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Study Summary
No. 2010-0782:.......Myeloproliferative Diseases......Srdan Verstovsek......Leukemia
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Study Summary Title
Study Summary
Number:
2010-0782
Study Title:A Phase 1/2 Multiple Ascending Dose Study to Evaluate the Safety, Efficacy,
Pharmacokinetics and Pharmacodynamics of BMS-911543 in Subjects with
Myelofibrosis
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Physician New Patient Referral
Name:Srdan VerstovsekPatients Call:800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)
Dept:LeukemiaReferring MD
Call:
800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)
Phone:713-792-7305
Contact us about clinical trials
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General Information
Disease Group:Myeloproliferative DiseasesSupported By:Bristol-Myers Squibb Co.
Phase of Study:Phase I/Phase IIReturn
Visit:
Treatment
Agents:
BMS-911543Home Care:
Treatment Loc:Both at MDACC & and Other Sites
Estimated
Length of Stay
in Houston:
Description/
Intervention:
The goal of Phase 1 of this clinical research study is to learn the highest
tolerable dose of BMS-911543 that can be given to patients with MF. The goal
of Phase 2 of this study is to learn if BMS-911543 can help to control MF. The
safety of BMS-911543 will also be studied. You are being asked to take part in
the Phase 1 portion of the study.
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Study Objectives / Outcomes
Primary Objectives:
Phase 1:
  • To assess the safety, tolerability, dose-limiting toxicities (DLTs), and to determine the maximum tolerated dose (MTD) and clinically active dose (CAD) range of BMS-911543 administered orally to symptomatic MF subjects.
Phase 2:
  • To assess the efficacy of BMS-911543 in subjects with symptomatic MF at a dose suitable for
Phase 2 studies.

Secondary Objectives:
Phase 1:
· To assess the efficacy of BMS-911543 in subjects with symptomatic MF.
Phase 1 and 2:
· To assess the effects of BMS-911543 on: heart rate (HR), pulse rate (PR), QRS, QTcF and ÄQTcF ntervals (from pre-dose value) on the electrocardiogram;
· To characterize the single and multiple dose PK of BMS-911543 and its active metabolite BMS-926796 (Met4);
· To evaluate in blood the PD effects (JAK/STATs pathway activity, number of circulating CD34+
stem/progenitor cells and mutant allele burden) and PK/PD relationships of BMS-911543 in
subjects with MF.
Phase 2:
· To establish the safety and tolerability of BMS-911543 on a once-daily dosing schedule (if appropriate).

Exploratory Objectives:All Subjects
· To gain a preliminary understanding of BMS-911543 circulating plasma metabolite profiles in selected samples;
  • To explore the levels of plasma cytokines in subjects with MF.
· To explore the possibility of predicting individual clinical responses to BMS-911543 using:
o a JAK2-driven STAT over-activity gene expression signature defined using a variety of cell types and that is predictive of a BMS-911543 clinical response in a range of nonclinical settings;
o a gene-expression signature that is predictive of a BMS-911543 induced clinical response derived from a de novo analysis of symptomatic MF subjects that respond to treatment with BMS-911543;
o pSTAT3 and pSTAT5 expression as determined by immunohistochemisty (IHC).
o Serum biomarker specific to theBMS 911543 clincal response collected in Phase II only.
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Study Status Information
Study Activation / Registration Date:
IRB Review and Approval Date:05/09/2011
Study Type:Phase Ii Or Phase I/Ii
Recruitment Status:Closed
Projected Accrual:Up to 68
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Enrollment Eligibility
If you do not meet the enrollment eligibility, there may be other treatment options for you. Please Contact the Referral Office for more information.

Inclusion Criteria:1) The signed informed consent form. Willing and able to give informed consent; this must be obtained before performing protocol-related procedures that are not part of standard patient care.

2) Phase 1 and Phase 2 i. Subjects with a diagnosis of primary or secondary MF (WHO 2008 criteria)29 with intermediate-1, intermediate-2 or high risk disease as assessed using the Dynamic International Prognostic Scoring System (DIPSS) international prognostic scoring system1,2. Subjects may be ii. JAK2 and/or MPL mutation positive or WT; iii. Symptomatic disease;, defined as subjects that have >1 of the following symptoms: 1. Severe night sweats 2. Severe pruritis 3. Recurrent fevers (at least once a week and in the absence of another identified cause) 4. Unintentional weight loss (>10 pounds in 6 months) 5. Diffuse bone pain (not joint pain or arthritis) 6. Abdominal pain, discomfort or early satiety in the context of splenomegaly >5cm; ; iv. Should not have received any MF therapy for equal to or greater than 2 weeks prior to commencement of treatment with the study drug;

3) Not willing to undergo, not a candidate for, or not having a donor for bone marrow transplantation (BMT).

4) Ability to comply with visits/procedures required by the protocol

5) Eastern Cooperative Oncology Group (ECOG) performance status 0-2;

6) Previous treatment-related toxicities from prior therapies must have resolved to NCI CTCAE v 4.0 equal to or less than Grade 1

7) The following laboratory results, within 7 days prior to BMS-911543 Cycle 1 Day 1 treatment commencement: i. ALT (alanine transaminase) and AST (aspartate transaminase) equal to or less than 1.5x IULN (or equal to or less than 5x IULN in the case of subjects with MF accompanied by hepatic extramedullary hematopoiesis as manifested by the presence of any degree of hepatomegaly); ii. Serum creatinine equal to or less than 1.5x institutional upper limit of normal (IULN) or creatinine clearance equal to or more than 60mL/min; iii. Total bilirubin equal to or less than 3x IULN; iv. Serum amylase and lipase eual to or less than 1.5x IULN; v. Platelet count equal to or more than 50,000 cells mm3; vi. Absolute neutrophil count (ANC) equal to or more than 1,000 cells/mm3; vii. Hemoglobin equal to or more than 8.0 g/dL.

8) Men and women, equal to or more than 18 years.

9) Women of childbearing potential (WOCBP) must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized.

10) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product.

11) Women must not be breastfeeding.

12) Sexually active fertile men must use effective birth control if their partners are WOCBP throughout the study and for up to 8 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized.

Exclusion Criteria:1) Primary central nervous system tumors

2) 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 localized malignancy that has undergone potentially curative therapy with no evidence of disease recurrence equal to or greater than 3 years and that is deemed by the Investigator to be at low risk of recurrence;

3) Any condition requiring chronic use of moderate/high dose steroids (equivalent to equal to or greater than 30mg daily prednisolone). Inhalation or oral steroids for mild pulmonary disease (not leading to exclusion using the defined criteria) are permitted.

4) Any clinically significant acute or chronic medical illness as judged by the treating physician

5) Current or recent (within 3 months of study drug administration) gastrointestinal disease

6) Any gastrointestinal surgery that could impact upon the absorption of study drug as judged by the treating physician

7) Inability to tolerate oral medication as judged by the Investigator

8) Evidence of uncontrolled active infection

9) Failure to recover (to CTCAE V4.0 Grade 0-1) from acute, reversible effects of prior chemotherapy or therapies associated with transplantation

10) Presence of active graft vs. host disease

11) Subjects who have significant cardiac disease or who have a personal or family history of congenital long QT syndrome, or have a baseline equal to or greater than 450 msec QTcF abnormality unless attributable to a pre-existing Bundle Branch Block;

12) Subjects with a history of myocardial infarction or uncontrolled angina equal to or less than 6 months prior to the administration of study medication

13) Symptomatic congestive cardiac failure (New York Heart Association equal to or less than Class 3, an unstable cardiac arrhythmia requiring medication, presence of a significant atrial or ventricular tachyarrhythmia, use of a cardiac pacemaker, complete left bundle branch block, or left ventricular ejection fraction (LVEF) < institutional lower limit of normal as determined by a MUGA or ECHO

14) The MUGA or ECHO must have been performed within 3 months of Cycle 1 Day 1 and be within normal limits

15) Presence of any underlying medical condition that could adversely affect the ability of the subject to comply with study procedures and/or study therapy as judged by the treating physician

16) Uncontrolled or significant inflammatory bowel disease (IBD) or uncontrolled peptic ulcer disease

17) Uncontrolled disseminated intravascular coagulation (DIC)

18) History of significant upper or lower gastrointestinal bleeding equal to or less than 6 months prior to enrollment

19) Splenic irradiation equal to or less than 3 months prior to treatment with study drug

20) Any other sound medical, psychiatric and/or social reason as determined by the Investigator and/or MM.

21) Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, or HIV-1, or HIV-2 antibodies

22) Abnormalities in serum electrolytes (sodium, potassium, calcium, phosphorus and magnesium) that are equal to or more than CTCAE v.4.0 Grade 2 and that are not correctable.

23) Abnormalities in serum electrolytes must be corrected to equal to or less than Grade 1 prior to study treatment

24) History of allergy to a JAK2 inhibitor

25) Prisoners or subjects who are involuntarily incarcerated

26) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness.

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Links
Registration Number: NCT01236352
Study Information on Clinical Trials Registry (clinicaltrials.gov)

Other Links:
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Results


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