Try the modernized ClinicalTrials.gov beta website. Learn more about the modernization effort.
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Multiple Ascending Dose of BMS-911543

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01236352
Recruitment Status : Terminated (Due to portfolio/business decisions by the sponsor)
First Posted : November 7, 2010
Results First Posted : May 21, 2019
Last Update Posted : July 31, 2019
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

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.

Condition or disease Intervention/treatment Phase
Cancer Drug: BMS-911543 Phase 1 Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 98 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 7, 2011
Actual Primary Completion Date : November 19, 2015
Actual Study Completion Date : November 19, 2015

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase 1 (Cohort 1): BMS-911543 (5 mg)
BMS-911543 5 mg capsule by mouth twice daily for 12 months or greater depending on response
Drug: BMS-911543
Other Name: JAK2 Inhibitor

Experimental: Phase 1 (Cohort 2): BMS-911543 (10 mg)
BMS-911543 10 mg capsule by mouth twice daily for 12 months or greater depending on response
Drug: BMS-911543
Other Name: JAK2 Inhibitor

Experimental: Phase 1 (Cohort 3): BMS-911543 (20 mg)
BMS-911543 20 mg capsule by mouth twice daily for 12 months or greater depending on response
Drug: BMS-911543
Other Name: JAK2 Inhibitor

Experimental: Phase 1 (Cohort 4): BMS-911543 (40 mg)
BMS-911543 40 mg capsule by mouth twice daily for 12 months or greater depending on response
Drug: BMS-911543
Other Name: JAK2 Inhibitor

Experimental: Phase 1 (Cohort 5): BMS-911543 (80 mg)
BMS-911543 80 mg capsule by mouth twice daily for 12 months or greater depending on response
Drug: BMS-911543
Other Name: JAK2 Inhibitor

Experimental: Phase 1 (Cohort 6): BMS-911543 (120 mg)
BMS-911543 120 mg capsule by mouth twice daily for 12 months or greater depending on response
Drug: BMS-911543
Other Name: JAK2 Inhibitor

Experimental: Phase 1 (Cohort 7): BMS-911543 (160 mg)
BMS-911543 160 mg capsule by mouth twice daily for 12 months or greater depending on response
Drug: BMS-911543
Other Name: JAK2 Inhibitor

Experimental: Phase 1 (Cohort 8): BMS-911543 (200 mg)
BMS-911543 200 mg capsule by mouth twice daily for 12 months or greater depending on response
Drug: BMS-911543
Other Name: JAK2 Inhibitor

Experimental: Phase 1 (Cohort 9): BMS-911543 (240 mg)
BMS-911543 240 mg capsule by mouth twice daily for 12 months or greater depending on response
Drug: BMS-911543
Other Name: JAK2 Inhibitor

Experimental: Phase 1 (Cohort 10): BMS-911543 (320 mg)
BMS-911543 320 mg capsule by mouth twice daily for 12 months or greater depending on response
Drug: BMS-911543
Other Name: JAK2 Inhibitor

Experimental: Phase 2 (Cohort 11): BMS-911543 (120 mg)
BMS-911543 120 mg capsule by mouth twice daily for 12 months or greater depending on response
Drug: BMS-911543
Other Name: JAK2 Inhibitor

Experimental: Phase 2 (Cohort 12): BMS-911543 (200 mg)
BMS-911543 200 mg capsule by mouth twice daily for 12 months or greater depending on response
Drug: BMS-911543
Other Name: JAK2 Inhibitor




Primary Outcome Measures :
  1. Number of Participants With Adverse Events [ Time Frame: 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 ]
    Safety assessments were based on a medical review of adverse event reports and the results of vital sign measurements, ECGs, physical examinations, and clinical laboratory tests and were evaluated for all treated participants using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 (NCI CTCAE v.4.0).

  2. Number of Participants With Best Overall Response [ Time Frame: Day 1, at each returning on-treatment visit and the first post-treatment visit ]
    Participants were clinically assessed for IWG-(International Working Group consensus criteria for treatment response in myelofibrosis with myeloid metaplasia) defined response at each returning on-treatment visit and the first post-treatment visit. IWG-MRT criteria for best overall response are ordered high to low: CR>PR>CI>SD>PD>R where CR = Complete Remission, PR= Partial Remission, CI = Clinical Improvement, SD = Stable Disease, PD = Progressive Disease and R = Relapse. Best overall response is the best response of the subject during the treatment period or at the first post-treatment visit.


Secondary Outcome Measures :
  1. Changes in (Janus Kinase) JAK/Signal Transducers and Activators of Transcription (STATs) Pathway Activities, Circulating CD34+ Cells and Plasma Cytokine Levels [ Time Frame: Up to 6 months ]
    JAK/STAT pathway activity will be evaluated by: 1) pSTATs levels using immunoassay; 2) expression levels of several JAK/STATs pathway genes. Whole blood will be collected at specific time-points. Due to portfolio/business decisions by the sponsor, the compound is no longer being developed and the study was terminated. Analysis was not completed because the study was terminated. This decision was not based on any safety concerns associated with BMS-911543.

  2. Maximum Observed Plasma Concentration (Cmax) of BMS-911543 and it's Metabolite BMS-926796 (Met4) [ Time Frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study ]
    Pharmacokinetic parameters of BMS-911543 and BMS-926796 (Met4) metabolite, will be derived from plasma concentration versus time. The pharmacokinetic parameters to be assessed include: Cmax Maximum observed plasma concentration

  3. Trough Observed (Pre-dose) Plasma Concentration (Cmin) of BMS-911543 and it's Metabolite Met4 [ Time Frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study ]
    Pharmacokinetic parameters of BMS-911543 and BMS-926796 (Met4) metabolite, will be derived from plasma concentration versus time. The pharmacokinetic parameters to be assessed include: Cmin (Trough observed (pre-dose) plasma concentration)

  4. Time of Maximum Observed Plasma Concentration (Tmax) of BMS-911543 and it's Metabolite Met4 [ Time Frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study ]
    Pharmacokinetic parameters of BMS-911543 and BMS-926796 (Met4) metabolite, will be derived from plasma concentration versus time. The pharmacokinetic parameters to be assessed include: Tmax = Time of maximum observed plasma concentration (Tmax) of BMS-911543 and it's metabolite Met4

  5. 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 [ Time Frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study ]
    Pharmacokinetic parameters of BMS-911543 and BMS-926796 (Met4) metabolite, will be derived from plasma concentration versus time. The pharmacokinetic parameters to be assessed include: AUC(INF) = 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

  6. 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 [ Time Frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study ]
    Pharmacokinetic parameters of BMS-911543 and BMS-926796 (Met4) metabolite, will be derived from plasma concentration versus time. The pharmacokinetic parameters to be assessed include: AUC (0-T) = Area under the plasma concentration-time curve from time zero to the time of last quantifiable plasma concentration (for single dose period only) of BMS-911543 and it's metabolite Met4

  7. Area Under the Concentration-time Curve in One Dosing Interval (AUC(TAU)) of BMS-911543 and it's Metabolite Met4 [ Time Frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study ]
    Pharmacokinetic parameters of BMS-911543 and BMS-926796 (Met4) metabolite, will be derived from plasma concentration versus time. The pharmacokinetic parameters to be assessed include: AUC (TAU) = Area under the concentration-time curve in one dosing interval of BMS-911543 and it's metabolite Met4

  8. The Terminal-phase Elimination Half-life in Plasma (T-HALF) of BMS-911543 and it's Metabolite Met4 [ Time Frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study ]
    Pharmacokinetic parameters of BMS-911543 and BMS-926796 (Met4) metabolite, will be derived from plasma concentration versus time. The pharmacokinetic parameters to be assessed include: T-HALF = The terminal-phase elimination half-life in plasma of BMS-911543 and it's metabolite Met4

  9. Apparent Total Clearance (for Parent Compound Only) (CLT/F) of BMS-911543 and it's Metabolite Met4 [ Time Frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study ]
    Pharmacokinetic parameters of BMS-911543 and BMS-926796 (Met4) metabolite, will be derived from plasma concentration versus time. The pharmacokinetic parameters to be assessed include: CLT/F = Apparent total clearance (for parent compound only) of BMS-911543 and it's metabolite Met4

  10. 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 [ Time Frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study ]
    Pharmacokinetic parameters of BMS-911543 and BMS-926796 (Met4) metabolite, will be derived from plasma concentration versus time. The pharmacokinetic parameters to be assessed include: Vz/F = Apparent volume of distribution after first dosing based on the terminal phase (for parent compound only) of BMS-911543 and it's metabolite Met4

  11. 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 [ Time Frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study ]
    Pharmacokinetic parameters of BMS-911543 and BMS-926796 (Met4) metabolite, will be derived from plasma concentration versus time. The pharmacokinetic parameters to be assessed include: 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

  12. 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) [ Time Frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study ]
    Pharmacokinetic parameters of BMS-911543 and BMS-926796 (Met4) metabolite, will be derived from plasma concentration versus time. The pharmacokinetic parameters to be assessed include: AUC Ratio = 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01236352


Locations
Layout table for location information
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, New York
The Mount Sinai School Of Medicine
New York, New York, United States, 10029
United States, Texas
The University Of Texas Md Anderson Cancer Center
Houston, Texas, United States, 77030
Australia, Victoria
Local Institution
East Melbourne, Victoria, Australia, 3002
Local Institution
Melbourne, Victoria, Australia, 3050
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Layout table for investigator information
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
Additional Information:
Layout table for additonal information
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01236352    
Other Study ID Numbers: CA215-001
First Posted: November 7, 2010    Key Record Dates
Results First Posted: May 21, 2019
Last Update Posted: July 31, 2019
Last Verified: July 2019
Keywords provided by Bristol-Myers Squibb:
Advanced Cancer, Various, NOS