Clinical trial NCT01236352: Multiple Ascending Dose of BMS-911543
Official title: A Phase 1/2 Multiple Ascending Dose Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of BMS-911543 in Subjects With Myelofibrosis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Cancer
Keywords: Advanced Cancer, Various, NOS
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2010-11-07
Enrollment: 98
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this first in human study is to determine if BMS-911543 is safe and tolerable in subjects with symptomatic intermediate-1, intermediate-2 or high risk myelofibrosis to permit clinical testing at the Maximum Tolerated Dose or at a Clinically Active Dose, and to determine if BMS-911543 will demonstrate efficacy in symptomatic myelofibrosis.


Eligibility criteria: For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com.

Inclusion Criteria:

* Men and Women at least 18 years old
* A diagnosis of symptomatic, primary or secondary Myelofibrosis (MF) \[World Health Organization (WHO) 2008 criteria\] with intermediate-1, intermediate-2 or high risk disease as assessed using the Dynamic International Prognostic Scoring System international prognostic scoring system
* Last therapeutic or diagnostic treatment at least 28 days prior
* Any toxicity from prior therapies must have resolved to Grade ≤1
* Adequate Liver and Kidney Function
* Serum amylase and lipase within normal institutional range
* Platelet count ≥50,000 cell mm³
* Absolute neutrophil count (ANC) ≥1,000 cells/mm3
* Hemoglobin ≥8.0 g/dL

Exclusion Criteria:

* Primary central nervous system tumors
* Subjects with currently active malignancy (other than MF) or with a prior history of malignancy with the exception of: (i) adequately treated basal cell carcinoma of the skin, (ii) curatively treated in situ carcinoma of the cervix, (iii) other malignancy that has undergone potentially curative therapy with no evidence of disease recurrence ≥3 years
* Any condition requiring chronic use of moderate/high dose steroids except inhalation or oral steroids for mild pulmonary disease
* Splenic irradiation ≤3 months prior to treatment with study drug
* Positive blood screen for hepatitis C antibody, hepatitis B surface antigen or Human Immunodeficiency Virus-1 (HIV-1), or HIV-2 antibodies
* Abnormalities in serum electrolytes
* Significant cardiovascular disease
* Current or recent gastrointestinal disease
* Previous history of pancreatitis and/or significant risk factors for pancreatitis as judged by the treating physician
* Evidence of uncontrolled active infection or active graft vs. host disease
* Inability to tolerate oral medication

Primary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: From the date of participant's written consent until 30 days post discontinuation of dosing or participation in the study if the last scheduled visit occured at a later time, assessed up to 4.5 years
measure: Number of Participants With Best Overall Response
timeFrame: Day 1, at each returning on-treatment visit and the first post-treatment visit
Secondary outcomes:
measure: Changes in (Janus Kinase) JAK/Signal Transducers and Activators of Transcription (STATs) Pathway Activities, Circulating CD34+ Cells and Plasma Cytokine Levels
timeFrame: Up to 6 months
measure: Maximum Observed Plasma Concentration (Cmax) of BMS-911543 and it's Metabolite BMS-926796 (Met4)
timeFrame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
measure: Trough Observed (Pre-dose) Plasma Concentration (Cmin) of BMS-911543 and it's Metabolite Met4
timeFrame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
measure: Time of Maximum Observed Plasma Concentration (Tmax) of BMS-911543 and it's Metabolite Met4
timeFrame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
measure: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time (for Single Dose Period Only) (AUC(INF)) of BMS-911543 and it's Metabolite Met4
timeFrame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Plasma Concentration (for Single Dose Period Only) (AUC(0-T)) of BMS-911543 and it's Metabolite Met4
timeFrame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
measure: Area Under the Concentration-time Curve in One Dosing Interval (AUC(TAU)) of BMS-911543 and it's Metabolite Met4
timeFrame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
measure: The Terminal-phase Elimination Half-life in Plasma (T-HALF) of BMS-911543 and it's Metabolite Met4
timeFrame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
measure: Apparent Total Clearance (for Parent Compound Only) (CLT/F) of BMS-911543 and it's Metabolite Met4
timeFrame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
measure: Apparent Volume of Distribution After First Dosing Based on the Terminal Phase (for Parent Compound Only) (Vz/F) of BMS-911543 and it's Metabolite Met4
timeFrame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
measure: Accumulation Index (AI): Ratio of AUC(TAU) on Day 15 to AUC(TAU) After the First Dose of BMS-911543 and it's Metabolite Met4
timeFrame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
measure: Ratio of BMS-926796 AUC(INF) to BMS-911543 AUC(INF) After 1st Dose and BMS-926796 AUC(TAU) to BMS-911543 AUC(TAU) on Day 15 (AUC Ratio)
timeFrame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: The Mount Sinai School Of Medicine
state: New York
city: Houston
country: United States
facility: The University Of Texas Md Anderson Cancer Center
state: Texas
city: East Melbourne
country: Australia
facility: Local Institution
state: Victoria
city: Melbourne
country: Australia
facility: Local Institution
state: Victoria
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: