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Safety Study Evaluating Twice-Daily Administration of Momelotinib in Primary Myelofibrosis or Post-Polycythemia Vera or Post-Essential Thrombocythemia Myelofibrosis

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ClinicalTrials.gov Identifier: NCT01423058
Recruitment Status : Completed
First Posted : August 25, 2011
Last Update Posted : February 4, 2019
Sponsor:
Information provided by (Responsible Party):
Sierra Oncology, Inc.

Tracking Information
First Submitted Date  ICMJE July 7, 2011
First Posted Date  ICMJE August 25, 2011
Last Update Posted Date February 4, 2019
Study Start Date  ICMJE August 2011
Actual Primary Completion Date June 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 16, 2015)
  • To determine the safety of momelotinib by characterization and relationship of adverse events, affects on vital signs and laboratory parameters, and QTc intervals as measured by electrocardiogram (ECG) [ Time Frame: 6 months ]
  • To determine maximum tolerated dose of momelotinib by characterization of Dose Limiting Toxicities [ Time Frame: 6 months ]
  • To confirm the half-life of momelotinib by pharmacokinetic analyses [ Time Frame: 6 months ]
  • To determine the efficacy of momelotinib by evaluation of spleen and liver size, disease related constitutional symptoms, transfusion dependence and anemia response. [ Time Frame: 6 months ]
Original Primary Outcome Measures  ICMJE
 (submitted: August 24, 2011)
  • To determine the safety of CYT387 by characterization and relationship of adverse events, affects on vital signs and laboratory parameters, and QTc intervals as measured by electrocardiogram (ECG) [ Time Frame: 6 months ]
  • To determine maximum tolerated dose of CYT387 by characterization of Dose Limiting Toxicities [ Time Frame: 6 months ]
  • To confirm the half-life of CYT387 by pharmacokinetic analyses [ Time Frame: 6 months ]
  • To determine the efficacy of CYT387 by evaluation of spleen and liver size, disease related constitutional symptoms, transfusion dependence and anemia response. [ Time Frame: 6 months ]
Change History Complete list of historical versions of study NCT01423058 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 16, 2015)
  • To determine the effect of momelotinib on JAK2V617F mutant allele burden via Polymerase Chain Reaction (PCR) analyses [ Time Frame: 6 months ]
  • To determine the effect of momelotinib on plasma levels of inflammatory, fibrogenic and angiogenic cytokines via Enzyme-Linked Immunosorbent Assay (ELISA) [ Time Frame: 6 months ]
  • To determine the effect of momelotinib on bone marrow or peripheral blood cytogenetic findings [ Time Frame: 6 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 24, 2011)
  • To determine the effect of CYT387 on JAK2V617F mutant allele burden via Polymerase Chain Reaction (PCR) analyses [ Time Frame: 6 months ]
  • To determine the effect of CYT387 on plasma levels of inflammatory, fibrogenic and angiogenic cytokines via Enzyme-Linked Immunosorbant Assay (ELISA) [ Time Frame: 6 months ]
  • To determine the effect of CYT387 on bone marrow or peripheral blood cytogenetic findings [ Time Frame: 6 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety Study Evaluating Twice-Daily Administration of Momelotinib in Primary Myelofibrosis or Post-Polycythemia Vera or Post-Essential Thrombocythemia Myelofibrosis
Official Title  ICMJE A Phase I/II, Open-Label Study Evaluating Twice-Daily Administration of CYT387 in Primary Myelofibrosis or Post-Polycythemia Vera or Post-Essential Thrombocythemia Myelofibrosis
Brief Summary

The myeloproliferative neoplasms (MPN), most notably polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are a diverse but inter-related suite of clonal disorders of pluripotent hematopoietic stem cells (Tefferi et al., 2008). The MPN share a range of biological, pathological, and clinical features including the relative overproduction of one or more cells of myeloid origin, growth factor independent colony formation in vitro, marrow hypercellularity, extramedullary hematopoiesis, spleno- and hepatomegaly, and thrombotic and/or hemorrhagic diatheses (Tefferi et al., 2005).

This is a multi-centre, open-label, non-randomized, dose-escalation study, to be conducted in two phases: a dose-escalation phase (Part 1), to determine the safety and tolerability of momelotinib (CYT387), and to identify a therapeutic dose for the expanded cohort; and a dose-confirmation phase (Part 2), which will be a cohort expansion at or below the MTD of momelotinib.

In the Part I dose-escalation phase of the study, subjects will be assigned to dose levels in successive cohorts starting with a dose in the first cohort of 200 mg BID (twice daily with doses taken approximately 12 hours apart). Doses will be escalated by 50 mg BID per cohort until dose-limiting toxicities are observed. The dose level at which ≥2 of 6 subjects develop a first cycle dose-limiting toxicity (DLT) is defined as the DLT level. The maximum tolerated dose (MTD) is defined as the dose level below the DLT level. New dose levels may begin accrual only if all subjects at the current dose level have been observed for a minimum of 28 days from the first day of treatment. The dose level chosen for study in the dose confirmation phase of the study will be the MTD or a lower dose shown to have significant clinical activity (efficacy) as determined by the safety review committee. Subjects will be evaluated weekly for the first cycle, every 2 weeks during cycle 2, then monthly for 4 cycles for a total of 6 cycles.

