Phase III Study Investigating the Efficacy and Safety of Ruxolitinib in Early Myelofibrosis Patients With High Molecular Risk Mutations. (ReTHINK)

A Randomized, Double Blind, Placebo-controlled, Multicenter, Phase III Study Investigating the Efficacy and Safety of Ruxolitinib in Early Myelofibrosis Patients With High Molecular Risk Mutations

Myelofibrosis patients with high molecular risk mutations have an intrinsically aggressive disease with increased risk of leukemic transformation and reduced overall survival. As there are no therapies currently established in the subset of high molecular risk patients with early myelofibrosis, the study aimed to evaluate ruxolitinib in this patient population.

Study Overview

• Status: Terminated
• Conditions: Myelofibrosis With High Molecular Risk Mutations
• Intervention / Treatment: Drug: Ruxolitinib; Drug: Ruxolitinib Placebo

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Concord NSW, New South Wales, Australia, 2139
      • Novartis Investigative Site
    • Liverpool, New South Wales, Australia, 2170
      • Novartis Investigative Site
  • Queensland
    • Wooloongabba, Queensland, Australia, 4102
      • Novartis Investigative Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Novartis Investigative Site
• Austria
  • Salzburg, Austria, 5020
    • Novartis Investigative Site
  • Vienna, Austria, A-1090
    • Novartis Investigative Site
• Belgium
  • Antwerpen, Belgium, 2060
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Liege, Belgium, 4000
    • Novartis Investigative Site
• Brazil
  • Sao Paulo, Brazil, 01236030
    • Novartis Investigative Site
  • SP
    • Sao Paulo, SP, Brazil, 05403 000
      • Novartis Investigative Site
    • São Paulo, SP, Brazil, 08270-070
      • Novartis Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
• Denmark
  • Aalborg, Denmark, DK 9000
    • Novartis Investigative Site
  • Herlev, Denmark, DK 2730
    • Novartis Investigative Site
• France
  • Angers Cedex 1, France, 49033
    • Novartis Investigative Site
  • Brest, France, 29200
    • Novartis Investigative Site
  • Chambéry Cedex, France, 73011
    • Novartis Investigative Site
  • Grenoble, France, 38043
    • Novartis Investigative Site
  • Lille Cedex, France, 59037
    • Novartis Investigative Site
  • Nice Cedex, France, 06202
    • Novartis Investigative Site
  • Rouen Cedex 1, France, 76038
    • Novartis Investigative Site
  • Vandoeuvre Les Nancy, France, 54511
    • Novartis Investigative Site
  • Bayonne Cedex
    • Bayonne, Bayonne Cedex, France, 64109
      • Novartis Investigative Site
• Germany
  • Aachen, Germany, 52074
    • Novartis Investigative Site
  • Bochum, Germany, 44787
    • Novartis Investigative Site
  • Bonn, Germany, 53105
    • Novartis Investigative Site
  • Chemnitz, Germany, 09113
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Halle S, Germany, 06120
    • Novartis Investigative Site
  • Heilbronn, Germany, 74072
    • Novartis Investigative Site
  • Koeln, Germany, 50671
    • Novartis Investigative Site
  • Leipzig, Germany, 04103
    • Novartis Investigative Site
  • Muenchen, Germany, 81241
    • Novartis Investigative Site
  • Nordhorn, Germany, 48527
    • Novartis Investigative Site
  • Rostock, Germany, 18057
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
  • Schleswig-holstein
    • Luebeck, Schleswig-holstein, Germany, 23563
      • Novartis Investigative Site
• Greece
  • Athens, Greece, 115 27
    • Novartis Investigative Site
  • Athens, Greece, 106 76
    • Novartis Investigative Site
  • Patras, Greece, 265 00
    • Novartis Investigative Site
  • GR
    • Athens, GR, Greece, 115 27
      • Novartis Investigative Site
    • Thessaloniki, GR, Greece, 570 10
      • Novartis Investigative Site
• Hong Kong
  • Hong Kong, Hong Kong
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, H 1083
    • Novartis Investigative Site
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
  • Kaposvar, Hungary, 7400
    • Novartis Investigative Site
• Israel
  • Afula, Israel, 1834111
    • Novartis Investigative Site
  • Haifa, Israel, 3525408
    • Novartis Investigative Site
  • Jerusalem, Israel, 91120
    • Novartis Investigative Site
  • Tel Aviv, Israel, 6423906
    • Novartis Investigative Site
  • Zrifin, Israel, 70300
    • Novartis Investigative Site
• Italy
  • BA
    • Bari, BA, Italy, 70124
      • Novartis Investigative Site
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • BS
    • Brescia, BS, Italy, 25123
      • Novartis Investigative Site
  • CT
    • Catania, CT, Italy, 95123
      • Novartis Investigative Site
  • FI
    • Firenze, FI, Italy, 50134
      • Novartis Investigative Site
  • Lazio
    • Roma, Lazio, Italy, 00168
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20122
      • Novartis Investigative Site
  • PV
    • Pavia, PV, Italy, 27100
      • Novartis Investigative Site
  • RE
    • Reggio Emilia, RE, Italy, 42123
      • Novartis Investigative Site
  • TO
    • Orbassano, TO, Italy, 10043
      • Novartis Investigative Site
  • TR
    • Terni, TR, Italy, 05100
      • Novartis Investigative Site
  • VA
    • Varese, VA, Italy, 21100
      • Novartis Investigative Site
• Japan
  • Osaka, Japan, 545-8586
    • Novartis Investigative Site
  • Aichi
    • Nagoya, Aichi, Japan, 453-8511
      • Novartis Investigative Site
  • Fukuoka
    • Fukuoka city, Fukuoka, Japan, 812-8582
      • Novartis Investigative Site
  • Gunma
    • Maebashi city, Gunma, Japan, 371 8511
      • Novartis Investigative Site
  • Hyogo
    • Kobe-city, Hyogo, Japan, 650-0047
      • Novartis Investigative Site
  • Kanagawa
    • Isehara, Kanagawa, Japan, 259-1193
      • Novartis Investigative Site
  • Osaka
    • Suita city, Osaka, Japan, 565 0871
      • Novartis Investigative Site
  • Tokyo
    • Bunkyo ku, Tokyo, Japan, 113-8431
      • Novartis Investigative Site
    • Shinjuku-ku, Tokyo, Japan, 160-0023
      • Novartis Investigative Site
  • Yamanashi
    • Chuo-city, Yamanashi, Japan, 409-3898
      • Novartis Investigative Site
• Norway
  • Bergen, Norway, N-5021
    • Novartis Investigative Site
  • Loerenskog, Norway, NO 1478
    • Novartis Investigative Site
• Poland
  • Lodz, Poland, 93-513
    • Novartis Investigative Site
  • Torun, Poland, 87 100
    • Novartis Investigative Site
  • Wroclaw, Poland, 50 367
    • Novartis Investigative Site
• Portugal
  • Faro, Portugal, 8000-386
    • Novartis Investigative Site
  • Porto, Portugal, 4200-072
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 129110
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 191024
    • Novartis Investigative Site
  • St Petersburg, Russian Federation, 194044
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119228
    • Novartis Investigative Site
  • Singapore, Singapore, 169608
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Andalucia
    • Cadiz, Andalucia, Spain, 11009
      • Novartis Investigative Site
    • Malaga, Andalucia, Spain, 29010
      • Novartis Investigative Site
• Sweden
  • Göteborg, Sweden, SE-413 45
    • Novartis Investigative Site
  • Huddinge, Sweden, SE-14186
    • Novartis Investigative Site
  • Lund, Sweden, SE-221 85
    • Novartis Investigative Site
  • Uddevalla, Sweden, 451 80
    • Novartis Investigative Site
• Switzerland
  • Basel, Switzerland, 4031
    • Novartis Investigative Site
  • St Gallen, Switzerland, 9001
    • Novartis Investigative Site
  • Zuerich, Switzerland, 8091
    • Novartis Investigative Site
• Taiwan
  • Kaohsiung City, Taiwan, 83301
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taoyuan, Taiwan, 33305
    • Novartis Investigative Site
  • Chiayi Hsien
    • Putzu City, Chiayi Hsien, Taiwan, 61363
      • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06460
    • Novartis Investigative Site
  • Istanbul, Turkey, 34890
    • Novartis Investigative Site
  • Samsun, Turkey, 55139
    • Novartis Investigative Site
  • Talas / Kayseri, Turkey, 38039
    • Novartis Investigative Site
• United Kingdom
  • Leeds, United Kingdom, LS9 7TF
    • Novartis Investigative Site
  • London, United Kingdom, SE1 9RT
    • Novartis Investigative Site
  • Manchester, United Kingdom, M20 4BX
    • Novartis Investigative Site
  • Birmingham
    • Edgbaston, Birmingham, United Kingdom, B15 2GW
      • Novartis Investigative Site
  • Bristol
    • Westbruy On Trym, Bristol, United Kingdom, BS10 5NB
      • 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:

• Confirmed diagnosis of MF with bone marrow fibrosis of at least Grade 1; irrespective of JAK2 mutational status
• Patients with at least one mutation in one of the five HMR genes (ASXL1, EZH2, SRSF2 and IDH1/2)
• Patients with non-palpable spleen or spleen palpable ≤ 5 cm from the left costal margin to the point of greatest splenic protrusion
• Patients with MF-7 score of ≤ 15, with each individual symptom score of ≤ 3

Exclusion Criteria:

• Patients with prior treatment with ruxolitinib or other JAK inhibitors.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ruxolitinib; Two tablets of ruxolitinib 5 mg were administered orally twice per day.	Drug: Ruxolitinib; 5 mg tablet for oral use; Other Names: INC424
Placebo Comparator: Ruxolitinib Placebo; Two tablets of 5mg placebo were administered orally twice per day.	Drug: Ruxolitinib Placebo; 5 mg placebo tablet for oral use

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS-1)	Progression free survival (PFS-1) from date of randomization until the occurrence of any of the criteria for disease progression: Progressive splenomegaly; Circulating peripheral blast counts > 10%; Leukemic transformation; Hb < 10g/dl with absolute decrease of at least 3 g/dl from baseline; White blood cell (WBC) counts > 25 x 103/ μL; MF-7 score ≥ 30; Death from any cause	From randomization till disease progression (estimated to be assessed up 48 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Primary Progression (TTP)	TTP is defined as time from randomization until disease progression as defined for PFS-1 excluding death as an event.	From randomization till progression (estimated to be assessed up to 48 months)
Percentage Change in Spleen Volume From Baseline	Change in spleen volume (by MRI/CT) from baseline	From baseline and assessed on 12 week intervals until end of treatment (EOT)
Percentage Change in Symptoms From Baseline Using MF-7	Percentage change from Baseline in MF-7 total symptom score and 7 individual symptoms at each visit was summarized with descriptive statistics. For this scale, symptoms range from 0 to 10 for the severity experienced within the past 24 hours, with 0 being for absence of symptoms and 10 for worst imaginable symptoms.	From Baseline and assessed every 4 weeks until end of treatment
Number of Participants With Specific Subscale Scores (From Baseline) Using EQ-5D	EQ-ED5 profiles were summarized at baseline and at each scheduled assessment for each of the 5 dimensions separately (Mobility, self-care, usual activities, pain discomfort, anxiety/depression) Only participants with baseline score and at least one non-missing post-baseline score during the treatment period were included. Percentages were based on all these evaluable participants. The 5 scores for mobility, self-care, usual activities, pain/discomfort and anxiety/depression are all self-explanatory (eg "I have no problems walking" to "I am unable to walk"), except for the following overall health check, where 100 is the best of health, and 0 is the worst health.	From Baseline and assessed every 4 weeks until end of treatment
Overall Survival	To evaluate the effect of ruxolitinib on overall survival	Time from randomization to date of death due to any cause (estimated to be assessed up to 48 months).
Plasma Ruxolitinib Concentrations	Characterize pharmacokinetics (PK)by utilizing a population PK approach.	Week 12, Wk 48
Progression Free Survival (PFS-2)	PFS-2 assessed by 25% increase over new baseline of PFS-1 in any of the following: ● Progressive splenomegaly ● 25 % increase in MF-7 score with absolute score ≥ 30	From date of randomization until second disease progression or death, whichever comes first (estimated to be assessed up to 72 months)
Quality-adjusted Life Years From Baseline	EQ-5D-5L (EuroQol-5D-5L, is a standardized instrument for measuring health outcomes, is consists of a descriptive system and a visual analogue scale - scores can be summarized into a single index score that provides a simple measure of health for clinical and economic appraisal ) The EQ-5D-5L health states will be converted into index values (utilities) from which the QALY (Quality - adjusted life years) will be calculated. QALY will be summarized descriptively by treatment arm.	Change from Baseline compared with scheduled study visits at the following intervals every 4 weeks up to week 24, every 8 weeks up to Week 48, every 12 weeks past Wk 48 until End of treatment and 30 day follow up visit
Time to First Progressive Splenomegaly (TTPS)	Time to first progressive splenomegaly as determined by spleen volume (by Magnetic Resonance Imaging (MRI)/Computed Tomography (CT).	From randomization until earliest time to progressive splenomegaly (estimated to be assessed up to 48 months)
Time to First Symptomatic Progression (TTSP)	Time to first symptomatic progression as determined by Myelofibrosis 7 Item Symptom Scale (MF-7)	From randomization until symptomatic progression (MF-7)(estimated to be assessed up to 48 months)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2016
• Primary Completion (Actual): October 23, 2017
• Study Completion (Actual): October 23, 2017

Study Registration Dates

• First Submitted: October 27, 2015
• First Submitted That Met QC Criteria: November 3, 2015
• First Posted (Estimate): November 5, 2015

Study Record Updates

• Last Update Posted (Actual): August 16, 2019
• Last Update Submitted That Met QC Criteria: July 8, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Ruxolitinib; INC424; Early Myelofibrosis; high molecular risk mutations.; High molecular risk mutations; HMR
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Primary Myelofibrosis
• Other Study ID Numbers: CINC424A2353; 2014-004928-21 (EudraCT Number)

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