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

A Multicenter Phase II, Open Label, Single Arm Study to Evaluate the Efficacy and Safety of Ruxolitinib in the Treatment of Anemic Myelofibrosis Patients.

This was a study of treatment with ruxolitinib in patients who presented with transfusion dependent or independent anemia. Starting dose was 10 mg BID. This dose was maintained for the first 12 weeks of the study and up-titrated thereafter unless the subject met criteria for dose hold or dose reduction

Study Overview

• Status: Completed
• Conditions: Primary Myelofibrosis; Post-Essential Thrombocythemia Myelofibrosis; Post-Polycythemia Vera-Myelofibrosis
• Intervention / Treatment: Drug: ruxolitinib

Detailed Description

This was 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 (maximum dose 25 mg BID) 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.

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 have been diagnosed with PMF, according to the 2016 revised International Standard Criteria, PPV MF or PET-MF, irrespective of JAK2 mutation status.
3. Patients must have had palpable splenomegaly that is equal to or greater than 5 cm below the left costal margin.
4. Patients must have had hemoglobin less than 10 g/dL
5. Patients must have had a history of transfusions must have a documented transfusion record in the previous 12 weeks to baseline.
6. Patients must have had ECOG performance status of 0, 1, or 2.
7. Patients must have had 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 who had prior treatment with any JAK1 or JAK2 inhibitor.
2. Patients who had known hypersensitivity to ruxolitinib or other JAK1/JAK2 inhibitors, or to their excipients.
3. Patients who had been eligible for hematopoietic stem cell transplantation (suitable candidate and a suitable donor is available).

4. Patients who had 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 who had severely impaired renal function defined by: Creatinine clearance less than 30 mL/min.

6. Patients who had 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 who were 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 have jeopardized the safety of the patient or compliance with the protocol.
15. Patients who were undergoing treatment with another investigational medication or had 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 who had a history of malignancy in the past 3 years, except for treated early stage squamous or basal cell carcinoma.
17. Patients who were 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 were using highly effective methods of contraception throughout the study duration inclusive of 30 day safety follow up.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: All Subjects; 10 mg BID (2 tablets of 5mg) was self-administered as starting dose for all patients. This dose was maintained for the first 12 weeks and titrated up thereafter unless they had met criteria for dose hold or dose reduction. Dose was to have been increased or decreased per standardized dosing paradigm and not to have exceeded 25 mg bid.	Drug: ruxolitinib; Ruxolitinib was supplied in 5 mg tablets to be taken orally approximately 12 hours apart (morning and night)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With at Least 50% Reduction in Spleen Length From Baseline at Week 24	Percentage of participants achieving a 50% reduction in spleen length at week 24. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen are imputed as 0. Subjects who had palpable, but missing spleen length at baseline is excluded from the analysis. Subjects with missing spleen length at Week 24 or who withdraw earlier from the study are considered as a non-responder. The 95% CI is computed using exact Clopper-Pearson method.	Baseline up to week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With at Least 50% Reduction in Spleen Length From Baseline at Week 48	Percentage of participants achieving a 50% reduction in spleen length at week 48. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen is imputed as 0. Subjects who had palpable, but missing spleen length at baseline is excluded from the analysis. Subjects with missing spleen length at Week 48 or who withdraw earlier from the study are considered as a non-responder. The 95% CI is computed using exact Clopper-Pearson method.	Baseline up to week 48
Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48	Participants who achieved a ≤ 50% reduction in spleen length at week 24 and 48 (reduction) and participants who had no increase greater than or equal to 50% (increase). 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. For subjects with palpable spleen at baseline and non-palpable at post-baseline, the post-baseline spleen is imputed as 0.	baseline, weeks 24 and 48
Percentage of Participants With at Least a 50% Reduction in Myelofibrosis 7 Item Symptom Scale (MF-7) and Myelofibrosis Symptom Assessment Form (MFSAF) at Week 24	The MF-7 is a disease specific questionnaire comprised of 7 items that measures the severity of seven of the most prevalent associated symptoms including: tiredness, early satiety, abdominal discomfort, night sweats, itching (pruritus), bone pain (diffuse not joint or arthritis) and pain under ribs on left side. Each item was scored on a scale ranging from 0 (absent) to 10 (worst imaginable). The MF-7 score is computed as the sum of the observed scores in the individual items to achieve a 0 to 70 score. There would be one recall period of 24 hours used in this questionnaire. A separate question on Inactivity was to be measured for severity of this symptom on a scale from 0 (absent) to 10 (worst imaginable). This would allow the computation of the MFSAF v2.0 questionnaire results, as 6 out of 7 items in the latter PRO are in overlap with MF7 (they also share same 0-10 range Likert scale and ascending order, absent to worst imaginable).	Baseline and week 24
Patient Global Impression of Change (PGIC) at Week 24 and Week 48	The PGIC is comprised of a single question intended to measure a subject's perspective of improvement or deterioration over time relative to treatment. The PGIC uses a seven-point scale where '1' equals very much improved and '7' equals very much worse.	Baseline up to week 48
Percentage of Participants Transfusion Independency From Baseline up to Week 96	Percentage is based on number of subjects who are transfusion dependent at baseline. Transfusion dependence (TD) is defined as subjects receiving 6 or more units of transfusions 12 weeks prior to baseline. Transfusion independence (TI) rate is defined as subjects who are transfusion dependent at baseline and require no unit of transfusion for ≥ 12 weeks at any time during the study. Transfusion response rate is defined as subjects who are TD at baseline and have 5 or less units of transfusion for ≥ 12 weeks at any time during the study.	Baseline up to week 96

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 31, 2017
• Primary Completion (ACTUAL): July 24, 2018
• Study Completion (ACTUAL): February 15, 2019

Study Registration Dates

• First Submitted: October 18, 2016
• First Submitted That Met QC Criteria: November 14, 2016
• First Posted (ESTIMATE): November 17, 2016

Study Record Updates

• Last Update Posted (ACTUAL): April 30, 2020
• Last Update Submitted That Met QC Criteria: April 28, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: adult; Ruxolitinib; anemia; INC424; PMF; Post-Essential Thrombocythemia Myelofibrosis; PET-MF; Primary Myelofibrosis; PPV-MF; Post-Polycythemia Vera-Myelofibrosis
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Myeloproliferative Disorders; Blood Coagulation Disorders; Blood Platelet Disorders; Bone Marrow Neoplasms; Hematologic Neoplasms; Primary Myelofibrosis; Thrombocytosis; Thrombocythemia, Essential; Polycythemia Vera; Polycythemia
• Other Study ID Numbers: CINC424A2411

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No