In the dose-confirmation phase of the study, approximately fifty (50) subjects will be treated at the MTD or at a lower dose shown to have significant clinical activity (efficacy) as chosen by the Safety Review Committee. In the dose confirmation phase of the study subjects will be evaluated every 2 weeks during the first treatment cycle, and then monthly for 5 cycles for a total of 6 cycles.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Primary Myelofibrosis
  • Post-Polycythemia Vera
  • Post-Essential Thrombocythemia Myelofibrosis
Intervention  ICMJE Drug: Momelotinib

In the Part I dose-escalation phase of the study, subjects will be assigned to dose levels in successive cohorts starting with a dose in the first cohort of 200 mg BID (twice daily with doses taken approximately 12 hours apart. Doses will be escalated by 50 mg BID in successive cohorts of 3 subjects per dose level. Subjects will be evaluated weekly for the first cycle, every 2 weeks during cycle 2, then monthly for 4 cycles for a total of 6 cycles.

In the dose confirmation phase of the study (Part 2), subjects will be evaluated every 2 weeks during the first treatment cycle, and then monthly for 5 cycles for a total of 6 cycles.

Other Name: CYT387
Study Arms  ICMJE Experimental: Momelotinib
Intervention: Drug: Momelotinib
Publications * Gupta V, Mesa RA, Deininger MW, Rivera CE, Sirhan S, Brachmann CB, Collins H, Kawashima J, Xin Y, Verstovsek S. A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis. Haematologica. 2017 Jan;102(1):94-102. doi: 10.3324/haematol.2016.148924. Epub 2016 Sep 15.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 17, 2013)
61
Original Estimated Enrollment  ICMJE
 (submitted: August 24, 2011)
60
Actual Study Completion Date  ICMJE June 2014
Actual Primary Completion Date June 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis of PMF or post-ET/PV MF as per revised World Health Organization (WHO) criteria (Section 16.4, Appendix 3).
  • High-risk or Intermediate-2 risk MF (as defined by the International Prognostic Scoring System [IPSS]; Section 16.6, Appendix 5); or Intermediate-1 risk MF (IPSS) associated with symptomatic splenomegaly/hepatomegaly and/or unresponsive to available therapy.
  • Must be at least 18 years of age with life expectancy of ≥ 12 weeks.
  • Must be able to provide informed consent and be willing to sign an informed consent form.
  • Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Section 16.3, Appendix 2).
  • Must have evidence of acceptable organ function within 7 days of initiating study drug as evidenced by the following:
  • AST or ALT less than or equal 2.5 x upper limit of normal (ULN) (or less than or equal to 5 x ULN if in the investigator's opinion the elevation is due to extramedullary hematopoiesis)
  • Direct Bilirubin less than or equal to 2.0 x ULN
  • Serum creatinine less than or equal to 2.5 x ULN
  • Absolute neutrophil count ≥ 500/µL
  • Platelet count ≥ 50,000/µL
  • Females of childbearing potential must have a negative pregnancy test within 4 days of initiating study drug.

Exclusion Criteria:

  • Any chemotherapy (e.g., hydroxyurea), immunomodulatory drug therapy (e.g., thalidomide), immunosuppressive therapy, corticosteroids >10 mg/day prednisone or equivalent, or growth factor treatment (e.g., erythropoietin) within 14 days prior to initiation of study drug.
  • Incomplete recovery from major surgery within four weeks of study entry.
  • Radiation therapy within four weeks of study entry.
  • Women of childbearing potential, unless surgically sterile for at least 3 months (i.e., hysterectomy), OR postmenopausal for at least 12 months (FSH > 30 U/mL), OR unless they agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through end of study. Permitted methods for preventing pregnancy must be communicated to study subjects and their understanding confirmed.
  • Men who partner with a woman of childbearing potential, unless they agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through to the end of study. Permitted methods for preventing pregnancy must be communicated to study subjects and their understanding confirmed.
  • Females who are pregnant or are currently breastfeeding.
  • Known positive status for HIV.
  • Positive serologic testing for hepatitis B (HBsAg and HBcAb total) and hepatitis C (anti-HCV)
  • Diagnosis of another malignancy unless free of disease for at least three years following therapy with curative intent. Patients with early-stage basal cell or squamous cell skin cancer, cervical intraepithelial neoplasia, cervical carcinoma in situ or superficial bladder cancer may be eligible participate at the Investigator's discretion.
  • Any acute active infection.
  • Cardiac dysrhythmias requiring treatment, or prolongation of the QTc (Fridericia) interval to >480 at pre-study screening, unless attributable to pre-existing bundle branch block.
  • Presence of ≥ grade 2 peripheral neuropathy.
  • Uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4), uncontrolled or unstable angina, myocardial infarction, cerebrovascular accident, or pulmonary embolism within 3 months prior to initiation of study drug.
  • Uncontrolled intercurrent illness or any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the patient or compliance with the protocol.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01423058
Other Study ID Numbers  ICMJE YM387-II-02
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sierra Oncology, Inc.
Study Sponsor  ICMJE Sierra Oncology, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Mark Kowalski, M.D. YM Biosciences Inc.
PRS Account Sierra Oncology, Inc.
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP