A Clinical Study of Ruxolitinib in Patients With Primary Myelofibrosis (PM), Post-polycythemia Vera (PV) Myelofibrosis, or Post-essential Thrombocythemia (ET) Myelofibrosis

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02087059
• Collaborator: (none)
• Enrollment: 51
• Locations: 29
• Arm: 1
• Duration (Months): 12
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is an open-label, multicenter clinical study in order to collect and examine data concerning the safety and efficacy of ruxolitinib in patients with Primary Myelofibrosis (MF), Post-Polycythemia Vera (PV) MF, Post-Essential Thrombocythemia (ET) MF.

Condition or Disease	Intervention/Treatment	Phase
Primary Myelofibrosis (MF)	Drug: Ruxolitinib	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Open-label Clinical Study of the JAK Inhibitor Ruxolitinib (INC424) in Patients With Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, or Post-essential Thrombocythemia Myelofibrosis
• Study Start Date: Apr 1, 2014
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ruxolitinib Ruxolitinib was administered orally twice daily at the starting dose of 5 mg, 15 mg or 20 mg bid based on Baseline platelet counts. The dosage was subsequently adjusted for safety and efficacy so that each patient was titrated to their most appropriate dose.	Drug: Ruxolitinib

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events as a Measure of Safety and Tolerability [24 weeks]

Secondary Outcome Measures

1. Charge in Spleen Size From Baseline at Specified Week [Baseline, 24 weeks]

   Number of patients with spleen length reduced by ≥ 50% at specified week

2. Charge in Spleen Size From Baseline up to the Specified Week [Baseline, 24 weeks]

   Number of patients with spleen length reduced by ≥ 50% up to specified week

3. Summary of Total Symptom Score as Measured by Seven-day Modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 by Time [24 weeks]

   The modified MFSAF v2.0 diary captures a patient's symptom severity on a scale of 0 (absent) to 10 (worst imaginable),with a maximal summary score of 60

4. Summary of Summary of EORTC QLQ-C30 Responses by Time [24 weeks]

   The QLQ-C30 version 1.0 (QLQ-C30) incorporates five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), a global health status / QoL scale, and a number of single items assessing additional symptoms commonly reported by cancer patients (dyspnoea, loss of appetite, insomnia, constipation and diarrhea) and perceived financial impact of the disease.All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. ≥18 years of age

2. Diagnosis of PMF, PPV-MF, or PET-MF, regardless of JAK2 mutational status. The diagnostic of PMF will be according to the World Health Organization (WHO) criteria (Thiele et al., 2008) and PPV-MF and PET-MF according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria (Barosi et al., 2008).

3. At least one risk factors provided in the definition of IWG-MRT (Cervantes et al., 2009; classified as intermediate risk-1, intermediate risk-2, or high risk)

4. Patients with intermediate risk-1 (patients who have only one of the IMG-MRT risk factors indicated above ) must have palpable splenomegaly with a length of ≥5 cm from the costal margin to the point of the greatest spleen protrusion.

5. Proportion of blasts in peripheral blood <10%

6. ECOG performance status of 0 to 2

7. The following values for bone marrow function prior to treatment:

8. Absolute neutrophil count ≥1,000/μL, and

9. Platelet count ≥50,000/μL without administration of a growth factor, thrombopoietin, or platelet transfusion

10. Stem cell transplantation is not a treatment option at present because it is not indicated or because there are no suitable donors.

11. All drugs used to treat MF were discontinued at least 28 days before treatment initiation.

12. Informed consent form should be signed before any screening procedures is performed

Exclusion Criteria:

1. Hepatic or renal impairment as indicated by the following:

• Direct bilirubin ≥2-fold than the upper limit of normal (ULN)

• Alanine aminotransferase (ALT) >2.5-fold ULN

• Creatinine >2.0 mg/dL

1. Clinically significant infection by bacteria, fungus, mycobacteria, parasite, or virus (screening and enrollment postponed until completion of antibiotic treatment in patients with an acute bacterial infection that requires antibiotic use)

2. Active hepatitis A, B, or C or HIV infection defined by a positive IgM-HA Ab test [hepatitis A virus antibody (immunoglobulin M [IgM])], HBs Ag test (hepatitis B surface antigen), HCV Ab test (hepatitis C virus antibody), or HIV Ab (human immunodeficiency virus antibody) at screening.

3. History of malignancy within the previous 3 years, except for early-stage squamous cell carcinoma and basal cell carcinoma.

4. History of serious congenital or acquired hemorrhagic disease

5. Previous platelet count <25,000/μL or absolute neutrophil count <500/μL, except for patients currently undergoing treatment for a myeloproliferative neoplasm or cytotoxic therapy for any other reason.

6. Splenic irradiation within 12 months before screening

7. Administration of hematopoietic growth factor receptor agonists (erythropoietin, granulocyte colony stimulating factor, romiplostim, eltrombopag) within 14 days before screening or 28 days before treatment initiation.

8. Currently receiving another investigational drug, or received another investigational drug within 30 days before the start of treatment.

9. History of myocardial infarction or acute coronary syndrome within 6 months before screening

10. Poorly controlled or unstable angina at present

11. Rapid or paroxysmal atrial fibrillation at present

12. Active alcohol or drug addiction that could hinder the patient's ability to comply with the study's requirements

13. Pregnant or currently breastfeeding woman

14. Women of childbearing potential or men with reproductive ability who are unwilling to take appropriate contraception measures

15. Patient with any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the patient or compliance with the protocol

16. History of hypersensitivity to the study drug or a drug with a similar chemical structure

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Nagoya-city	Aichi	Japan	467-8602
2	Novartis Investigative Site	Matsuyama	Ehime	Japan	790-8524
3	Novartis Investigative Site	Toon-city	Ehime	Japan	791-0295
4	Novartis Investigative Site	Fukuoka-city	Fukuoka	Japan	812-8582
5	Novartis Investigative Site	Kurume-city	Fukuoka	Japan	830-0011
6	Novartis Investigative Site	Maebashi-city	Gunma	Japan	371-8511
7	Novartis Investigative Site	Sapporo-city	Hokkaido	Japan	060-8543
8	Novartis Investigative Site	Sapporo-city	Hokkaido	Japan	060-8648
9	Novartis Investigative Site	Kobe-city	Hyogo	Japan	650-0017
10	Novartis Investigative Site	Kobe-city	Hyogo	Japan	650-0047
11	Novartis Investigative Site	Kumamoto City	Kumamoto	Japan	860-8556
12	Novartis Investigative Site	Kyoto-city	Kyoto	Japan	606-8507
13	Novartis Investigative Site	Tsu-city	Mie	Japan	514-8507
14	Novartis Investigative Site	Sendai-city	Miyagi	Japan	980-8574
15	Novartis Investigative Site	Miyazaki-city	Miyazaki	Japan	889-1692
16	Novartis Investigative Site	Okayama-city	Okayama	Japan	700-8558
17	Novartis Investigative Site	Hirakata-city	Osaka	Japan	573-1191
18	Novartis Investigative Site	OsakaSayama	Osaka	Japan	589-8511
19	Novartis Investigative Site	Suita-city	Osaka	Japan	565-0871
20	Novartis Investigative Site	Shimotsuke-city	Tochigi	Japan	329-0498
21	Novartis Investigative Site	Bunkyo-ku	Tokyo	Japan	113-8431
22	Novartis Investigative Site	Bunkyo-ku	Tokyo	Japan	113-8519
23	Novartis Investigative Site	Bunkyo-ku	Tokyo	Japan	113-8603
24	Novartis Investigative Site	Bunkyo-ku	Tokyo	Japan	113-8677
25	Novartis Investigative Site	Shinjuku-ku	Tokyo	Japan	160-0023
26	Novartis Investigative Site	Shinjuku-ku	Tokyo	Japan	162-8666
27	Novartis Investigative Site	Chuo-city	Yamanashi	Japan	409-3898
28	Novartis Investigative Site	Akita		Japan	010-8543
29	Novartis Investigative Site	Gifu		Japan	501-1194

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02087059
• Other Study ID Numbers: CINC424AJP01
• First Posted: Mar 14, 2014
• Last Update Posted: Jul 11, 2016
• Last Verified: May 1, 2016

• Keywords provided by Novartis Pharmaceuticals: Post-Polycythemia Vera (PV) MF; Post-Essential Thrombocythemia (ET) MF
• Additional relevant MeSH terms: Polycythemia Vera; Primary Myelofibrosis; Polycythemia; Thrombocytosis; Thrombocythemia, Essential

Study Results

Participant Flow

Arm/Group Title	Ruxolitinib
Arm/Group Description	Ruxolitinib was administered orally twice daily at the starting dose of 5 mg, 15 mg or 20 mg bid based on Baseline platelet counts. The dosage was subsequently adjusted for safety and efficacy so that each patient was titrated to their most appropriate dose.
Period Title: Overall Study
STARTED	51
COMPLETED	44
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Ruxolitinib
Arm/Group Description	Ruxolitinib was administered orally twice daily at the starting dose of 5 mg, 15 mg or 20 mg bid based on Baseline platelet counts. The dosage was subsequently adjusted for safety and efficacy so that each patient was titrated to their most appropriate dose.
Overall Participants	51
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.7 (8.8)
Sex: Female, Male (Count of Participants)
Female	24 47.1%
Male	27 52.9%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ruxolitinib
Arm/Group Description	Ruxolitinib was administered orally twice daily at the starting dose of 5 mg, 15 mg or 20 mg bid based on Baseline platelet counts. The dosage was subsequently adjusted for safety and efficacy so that each patient was titrated to their most appropriate dose.
Measure Participants	51
AEs, regardless of study treatment relationship	50 98%
AEs suspected to be related to study treatment	46 90.2%
SAEs, regardless of study treatment relationship	12 23.5%
SAEs suspected to be related to study treatment	5 9.8%
AEs of CTC grade 3/4, regardless study treatment	36 70.6%
AEs of CTC grade 3/4 suspected related treatment	33 64.7%
AEs leading to the study treatment discontinuation	5 9.8%
AEs requiring reduction or interruption treatment	38 74.5%
AEs requiring concomitant medication	33 64.7%

2. Secondary Outcome

Title	Charge in Spleen Size From Baseline at Specified Week
Description	Number of patients with spleen length reduced by ≥ 50% at specified week
Time Frame	Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ruxolitinib
Arm/Group Description	Ruxolitinib was administered orally twice daily at the starting dose of 5 mg, 15 mg or 20 mg bid based on Baseline platelet counts. The dosage was subsequently adjusted for safety and efficacy so that each patient was titrated to their most appropriate dose.
Measure Participants	51
Week 2	12
Week 4	14
Week 8	14
Week 12	11
Week 16	14
Week 20	13
Week 24	15

3. Secondary Outcome

Title	Charge in Spleen Size From Baseline up to the Specified Week
Description	Number of patients with spleen length reduced by ≥ 50% up to specified week
Time Frame	Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ruxolitinib
Arm/Group Description	Ruxolitinib was administered orally twice daily at the starting dose of 5 mg, 15 mg or 20 mg bid based on Baseline platelet counts. The dosage was subsequently adjusted for safety and efficacy so that each patient was titrated to their most appropriate dose.
Measure Participants	51
Week 4	18
Week 8	22
Week 12	23
Week 16	26
Week 20	26
Week 24	26

4. Secondary Outcome

Title	Summary of Total Symptom Score as Measured by Seven-day Modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 by Time
Description	The modified MFSAF v2.0 diary captures a patient's symptom severity on a scale of 0 (absent) to 10 (worst imaginable),with a maximal summary score of 60
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ruxolitinib
Arm/Group Description	Ruxolitinib was administered orally twice daily at the starting dose of 5 mg, 15 mg or 20 mg bid based on Baseline platelet counts. The dosage was subsequently adjusted for safety and efficacy so that each patient was titrated to their most appropriate dose.
Measure Participants	51
Night Sweats baseline (n=51)	2.9 (3.07)
Night Sweats week 24 (n=43)	0.6 (1.35)
Itching baseline (n=51)	1.8 (2.39)
Itching week 24 (n=43	0.6 (1.25)
Abdominal Discomfort baseline( n=51)	4.4 (3.18)
Abdominal Discomfort week 24(n=43)	1.4 (1.84)
Pain under ribs on left Baseline (=51)	2.2 (2.72)
Pain under ribs on left week 24 (=43)	0.7 (1.26)
Feeling of fullness Baseline (n=51)	3.2 (2.91)
Feeling of fullness week 24 (n=43)	1.3 (1.8)
Bone/muscle pain Baseline (n=51)	2.3 (2.83)
Bone/muscle pain week 24 (n=43)	1.0 (1.83)
Degree of inactivity Baseline (n=51)	2.3 (2.84)
Degree of inactivity week 24 (n=43)	1.0 (1.66)
Total symptom score baseline (n=51)	16.8 (12.30)
Total symptom score week 24 (n=43)	5.7 (6.48)

5. Secondary Outcome

Title	Summary of Summary of EORTC QLQ-C30 Responses by Time
Description	The QLQ-C30 version 1.0 (QLQ-C30) incorporates five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), a global health status / QoL scale, and a number of single items assessing additional symptoms commonly reported by cancer patients (dyspnoea, loss of appetite, insomnia, constipation and diarrhea) and perceived financial impact of the disease.All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Ruxolitinib
Arm/Group Description	Ruxolitinib was administered orally twice daily at the starting dose of 5 mg, 15 mg or 20 mg bid based on Baseline platelet counts. The dosage was subsequently adjusted for safety and efficacy so that each patient was titrated to their most appropriate dose.
Measure Participants	51
Physical Functioning baseline	79.35 (17.951)
Physical Functioning 24(n=43)	86.67 (17.959)
Role Functioning Baseline(n=51)	77.78 (23.254)
Role Functioning Week 24(n=43)	83.72 (19.068)
Emotional Functioning Baseline(n=51)	85.46 (17.705)
Emotional Functioning Week 24(n=43)	92.05 (13.357)
Cognitive Functioning Baseline(n=51)	78.43 (20.356)
Cognitive Functioning week 24 (n=43)	79.84 (17.653)
Social Functioning Baseline (n=51)	85.62 (19.154)
Social Functioning week 24(n=43)	87.60 (17.852)
Global Health Status/QOL Baseline (n=51)	55.72 (22.882)
Global Health Status/QOL week 24 (n=43)	66.47 (22.456)
Fatigue Baseline(n=51)	40.31 (23.787)
Fatigue week 24 (n=43)	28.68 (23.412)
Nausea and Vomiting baseline (n=51)	4.90 (13.862)
Nausea and Vomiting week 24 (n=43)	0.39 (2.542)
Pain Baseline	21.57 (21.678)
Pain week 24 (n=43)	10.08 (15.911)
Dyspnoea baseline (n=51)	22.88 (25.377)
Dyspnoea Week 24 (n=43)	25.58 (23.946)
Insomnia baseline (n=51)	23.53 (29.283)
Insomnia Week 24 (n=43)	15.50 (23.400)
Appetite Lose baseline (n=51)	21.57 (27.787)
Appetite Lose Week 24 (n=43)	9.30 (16.786)
Constipation baseline (n=51)	8.50 (20.916)
Constipation Week 24 (n=43)	8.53 (16.416)
Diarrhoea baseline (n=51)	18.30 (24.325)
Diarrhoea Week 24 (n=43)	12.40 (23.029)
Financial Difficulties baseline (n=51)	15.69 (25.257)
Financial Difficulties Week 24 (n=43)	20.93 (30.012)

Adverse Events

Arm/Group Title	Ruxolitinib
Arm/Group Description	Ruxolitinib was administered orally twice daily at the starting dose of 5 mg, 15 mg or 20 mg bid based on Baseline platelet counts. The dosage was subsequently adjusted for safety and efficacy so that each patient was titrated to their most appropriate dose.
All Cause Mortality
	Ruxolitinib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ruxolitinib
	Affected / at Risk (%)	# Events
Total	12/51 (23.5%)
Blood and lymphatic system disorders
Anaemia	1/51 (2%)
Disseminated intravascular coagulation	1/51 (2%)
Cardiac disorders
Cardiac failure congestive	1/51 (2%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	1/51 (2%)
Oesophageal varices haemorrhage	1/51 (2%)
General disorders
Multi-organ failure	1/51 (2%)
Hepatobiliary disorders
Drug-induced liver injury	1/51 (2%)
Infections and infestations
Empyema	1/51 (2%)
Sepsis	1/51 (2%)
Urinary tract infection	1/51 (2%)
Injury, poisoning and procedural complications
Spinal compression fracture	1/51 (2%)
Metabolism and nutrition disorders
Gout	1/51 (2%)
Tumour lysis syndrome	1/51 (2%)
Psychiatric disorders
Withdrawal syndrome	1/51 (2%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/51 (2%)
Interstitial lung disease	1/51 (2%)
Pleural effusion	1/51 (2%)
Pneumonitis	1/51 (2%)
Other (Not Including Serious) Adverse Events
	Ruxolitinib
	Affected / at Risk (%)	# Events
Total	49/51 (96.1%)
Blood and lymphatic system disorders
Anaemia	32/51 (62.7%)
Leukopenia	3/51 (5.9%)
Lymphopenia	3/51 (5.9%)
Thrombocytopenia	15/51 (29.4%)
Gastrointestinal disorders
Abdominal pain	4/51 (7.8%)
Constipation	7/51 (13.7%)
Diarrhoea	4/51 (7.8%)
Nausea	3/51 (5.9%)
Vomiting	3/51 (5.9%)
General disorders
Oedema peripheral	3/51 (5.9%)
Pyrexia	5/51 (9.8%)
Hepatobiliary disorders
Hepatic function abnormal	6/51 (11.8%)
Infections and infestations
Nasopharyngitis	6/51 (11.8%)
Pneumonia	4/51 (7.8%)
Investigations
Electrocardiogram QT prolonged	5/51 (9.8%)
Lymphocyte count decreased	4/51 (7.8%)
Neutrophil count decreased	3/51 (5.9%)
Platelet count decreased	12/51 (23.5%)
Weight increased	3/51 (5.9%)
Musculoskeletal and connective tissue disorders
Back pain	4/51 (7.8%)
Nervous system disorders
Headache	3/51 (5.9%)
Psychiatric disorders
Insomnia	3/51 (5.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.