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Efficacy and Safety of Ruxolitinib in the Treatment of Anemic Myelofibrosis Patients. (REALISE)

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ClinicalTrials.gov Identifier: NCT02966353
Recruitment Status : Completed
First Posted : November 17, 2016
Last Update Posted : July 2, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This is a study of treatment with ruxolitinib in patients who present with transfusion dependent or independent anemia with 10 mg BID starting dose and subsequent up titrations depending on safety and efficacy.

Condition or disease Intervention/treatment Phase
Primary Myelofibrosis Post-Polycythemia Vera-Myelofibrosis Post-Essential Thrombocythemia Myelofibrosis Drug: ruxolitinib Phase 2

Detailed Description:
This is a study of treatment with ruxolitinib in patients who present with transfusion dependent or independent anemia at screening defined as an hemoglobin <10 g/dL with 10 mg BID starting dose with subsequent up titrations depending on safety and efficacy. This dosing approach for anemic MF patients will be systematically studied in this prospective multicenter phase II open label single arm trial to determine if the levels of spleen length reduction and symptom improvement are consistent with those reported in previous clinical trials with ruxolitinib in patients with anemia and doses according to platelet counts at the moment of treatment initiation, and whether this lower starting dose and up titration approach may minimize the initial hemoglobin and platelet declines and transfusion requirements.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 51 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter Phase II, Open Label, Single Arm Study to Evaluate the Efficacy and Safety of Ruxolitinib in the Treatment of Anemic Myelofibrosis Patients.
Actual Study Start Date : March 31, 2017
Actual Primary Completion Date : July 24, 2018
Actual Study Completion Date : March 25, 2019


Arm Intervention/treatment
Experimental: Ruxolitinib
10 mg BID (2 tablets of 5mg) will be self-administered as starting dose for all patients. This dose will be maintained for the first 12 weeks and titrated up thereafter unless they have met criteria for dose hold or dose reduction. Dose to be increased or decreased per standardized dosing paradigm and not to exceed 25 mg bid.
Drug: ruxolitinib
Ruxolitinib will be supplied to the investigator by sponsor in 5 mg tablets. Ruxolitinib should be taken orally, approximately 12 hours apart (morning and night) without regard to food unless instructed to temporarily hold taking drug by investigator.




Primary Outcome Measures :
  1. Spleen length response rate [ Time Frame: at week 24 ]
    Proportion of patients achieving a 50% reduction in spleen length at week 24.


Secondary Outcome Measures :
  1. Spleen length response rate [ Time Frame: at week 48 ]
    Proportion of patients achieving a 50% reduction in spleen length at week 48.

  2. Percent change from baseline on spleen length [ Time Frame: baseline, weeks 4, 8, 12, 16, 20, 24/ 36, 48 ]
    Percent change from baseline in spleen length at specified time points.The edge of the spleen shall be determined by palpation, measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion.

  3. Effect of ruxolitinib on symptoms - MFSAF [ Time Frame: up to week 48 ]
    Summary of the Modified MFSAF v2.0 over time.

  4. Effect of ruxolitinib on Patient Global Impression of Change (PGIC). [ Time Frame: up to week 48 ]
    PGIC at each visit where measured.

  5. Effect of ruxolitinib on transfusion requirements. [ Time Frame: week 48 ]
    Summary of transfusions over time. For Transfusion Dependent (TD) patients:Transfusion independence (TI) rate (requiring no transfusion for ≥12 weeks at any time).Transfusion response rate (not TD: having 5 or less transfusion for ≥12 weeks at any time).

  6. Effect of ruxolitinib on symptoms - MF-7 [ Time Frame: up to week 48 ]
    Summary of the MF-7 over time.

  7. Effect of ruxolitinib on transfusion requirements [ Time Frame: week 48 ]
    Summary of transfusions over time. For Transfusion Dependent (TD) patients:Transfusion independence (TI) rate (requiring no transfusion for ≥12 weeks at any time).Transfusion response rate (not TD: having 5 or less transfusion for ≥12 weeks at any time).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Written informed consent must be obtained prior to any screening procedures.

  1. Male or female patients aged ≥ 18 years of age.
  2. Patients must be diagnosed with PMF, according to the 2016 revised International Standard Criteria, PPV MF or PET-MF, irrespective of JAK2 mutation status.
  3. Patients with palpable splenomegaly that is equal to or greater than 5 cm below the left costal margin.
  4. Patients with a hemoglobin less than 10 g/dL
  5. Patients with a history of transfusions must have a documented transfusion record in the previous 12 weeks to baseline.
  6. Patients with an ECOG performance status of 0, 1, or 2.
  7. Patients with a peripheral blood blast percentage count of < 10%.
  8. Patients must have recovered or stabilized sufficiently from any adverse drug reactions associated with prior treatments before beginning treatment with ruxolitinib.

Exclusion Criteria:

  1. Patients with prior treatment with any JAK1 or JAK2 inhibitor.
  2. Patients with known hypersensitivity to ruxolitinib or other JAK1/JAK2 inhibitors, or to their excipients.
  3. Patients eligible for hematopoietic stem cell transplantation (suitable candidate and a suitable donor is available).
  4. Patients with inadequate bone marrow reserve at baseline as demonstrated by at least one of the following:

    1. ANC that is ≤ 1,000/µL.
    2. Platelet count that is <50,000/µL without the assistance of growth factors, thrombopoietic factors or platelet transfusions.
    3. Hemoglobin count that is ≤ 6.5 g/dL despite transfusions.
  5. Patients with severely impaired renal function defined by: Creatinine clearance less than 30 mL/min.
  6. Patients with inadequate liver function defined by any of these:

    1. Total bilirubin ≥ 2.5 x ULN and subsequent determination of direct bilirubin ≥ 2.5 x ULN;
    2. Alanine aminotransferase (ALT) > 2.5 x ULN;
    3. Aspartate aminotransferase (AST) > 2.5 x ULN.
  7. Patients being treated concurrently with a strong (potent) systemic inhibitor or inducer of CYP3A4 at the time of Screening.
  8. Presence of active bacterial, fungal, parasitic, or viral infection which requires therapy.
  9. Known history of human immunodeficiency virus (HIV) infection or other immunodeficiency syndromes such as X-linked agammaglobulinemia and common variable immune deficiency.
  10. Acute viral hepatitis or active chronic hepatitis B or C infection. Patients with inactive chronic infection (without viral replication) can be enrolled
  11. History of progressive multifocal leuko-encephalopathy.
  12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ruxolitinib .
  13. History or current diagnosis of uncontrolled or significant cardiac disease, including any of the following:

    1. Myocardial infarction within last 6 months
    2. Uncontrolled congestive heart failure
    3. Unstable angina within last 6 months
    4. Clinically significant (symptomatic) cardiac arrhythmias (e.g. bradyarrhythmias, sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker)
  14. Significant concurrent, uncontrolled medical condition which, in the investigator's opinion, would jeopardize the safety of the patient or compliance with the protocol.
  15. Patients undergoing treatment with another investigational medication or having been treated with an investigational medication within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study drug.
  16. Patients with a history of malignancy in the past 3 years, except for treated early stage squamous or basal cell carcinoma.
  17. Patients who are unable to comprehend or are unwilling to sign an ICF.
  18. Pregnant or nursing (lactating) women
  19. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception throughout the study duration inclusive of 30 day safety follow up.

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): NCT02966353


Locations
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Austria
Novartis Investigative Site
Vienna, Austria, A-1090
Belgium
Novartis Investigative Site
Antwerpen, Belgium, 2060
Novartis Investigative Site
Leuven, Belgium, 3000
Bulgaria
Novartis Investigative Site
Sofia, Bulgaria, 1413
Novartis Investigative Site
Sofia, Bulgaria, 1756
Canada, British Columbia
Novartis Investigative Site
Vancouver, British Columbia, Canada, V5Z 1M9
Germany
Novartis Investigative Site
Halle S, Germany, 06120
Greece
Novartis Investigative Site
Athens, GR, Greece, 115 27
Novartis Investigative Site
Thessaloniki, GR, Greece, 570 10
Italy
Novartis Investigative Site
Bologna, BO, Italy, 40138
Novartis Investigative Site
Firenze, FI, Italy, 50134
Novartis Investigative Site
Palermo, PA, Italy, 90127
Japan
Novartis Investigative Site
Bunkyo ku, Tokyo, Japan, 113-8431
Russian Federation
Novartis Investigative Site
Moscow, Russian Federation, 125167
Novartis Investigative Site
Moscow, Russian Federation, 129110
Novartis Investigative Site
Petrozavodsk, Russian Federation, 185019
Spain
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08036
Novartis Investigative Site
Alicante, Comunidad Valenciana, Spain, 03010
Novartis Investigative Site
Santiago de Compostela, Galicia, Spain, 15706
Turkey
Novartis Investigative Site
Istanbul, Turkey, 34093
Novartis Investigative Site
Kocaeli, Turkey, 41380
Sponsors and Collaborators
Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02966353     History of Changes
Other Study ID Numbers: CINC424A2411
First Posted: November 17, 2016    Key Record Dates
Last Update Posted: July 2, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Ruxolitinib
anemia
Primary Myelofibrosis
PMF
Post-Polycythemia Vera-Myelofibrosis
PPV-MF
Post-Essential Thrombocythemia Myelofibrosis
PET-MF
Additional relevant MeSH terms:
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Polycythemia Vera
Primary Myelofibrosis
Polycythemia
Thrombocytosis
Thrombocythemia, Essential
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Neoplasms
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders