagnosis of MPN-BP as defined by 20% blasts in the blood or bone marrow following a previous diagnosis of ET, PV or PMF. * Subjects must have adequate organ function documented within 14 days of study entry as follows: 1. Estimated creatinine clearance (by Cockcroft-Gault Equation) of ≥ 50 mL/min 2. Serum total bilirubin ≤ 1.5 × ULN (unless attributable to Gilbert's disease or hemolysis, in which case the direct bilirubin level must be ≤ 1.5 × upper limit of normal (ULN)). 3. Alkaline phosphatase, serum aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN. * ≥ 18 years of age. * Eastern Cooperative Oncology Group (ECOG) Performance status of 0-2. Patients with ECOG performance status of 3 will be eligible if the lower performance status is deemed by the investigator to be due entirely to MPN-AP/BP and not due to another comorbidity.
Exclusion criteria
* Receipt of chemotherapy or investigational therapy, with the exception of hydroxyurea, within 4 weeks of study entry. Previous treatment at any time with decitabine, fedratinib or ruxolitinib as single agents will not exclude eligibility. Previous stem cell transplant will not exclude eligibility as long as other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Decitabine and Fedratinib | Up to 8 weeks for each dosing cohort | The MTD will be determined using a 3+3 algorithm. If \< 33% of the subjects enrolled at a dose level experience a dose-limiting toxicity (DLT), escalation to the next designated dose cohort will continue. If ≥ 33% of the subjects enrolled at a dose level experience a DLT, the previous dosing cohort will be considered the MTD. DLT is defined as: (1) Grade 3, 4, or 5 non-hematologic toxicity considered at least possibly related to the study drug, except for infection, bleeding, fever, fatigue, dyspnea, and (2) Grade 3, 4, or 5 anemia, neutropenia or thrombocytopenia with a hypocellular bone marrow and \< 5% marrow blasts lasting for 42 days or more. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission (CR) Rate | Up to 3 years | Complete remission defined as participants that are free of all symptoms related to leukemia and have an absolute neutrophil count ≥ 1 x 10\^9/L, no need for red blood cell transfusion, platelet count ≥ 100 x 10\^9/L, and normal marrow differential (≤ 5 % blasts) in a normo- or hypercellular marrow. |
| Composite Complete Remission (CRc) Rate | Up to 3 years | CRc defined as (CR + Complete remission with incomplete count recovery (CRi)). CRi defined as CR but incomplete count recovery (absolute neutrophil count \< 1000/microL or platelet count \< 100,000/micro/L). |
| Partial Remission (PR) Rate | Up to 3 years | PR defined as CR with 6 - 25 % abnormal cells in the marrow or 50 % decrease in bone marrow blasts. |
| Progression Free Survival (PFS) | Up to 3 years | PFS is defined as the duration of time from entry on study to time of recurrence, flow cytometric relapse, cytogenetic relapse, molecular relapse, or death, whichever occurs first. |
| Overall Survival (OS) | Up to 3 years | OS is defined as the duration of time from entry on study to time of death from any cause. |
Countries
United States
Outcome results
None listed