Clinical trial NCT02966353: Efficacy and Safety of Ruxolitinib in the Treatment of Anemic Myelofibrosis Patients.
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Myelofibrosis
Post-Polycythemia Vera-Myelofibrosis
Post-Essential Thrombocythemia Myelofibrosis
Keywords: Ruxolitinib
anemia
Primary Myelofibrosis
PMF
Post-Polycythemia Vera-Myelofibrosis
PPV-MF
Post-Essential Thrombocythemia Myelofibrosis
PET-MF
adult
INC424
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-11-17
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility 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 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.

Primary outcomes:
measure: Percentage of Participants With at Least 50% Reduction in Spleen Length From Baseline at Week 24
timeFrame: Baseline up to week 24
Secondary outcomes:
measure: Percentage of Participants With at Least 50% Reduction in Spleen Length From Baseline at Week 48
timeFrame: Baseline up to week 48
measure: Percentage of Participants by Spleen Length Reduction or no Increase From Baseline Category at Week 24 and Week 48
timeFrame: baseline, weeks 24 and 48
measure: 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
timeFrame: Baseline and week 24
measure: Patient Global Impression of Change (PGIC) at Week 24 and Week 48
timeFrame: Baseline up to week 48
measure: Percentage of Participants Transfusion Independency From Baseline up to Week 96
timeFrame: Baseline up to week 96
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Novartis Investigative Site
city: Antwerpen
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Halle S
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
state: GR
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Palermo
country: Italy
facility: Novartis Investigative Site
state: PA
city: Bunkyo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Petrozavodsk
country: Russian Federation
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Alicante
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Santiago de Compostela
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Kocaeli
country: Turkey
facility: Novartis Investigative Site
Study officials:
References: