Cancer
Conditions
Keywords
Advanced Cancer, Various, NOS
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.
Interventions
DRUGBMS-911543
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | 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). |
| Number of Participants With Best Overall Response | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 |
| 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) | 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 |
| Changes in (Janus Kinase) JAK/Signal Transducers and Activators of Transcription (STATs) Pathway Activities, Circulating CD34+ Cells and Plasma Cytokine Levels | 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. |
| Maximum Observed Plasma Concentration (Cmax) of BMS-911543 and it's Metabolite BMS-926796 (Met4) | 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 |
| Trough Observed (Pre-dose) Plasma Concentration (Cmin) of BMS-911543 and it's Metabolite Met4 | 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) |
| Time of Maximum Observed Plasma Concentration (Tmax) of BMS-911543 and it's Metabolite Met4 | 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 |
| 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 | 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 |
| 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 | 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 |
| Area Under the Concentration-time Curve in One Dosing Interval (AUC(TAU)) of BMS-911543 and it's Metabolite Met4 | 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 |
| The Terminal-phase Elimination Half-life in Plasma (T-HALF) of BMS-911543 and it's Metabolite Met4 | 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 |
| Apparent Total Clearance (for Parent Compound Only) (CLT/F) of BMS-911543 and it's Metabolite Met4 | 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 |
| 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 | 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 |
Countries
Australia, United States
Participant flow
Pre-assignment details
98 participants were enrolled and 84 participants were treated. 14 participants did not enter treatment period (13 no longer met study criteria and 1 due to other reasons). 42 entered Phase 1 and 42 entered Phase 2
Participants by arm
| Arm | Count |
|---|---|
| 5 mg Phase I BMS-911543 5 mg capsule by mouth twice daily | 4 |
| 10 mg Phase I BMS-911543 10 mg capsule by mouth twice daily | 4 |
| 20 mg Phase I BMS-911543 20 mg capsule by mouth twice daily | 4 |
| 40 mg Phase I BMS-911543 40 mg capsule by mouth twice daily | 4 |
| 80 mg Phase I BMS-911543 80 mg capsule by mouth twice daily | 4 |
| 120 mg Phase I BMS-911543 120 mg capsule by mouth twice daily | 4 |
| 160 mg Phase I BMS-911543 160 mg capsule by mouth twice daily | 8 |
| 200 mg Phase I BMS-911543 2000 mg capsule by mouth twice daily | 7 |
| 240 mg Phase I BMS-911543 240 mg capsule by mouth twice daily | 3 |
| 120 mg Phase II BMS-911543 120 mg capsule by mouth twice daily | 22 |
| 200 mg Phase II BMS-911543 200 mg capsule by mouth twice daily | 20 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 4 | 1 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Disease progression | 1 | 2 | 1 | 2 | 2 | 2 | 1 | 3 | 2 | 2 | 2 |
| Overall Study | Lack of response to drug | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Maximum clinical benefit | 1 | 1 | 1 | 0 | 2 | 0 | 3 | 1 | 1 | 4 | 2 |
| Overall Study | Patient moving to allogeneic transplant | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Patient transferred to IST | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 6 |
| Overall Study | Poor/Non-compliance | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Relapse of Splenomegaly and symptoms | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Study drug toxicity | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 2 | 2 |
| Overall Study | Subject request to discontinue treatment | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 0 | 1 | 4 |
| Overall Study | Subject to receive drug via EAP | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 2 | 0 | 4 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | 5 mg Phase I | 10 mg Phase I | 20 mg Phase I | 40 mg Phase I | 80 mg Phase I | 120 mg Phase I | 160 mg Phase I | 200 mg Phase I | 240 mg Phase I | 120 mg Phase II | 200 mg Phase II | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 76.8 Years STANDARD_DEVIATION 4.5 | 56.5 Years STANDARD_DEVIATION 3.7 | 70.5 Years STANDARD_DEVIATION 4.8 | 64.0 Years STANDARD_DEVIATION 7.7 | 69.8 Years STANDARD_DEVIATION 9.54 | 63.3 Years STANDARD_DEVIATION 12.97 | 70.1 Years STANDARD_DEVIATION 10.79 | 62.3 Years STANDARD_DEVIATION 6.47 | 63.0 Years STANDARD_DEVIATION 6.93 | 61.0 Years STANDARD_DEVIATION 11.09 | 62.5 Years STANDARD_DEVIATION 11.13 | 64.0 Years STANDARD_DEVIATION 10.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 00 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 4 Participants | 7 Participants | 6 Participants | 3 Participants | 16 Participants | 19 Participants | 70 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 5 Participants | 1 Participants | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 8 Participants | 7 Participants | 3 Participants | 20 Participants | 20 Participants | 82 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 4 Participants | 2 Participants | 1 Participants | 7 Participants | 12 Participants | 39 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 4 Participants | 5 Participants | 2 Participants | 15 Participants | 8 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 4 | 0 / 4 | 0 / 4 | 0 / 4 | 1 / 4 | 1 / 4 | 1 / 8 | 2 / 7 | 0 / 3 | 1 / 22 | 0 / 20 |
| other Total, other adverse events | 4 / 4 | 4 / 4 | 4 / 4 | 4 / 4 | 4 / 4 | 4 / 4 | 8 / 8 | 7 / 7 | 3 / 3 | 22 / 22 | 20 / 20 |
| serious Total, serious adverse events | 3 / 4 | 2 / 4 | 2 / 4 | 1 / 4 | 4 / 4 | 2 / 4 | 6 / 8 | 2 / 7 | 1 / 3 | 9 / 22 | 10 / 20 |
Outcome results
Primary
Number of Participants With Adverse Events
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).
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
Population: All treated participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 5 mg Phase I | Number of Participants With Adverse Events | No. of deaths | 1 Participants |
| 5 mg Phase I | Number of Participants With Adverse Events | No. of participants discontinued due to AEs | 1 Participants |
| 5 mg Phase I | Number of Participants With Adverse Events | No. of participants with Serious AEs | 3 Participants |
| 5 mg Phase I | Number of Participants With Adverse Events | Number of participants with AEs | 4 Participants |
| 10 mg Phase I | Number of Participants With Adverse Events | No. of participants discontinued due to AEs | 1 Participants |
| 10 mg Phase I | Number of Participants With Adverse Events | Number of participants with AEs | 4 Participants |
| 10 mg Phase I | Number of Participants With Adverse Events | No. of participants with Serious AEs | 2 Participants |
| 10 mg Phase I | Number of Participants With Adverse Events | No. of deaths | 0 Participants |
| 20 mg Phase I | Number of Participants With Adverse Events | Number of participants with AEs | 4 Participants |
| 20 mg Phase I | Number of Participants With Adverse Events | No. of deaths | 0 Participants |
| 20 mg Phase I | Number of Participants With Adverse Events | No. of participants with Serious AEs | 2 Participants |
| 20 mg Phase I | Number of Participants With Adverse Events | No. of participants discontinued due to AEs | 0 Participants |
| 40 mg Phase I | Number of Participants With Adverse Events | No. of participants with Serious AEs | 1 Participants |
| 40 mg Phase I | Number of Participants With Adverse Events | No. of participants discontinued due to AEs | 0 Participants |
| 40 mg Phase I | Number of Participants With Adverse Events | Number of participants with AEs | 4 Participants |
| 40 mg Phase I | Number of Participants With Adverse Events | No. of deaths | 0 Participants |
| 80 mg Phase I | Number of Participants With Adverse Events | No. of deaths | 1 Participants |
| 80 mg Phase I | Number of Participants With Adverse Events | No. of participants discontinued due to AEs | 1 Participants |
| 80 mg Phase I | Number of Participants With Adverse Events | Number of participants with AEs | 4 Participants |
| 80 mg Phase I | Number of Participants With Adverse Events | No. of participants with Serious AEs | 4 Participants |
| 120 mg Phase I | Number of Participants With Adverse Events | No. of deaths | 1 Participants |
| 120 mg Phase I | Number of Participants With Adverse Events | No. of participants with Serious AEs | 2 Participants |
| 120 mg Phase I | Number of Participants With Adverse Events | No. of participants discontinued due to AEs | 1 Participants |
| 120 mg Phase I | Number of Participants With Adverse Events | Number of participants with AEs | 4 Participants |
| 160 mg Phase I | Number of Participants With Adverse Events | No. of participants discontinued due to AEs | 3 Participants |
| 160 mg Phase I | Number of Participants With Adverse Events | Number of participants with AEs | 8 Participants |
| 160 mg Phase I | Number of Participants With Adverse Events | No. of deaths | 1 Participants |
| 160 mg Phase I | Number of Participants With Adverse Events | No. of participants with Serious AEs | 6 Participants |
| 200 mg Phase I | Number of Participants With Adverse Events | No. of participants with Serious AEs | 2 Participants |
| 200 mg Phase I | Number of Participants With Adverse Events | No. of deaths | 2 Participants |
| 200 mg Phase I | Number of Participants With Adverse Events | Number of participants with AEs | 7 Participants |
| 200 mg Phase I | Number of Participants With Adverse Events | No. of participants discontinued due to AEs | 0 Participants |
| 240 mg Phase I | Number of Participants With Adverse Events | No. of participants discontinued due to AEs | 1 Participants |
| 240 mg Phase I | Number of Participants With Adverse Events | No. of participants with Serious AEs | 1 Participants |
| 240 mg Phase I | Number of Participants With Adverse Events | Number of participants with AEs | 3 Participants |
| 240 mg Phase I | Number of Participants With Adverse Events | No. of deaths | 0 Participants |
| 120 mg Phase II | Number of Participants With Adverse Events | No. of participants with Serious AEs | 9 Participants |
| 120 mg Phase II | Number of Participants With Adverse Events | Number of participants with AEs | 22 Participants |
| 120 mg Phase II | Number of Participants With Adverse Events | No. of participants discontinued due to AEs | 7 Participants |
| 120 mg Phase II | Number of Participants With Adverse Events | No. of deaths | 1 Participants |
| 200 mg Phase II | Number of Participants With Adverse Events | Number of participants with AEs | 20 Participants |
| 200 mg Phase II | Number of Participants With Adverse Events | No. of deaths | 0 Participants |
| 200 mg Phase II | Number of Participants With Adverse Events | No. of participants with Serious AEs | 10 Participants |
| 200 mg Phase II | Number of Participants With Adverse Events | No. of participants discontinued due to AEs | 5 Participants |
Primary
Number of Participants With Best Overall Response
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.
Time frame: Day 1, at each returning on-treatment visit and the first post-treatment visit
Population: All treated participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 5 mg Phase I | Number of Participants With Best Overall Response | Clinical Improvement | 1 Participants |
| 5 mg Phase I | Number of Participants With Best Overall Response | Partial Remission | 0 Participants |
| 5 mg Phase I | Number of Participants With Best Overall Response | Relapse | 0 Participants |
| 5 mg Phase I | Number of Participants With Best Overall Response | Complete Remission | 0 Participants |
| 5 mg Phase I | Number of Participants With Best Overall Response | Progressive Disease | 0 Participants |
| 5 mg Phase I | Number of Participants With Best Overall Response | Stable Disease | 3 Participants |
| 10 mg Phase I | Number of Participants With Best Overall Response | Clinical Improvement | 1 Participants |
| 10 mg Phase I | Number of Participants With Best Overall Response | Complete Remission | 0 Participants |
| 10 mg Phase I | Number of Participants With Best Overall Response | Stable Disease | 2 Participants |
| 10 mg Phase I | Number of Participants With Best Overall Response | Relapse | 0 Participants |
| 10 mg Phase I | Number of Participants With Best Overall Response | Partial Remission | 0 Participants |
| 10 mg Phase I | Number of Participants With Best Overall Response | Progressive Disease | 1 Participants |
| 20 mg Phase I | Number of Participants With Best Overall Response | Stable Disease | 3 Participants |
| 20 mg Phase I | Number of Participants With Best Overall Response | Complete Remission | 0 Participants |
| 20 mg Phase I | Number of Participants With Best Overall Response | Progressive Disease | 0 Participants |
| 20 mg Phase I | Number of Participants With Best Overall Response | Clinical Improvement | 1 Participants |
| 20 mg Phase I | Number of Participants With Best Overall Response | Relapse | 0 Participants |
| 20 mg Phase I | Number of Participants With Best Overall Response | Partial Remission | 0 Participants |
| 40 mg Phase I | Number of Participants With Best Overall Response | Relapse | 0 Participants |
| 40 mg Phase I | Number of Participants With Best Overall Response | Partial Remission | 0 Participants |
| 40 mg Phase I | Number of Participants With Best Overall Response | Stable Disease | 3 Participants |
| 40 mg Phase I | Number of Participants With Best Overall Response | Complete Remission | 0 Participants |
| 40 mg Phase I | Number of Participants With Best Overall Response | Progressive Disease | 0 Participants |
| 40 mg Phase I | Number of Participants With Best Overall Response | Clinical Improvement | 1 Participants |
| 80 mg Phase I | Number of Participants With Best Overall Response | Stable Disease | 1 Participants |
| 80 mg Phase I | Number of Participants With Best Overall Response | Complete Remission | 0 Participants |
| 80 mg Phase I | Number of Participants With Best Overall Response | Relapse | 0 Participants |
| 80 mg Phase I | Number of Participants With Best Overall Response | Partial Remission | 0 Participants |
| 80 mg Phase I | Number of Participants With Best Overall Response | Progressive Disease | 1 Participants |
| 80 mg Phase I | Number of Participants With Best Overall Response | Clinical Improvement | 2 Participants |
| 120 mg Phase I | Number of Participants With Best Overall Response | Progressive Disease | 0 Participants |
| 120 mg Phase I | Number of Participants With Best Overall Response | Complete Remission | 0 Participants |
| 120 mg Phase I | Number of Participants With Best Overall Response | Partial Remission | 0 Participants |
| 120 mg Phase I | Number of Participants With Best Overall Response | Clinical Improvement | 0 Participants |
| 120 mg Phase I | Number of Participants With Best Overall Response | Stable Disease | 4 Participants |
| 120 mg Phase I | Number of Participants With Best Overall Response | Relapse | 0 Participants |
| 160 mg Phase I | Number of Participants With Best Overall Response | Relapse | 0 Participants |
| 160 mg Phase I | Number of Participants With Best Overall Response | Complete Remission | 0 Participants |
| 160 mg Phase I | Number of Participants With Best Overall Response | Clinical Improvement | 3 Participants |
| 160 mg Phase I | Number of Participants With Best Overall Response | Stable Disease | 4 Participants |
| 160 mg Phase I | Number of Participants With Best Overall Response | Partial Remission | 0 Participants |
| 160 mg Phase I | Number of Participants With Best Overall Response | Progressive Disease | 0 Participants |
| 200 mg Phase I | Number of Participants With Best Overall Response | Relapse | 0 Participants |
| 200 mg Phase I | Number of Participants With Best Overall Response | Stable Disease | 3 Participants |
| 200 mg Phase I | Number of Participants With Best Overall Response | Clinical Improvement | 3 Participants |
| 200 mg Phase I | Number of Participants With Best Overall Response | Complete Remission | 0 Participants |
| 200 mg Phase I | Number of Participants With Best Overall Response | Progressive Disease | 0 Participants |
| 200 mg Phase I | Number of Participants With Best Overall Response | Partial Remission | 1 Participants |
| 240 mg Phase I | Number of Participants With Best Overall Response | Clinical Improvement | 1 Participants |
| 240 mg Phase I | Number of Participants With Best Overall Response | Stable Disease | 2 Participants |
| 240 mg Phase I | Number of Participants With Best Overall Response | Partial Remission | 0 Participants |
| 240 mg Phase I | Number of Participants With Best Overall Response | Progressive Disease | 0 Participants |
| 240 mg Phase I | Number of Participants With Best Overall Response | Complete Remission | 0 Participants |
| 240 mg Phase I | Number of Participants With Best Overall Response | Relapse | 0 Participants |
| 120 mg Phase II | Number of Participants With Best Overall Response | Relapse | 0 Participants |
| 120 mg Phase II | Number of Participants With Best Overall Response | Complete Remission | 0 Participants |
| 120 mg Phase II | Number of Participants With Best Overall Response | Clinical Improvement | 12 Participants |
| 120 mg Phase II | Number of Participants With Best Overall Response | Partial Remission | 2 Participants |
| 120 mg Phase II | Number of Participants With Best Overall Response | Stable Disease | 6 Participants |
| 120 mg Phase II | Number of Participants With Best Overall Response | Progressive Disease | 0 Participants |
| 200 mg Phase II | Number of Participants With Best Overall Response | Partial Remission | 1 Participants |
| 200 mg Phase II | Number of Participants With Best Overall Response | Complete Remission | 0 Participants |
| 200 mg Phase II | Number of Participants With Best Overall Response | Clinical Improvement | 9 Participants |
| 200 mg Phase II | Number of Participants With Best Overall Response | Relapse | 0 Participants |
| 200 mg Phase II | Number of Participants With Best Overall Response | Progressive Disease | 0 Participants |
| 200 mg Phase II | Number of Participants With Best Overall Response | Stable Disease | 10 Participants |
Secondary
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
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
Time frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
Population: Data for this outcome measure was not collected for any participants because the study was terminated
Secondary
Apparent Total Clearance (for Parent Compound Only) (CLT/F) of BMS-911543 and it's Metabolite Met4
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
Time frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
Population: Data for this outcome measure was not collected for any participants because the study was terminated
Secondary
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
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
Time frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
Population: Data for this outcome measure was not collected for any participants because the study was terminated
Secondary
Area Under the Concentration-time Curve in One Dosing Interval (AUC(TAU)) of BMS-911543 and it's Metabolite Met4
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
Time frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
Population: Data for this outcome measure was not collected for any participants because the study was terminated
Secondary
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
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
Time frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
Population: Data for this outcome measure was not collected for any participants because the study was terminated
Secondary
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
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
Time frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
Population: Data for this outcome measure was not collected for any participants because the study was terminated
Secondary
Changes in (Janus Kinase) JAK/Signal Transducers and Activators of Transcription (STATs) Pathway Activities, Circulating CD34+ Cells and Plasma Cytokine Levels
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.
Time frame: Up to 6 months
Population: Data for this outcome measure was not collected for any participants because the study was terminated
Secondary
Maximum Observed Plasma Concentration (Cmax) of BMS-911543 and it's Metabolite BMS-926796 (Met4)
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
Time frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
Population: Data for this outcome measure was not collected for any participants because the study was terminated
Secondary
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)
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
Time frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
Population: Data for this outcome measure was not collected for any participants because the study was terminated
Secondary
The Terminal-phase Elimination Half-life in Plasma (T-HALF) of BMS-911543 and it's Metabolite Met4
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
Time frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
Population: Data for this outcome measure was not collected for any participants because the study was terminated
Secondary
Time of Maximum Observed Plasma Concentration (Tmax) of BMS-911543 and it's Metabolite Met4
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
Time frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
Population: Data for this outcome measure was not collected for any participants because the study was terminated
Secondary
Trough Observed (Pre-dose) Plasma Concentration (Cmin) of BMS-911543 and it's Metabolite Met4
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)
Time frame: Day -1, Day 1, Day 8, Day 15, Day 21 and Day 28 or off-study
Population: Data for this outcome measure was not collected for any participants because the study was terminated