Clinical Trials /

A Study to Evaluate the Efficacy and Safety of Vismodegib in Combination With Ruxolitinib for the Treatment of Intermediate- or High-Risk Myelofibrosis (MF)

NCT02593760

Description:

This multicenter, randomized, double-blind, placebo-controlled study will evaluate the efficacy and safety of vismodegib plus (+) ruxolitinib versus placebo + ruxolitinib in participants with intermediate- or high-risk MF. The study will be divided into 2 components. The Phase Ib portion of the study consists of participants receiving open-label vismodegib (150 milligrams [mg] orally [PO] once daily [QD]) + ruxolitinib (PO twice daily [BID]). A safety assessment will be performed after the first 10 participants have been treated for 6 weeks. An analysis for efficacy and safety is planned in the first 10 participants at Week 24. There will be a hold on participant screening and enrollment during this assessment. Another 10 participants may be enrolled, thereafter, to further assess efficacy and safety (at Week 24) before the initiation of the Phase III randomization portion of the study. Similarly, there will be another hold on participant screening and enrollment during this assessment. The participants enrolled in the Phase Ib portion of the study will continue to receive vismodegib (150 mg PO QD) + ruxolitinib (PO BID) for up to 48 weeks, if clinical benefit is observed after 24 weeks. The Phase III randomized, double-blind portion of the study will enroll approximately 84 participants. Participants will be randomly assigned in a 1:1 ratio (double blind) to receive either vismodegib (150 mg PO QD) + ruxolitinib (PO BID) or placebo (PO QD) + ruxolitinib (PO BID) for up to 48 weeks.

Related Conditions:
  • Myelofibrosis Transformation in Essential Thrombocythemia
  • Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase
  • Primary Myelofibrosis
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title:A Study to Evaluate Efficacy and Safety of Vismodegib (Erivedge) in Combination With Ruxolitinib for the Treatment of Intermediate- or High-Risk Myelofibrosis (MF)
  • Official Title:

Clinical Trial IDs

  • ORG STUDY ID: WO29806
  • SECONDARY ID: 2015-001620-33
  • NCT ID: NCT02593760

Trial Conditions

  • Myelofibrosis

Trial Interventions

DrugSynonymsArms
RuxolitinibPlacebo + Ruxolitinib
VismodegibErivedgeVismodegib + Ruxolitinib

Trial Purpose

This multicenter, randomized, double-blind, placebo-controlled study will evaluate the efficacy and safety of vismodegib plus (+) ruxolitinib versus placebo + ruxolitinib in participants with intermediate- or high-risk MF. The study will be divided into 2 components. The Phase 1b portion of the study will be started with 6-week safety run-in period with 10 participants who will receive vismodegib (150 milligrams [mg] orally [PO] once daily [QD]) + ruxolitinib (PO twice daily [BID]) for the assessment of acute safety events associated with this combined therapy. After getting confirmation about the safety and toxicity of this combination, the Phase 3 randomization portion of the study will begin during which approximately 84 participants will randomly assign in 1:1 ratio to receive either vismodegib (150 mg PO QD) plus ruxolitinib (PO BID) or placebo (PO QD) plus ruxolitinib (PO BID) for up to 48 weeks or until withdrawal or discontinuation, whichever occurs first.

Detailed Description

Trial Arms

NameTypeDescriptionInterventions
Placebo + RuxolitinibActive ComparatorParticipants will receive placebo (PO QD) in combination with ruxolitinib (dose will depend on the participant's baseline platelet count) for up to 48 weeks.
    • Ruxolitinib
    Vismodegib + RuxolitinibExperimentalParticipants will receive vismodegib (150 mg PO QD) in combination with ruxolitinib (dose will depend on the participant's baseline platelet count) for up to 48 weeks.
      • Ruxolitinib
      • Vismodegib

    Eligibility Criteria

    Inclusion Criteria:

    - Pathologically confirmed diagnosis of primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, according to the 2008 revised World Health Organization criteria

    - Intermediate-1, intermediate-2, or high-risk according to the International Working Group- Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Dynamic International Prognostic Scoring System (DIPSS)

    - Participants aged greater than or equal to (>=) 18 years

    - Life expectancy >=6 months

    - Peripheral blood blast count of less than (<) 10%

    - Palpable splenomegaly of greater than (>) 5 centimeters (cm) below the left costal margin

    - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2

    - Adequate hepatic and renal function as assessed by:

    Total bilirubin less than or equal to (<=) 2.0*upper limit of normal (ULN), unless resulting from hemolysis and Gilbert's Syndrome Aspartate transaminase and alanine transaminase <=2.5*ULN (<=5*ULN if liver is involved by extramedullary hematopoiesis as determined by investigator) Serum creatinine <=1.5*ULN and creatinine clearance greater than (>) 30 milliliters per minute (mL/min)

    Exclusion Criteria:

    - Prior treatment with a Hedgehog or Janus kinase (JAK) pathway inhibitor

    - Treatment with strong cytochrome P450 (CYP) 3A4 inhibitors/inducers within 28 days prior to Day 1

    - Prior therapy for the treatment of intermediate- or high-risk MF including chemotherapy, interferon, thalidomide, busulfan, lenalidomide, anagrelide, or androgens within 28 days prior to Day 1

    - Prior splenectomy or splenic irradiation

    - Inadequate bone marrow reserve as follows:

    Absolute neutrophil count of <=1000/microliters (mcL) Platelet count of <100,000/mcL without the assistance of growth factors, thrombopoietic factors, or platelet transfusions

    - Participants with any history of platelet counts of <50,000/mccL or ANC of <500/mL, except during treatment for myeloproliferative neoplasm (MPN) or treatment with cytotoxic therapy for any other reason

    - Planned allogeneic bone marrow transplant during the study

    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:Both
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Percentage of participants who achieve a greater than equal to (>=) 35% reduction in spleen volume at Week 24, as determined by an IRC using IWG-MRT revised response criteria
    Time Frame:Week 24
    Safety Issue:No
    Description:

    Secondary Outcome Measures

    Measure:Plasma vismodegib concentration at steady state
    Time Frame:Predose, Weeks 6, 12, 24, 36, and 48
    Safety Issue:No
    Description:
    Measure:Percentage of participants who achieve a >=35% reduction in spleen volume, as determined by an IRC using IWG-MRT revised response criteria at Week 48 and by an Investigator at Weeks 24 and 48
    Time Frame:Weeks 24 and 48
    Safety Issue:No
    Description:
    Measure:Percentage of participants with CR and PR, as determined by an IRC using IWG-MRT revised response criteria at Week 48 and by an Investigator at Weeks 24 and 48
    Time Frame:Weeks 24 and 48
    Safety Issue:No
    Description:
    Measure:Percentage of Participants with objective response rate (CR, PR and clinical improvement) at Weeks 24 and 48, as determined by an IRC and the investigator using IWG-MRT revised response criteria
    Time Frame:Weeks 24 and 48
    Safety Issue:No
    Description:
    Measure:Percentage of participants who achieve anemia response at Weeks 24 and 48, as determined by the Investigator using IWG-MRT revised response criteria
    Time Frame:Weeks 24 and 48
    Safety Issue:No
    Description:
    Measure:Percentage of participants with symptom response rate (participants who achieve a >=50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score [MPN-SAF TSS])
    Time Frame:Baseline, Weeks 24 and 48
    Safety Issue:No
    Description:
    Measure:Duration of response, determined by the Investigator and an IRC using IWG-MRT revised response criteria or death from any cause during the study
    Time Frame:28 days after the last dose of study drug (52 weeks)
    Safety Issue:No
    Description:
    Measure:Percentage of participants with improvement in bone marrow fibrosis at Weeks 24 and 48, as determined by the Investigator and independent pathology review using the European consensus grading system
    Time Frame:Weeks 24 and 48
    Safety Issue:No
    Description:
    Measure:Progression free survival
    Time Frame:up to the end of the study (up to 1 year after completing 48 weeks of treatment by the last participant)
    Safety Issue:No
    Description:
    Measure:Percentage of participants who achieve a >=50% reduction in fatigue from baseline to Weeks 24 \nand 48
    Time Frame:Baseline, Weeks 24 and 48
    Safety Issue:No
    Description:
    Measure:Percentage of participants who achieve a >=50% reduction in other symptom and impact item scores from baseline to Weeks 24 and 48, as measured by the MPN-SAF
    Time Frame:Baseline, Weeks 24 and 48
    Safety Issue:No
    Description:
    Measure:Percentage of participants who achieved a meaningful improvement on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) scale scores from baseline to Weeks 24 and 48
    Time Frame:Baseline, Weeks 24 and 48
    Safety Issue:No
    Description:
    Measure:Overall survival
    Time Frame:up to the end of the study (up to 1 year after completing 48 weeks treatment by the last participant)
    Safety Issue:No
    Description:

    Trial Keywords