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Exploratory Phase II Study of INC424 Patients With Primary Myelofibrosis (PMF) or Post Polycythaemia Myelofibrosis (PPV MF) or Post Essential Thrombocythaemia Myelofibrosis (PET-MF) (MACS2030)

Primary Purpose

Primary Myelofibrosis (PMF), Post Polycythaemia Myelofibrosis (PPV MF), Post Essential Thrombocythaemia Myelofibrosis (PET-MF)

Status
Completed
Phase
Phase 4
Locations
United Kingdom
Study Type
Interventional
Intervention
INC424
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Myelofibrosis (PMF) focused on measuring Ruxolitinib, INC424, myelofibrosis, PMF, post polycythemia myelofibrosis, PPV MF, post-essential thrombocythemia myelofibrosis, PET-MF, Primary Myelofibrosis, Polycythemia, Thrombocythemia, Essential Thrombocytosis, myeloproliferative Disorders, Bone Marrow Diseases, Haematologic Diseases, Blood Coagulation Disorders, Blood Platelet Disorders, Haemorrhagic Disorders

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients must not be eligible for another ongoing INC424 clinical trial.
  • Patients must be diagnosed with PMF, PPV MF or PET-MF, according to the 2008 revised World Health Organization criteria irrespective of JAK2 mutation status.
  • Patients with PMF requiring therapy must be classified as high risk (3 prognostic factors) OR intermediate risk level 2 (2 prognostic factors, no more), OR intermediate risk level 1 (1 prognostic factor, no more) with an enlarged spleen. The prognostic factors, defined by the International Working Group are:

    1. Age > 65 years;
    2. Presence of constitutional symptoms (weight loss, fever, night sweats); marked anemia (Hgb < 10g/dL)*;
    3. Leukocytosis (history of WBC > 25 x109/L);
    4. Circulating blasts > 1%. • A hemoglobin value < 10 g/dL must be demonstrated during the Screening Visit for patients who are not transfusion dependent. Patients receiving regular transfusions of packed red blood cells will be considered to have hemoglobin < 10 g/dL for the purpose of evaluation of risk factors.
  • Patients with Intermediate-1 disease and splenomegaly must have a palpable spleen measuring 5 cm or greater from the costal margin to the point of greatest splenic protrusion.
  • Patients must have a peripheral blood blast count of < 10%.
  • Patients with adequate liver function defined as direct bilirubin ≤ 2.0 x ULN and ALT ≤ 2.5 x ULN.
  • Patients with adequate renal function defined as serum creatinine ≤ 2 x ULN.
  • Patients with an ECOG performance status of 0, 1, or 2 (Appendix 5).

Exclusion criteria:

  • Patients eligible for hematopoietic stem cell transplantation (suitable candidate and a suitable donor is available).
  • Patients with history of malignancy in past 3 years except for treated, early-stage squamous or basal cell carcinoma in situ.
  • Patients undergoing treatment with hematopoietic growth factor receptor agonists (i.e., erythropoietin [Epo], granulocyte colony stimulating factor (GCSF [Neupogen; Neulasta], romiplostim, eltrombopag) at any time within 2 weeks prior to Screening or 4 weeks prior to Baseline.
  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral INC424 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
  • Patients with cardiac disease which in the Investigator's opinion may jeopardize the safety of the patient or the compliance with the protocol.
  • Patients with clinically significant bacterial, fungal, parasitic or viral infection which require therapy. Patients with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed.
  • Patients with known active hepatitis A, B, C or who are HIV-positive.
  • Patients with inadequate bone marrow reserve as demonstrated by:

    1. Absolute neutrophil count (ANC) that is ≤ 1000/µL.
    2. Platelet count that is < 100,000/µL without the assistance of growth factors, thrombopoietic factors or platelet transfusions.
  • Patients with any history of platelet counts < 50,000/µL or ANC < 500/µL except during treatment for a myeloproliferative disorder or treatment with cytotoxic therapy for any other reason.
  • Patients with coagulation parameters (PT, PTT, INR) ≥ 1.5.
  • Patients with known hypersensitivity to INC424 or other JAK1/2 inhibitors, or to their excipients.
  • Patients under ongoing treatment with another investigational medication or having been treated with an investigational medication within 30 days of screening.
  • Patients with any concurrent condition that, in the Investigator's opinion would jeopardize the safety of the patient or compliance with the protocol.

Other protocol-defined inclusion/exclusion criteria may apply.

Sites / Locations

  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

INC424

Arm Description

Patients diagnosed with PMF, PPV MF, or PET-MF were treated with oral INC424 at a dose of 15 - 20 mg (dose based on Baseline platelet count) twice daily.

Outcomes

Primary Outcome Measures

Percentage of Participants With Treatment Success
Treatment success was defined as a 50% or greater reduction in palpable spleen length versus baseline at 48 weeks and/or a 50% or greater improvement in total symptom score (derived from the MF symptom assessment form (MFSAF) questionnaire) versus baseline at the week 48 time point. The MFSAF assesses the following symptoms (all scored from absent (0) to worst imaginable (10)): general fatigue, abdominal pain (and discomfort), inactivity (ability to move and walk around), cough, night sweats, itching (pruritus), bone pain (diffuse not joint pain or arthritis), fever, change in appetite/unintentional weight loss (or gain) in past 6 months, overall quality of life (QoL).

Secondary Outcome Measures

Percentage of Participants With Best Overall Response
Response to treatment and disease progression was assessed by physical examination, specifically assessing changes in spleen size by palpation. Disease response and progression was evaluated using the International Working Group for myelofibrosis Research and Treatment Response Criteria.
Change From Baseline in Myelofibrosis Symptoms Assessment Form (MF-SAF)
The MF-SAF consists of seven questions about key symptoms and impact of MF. Questions are scored on a scale of 0-10, with higher scores indicating more severe symptoms and greater inactivity. Questions 1-6, which together comprise a Total Symptom Score (TSS), investigate the following symptoms: night sweats, pruritus/itching, abdominal discomfort, pain under the ribs, early satiety and bone/muscle pain. Question 7 asks patients to report levels of inactivity. The TSS reflects the sum of the scores of these symptoms excluding inactivity, with the maximum possible score being 60 (most severe symptom experienced).
Change From Baseline in EQ5D Preference Index (5 Level EuroQol Questionnaire Determining Quality of Life) From Baseline
The EQ-5D is a standardized instrument used for measuring health outcomes in a wide range of health conditions and treatment. It consists of a descriptive system and a visual analogue scale (EQ-VAS). The descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The EQ-VAS records the participant's self-rated health on a vertical, VAS where the endpoints are labeled 'best imaginable health state' and 'worst imaginable health state'. The EQ-5D health state was converted to a single summary index by applying a formula that attaches a weight to each of the levels in each dimension. The final EQ5D preference index scores range from 0 to 1 with higher scores indicating better health.
Number of Hospitalizations
Medical resource utilization (MRU) was assessed according to the number of hospitalizations.
Duration of Hospitalizations
MRU was assessed according to the mean duration of hospitalization visits.
Number of Accident & Emergency Visits From Baseline
MRU was assessed according to the number of accidents and emergency room visits.
Number of General Practitioner (GP), Specialists' and Urgent Care Visits
MRU was assessed according to the number of GP, specialists', and urgent care visits.
Percentage of Participants With Transfusion Dependency Status
Transfusion dependency status from baseline through the end of study was assessed. New onset of transfusion dependency was defined as the use of 2 or more units of red blood cell products during the 8 weeks prior to a study visit. New onset of transfusion independency was defined as the use of 0 or 1 unit of red blood cell products during the 8 weeks prior to a study visit.

Full Information

First Posted
March 16, 2012
Last Updated
March 1, 2015
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01558739
Brief Title
Exploratory Phase II Study of INC424 Patients With Primary Myelofibrosis (PMF) or Post Polycythaemia Myelofibrosis (PPV MF) or Post Essential Thrombocythaemia Myelofibrosis (PET-MF)
Acronym
MACS2030
Official Title
A UK Open-label, Multicentre, Exploratory Phase II Study of INC424 for Patients With Primary Myelofibrosis (PMF) or Post Polycythaemia Myelofibrosis (PPV MF) or Post Essential Thrombocythaemia Myelofibrosis (PET-MF)
Study Type
Interventional

2. Study Status

Record Verification Date
March 2015
Overall Recruitment Status
Completed
Study Start Date
May 2012 (undefined)
Primary Completion Date
January 2014 (Actual)
Study Completion Date
January 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The primary objective of this study is to evaluate the efficacy of INC424 in patients with PMF, PPV MF, or PET-MF using a composite measure of either an objective endpoint (> 50% reduction in splenomegaly using palpitation at 48 weeks) and/or a subjective endpoint (>50% reduction in total symptom score at 48 weeks).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Myelofibrosis (PMF), Post Polycythaemia Myelofibrosis (PPV MF), Post Essential Thrombocythaemia Myelofibrosis (PET-MF)
Keywords
Ruxolitinib, INC424, myelofibrosis, PMF, post polycythemia myelofibrosis, PPV MF, post-essential thrombocythemia myelofibrosis, PET-MF, Primary Myelofibrosis, Polycythemia, Thrombocythemia, Essential Thrombocytosis, myeloproliferative Disorders, Bone Marrow Diseases, Haematologic Diseases, Blood Coagulation Disorders, Blood Platelet Disorders, Haemorrhagic Disorders

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
48 (Actual)

8. Arms, Groups, and Interventions

Arm Title
INC424
Arm Type
Experimental
Arm Description
Patients diagnosed with PMF, PPV MF, or PET-MF were treated with oral INC424 at a dose of 15 - 20 mg (dose based on Baseline platelet count) twice daily.
Intervention Type
Drug
Intervention Name(s)
INC424
Intervention Description
Ruxolitinib was provided in 5 mg tablets, packaged in bottles. 15 - 20 mg (dose based on Baseline platelet count) twice daily.
Primary Outcome Measure Information:
Title
Percentage of Participants With Treatment Success
Description
Treatment success was defined as a 50% or greater reduction in palpable spleen length versus baseline at 48 weeks and/or a 50% or greater improvement in total symptom score (derived from the MF symptom assessment form (MFSAF) questionnaire) versus baseline at the week 48 time point. The MFSAF assesses the following symptoms (all scored from absent (0) to worst imaginable (10)): general fatigue, abdominal pain (and discomfort), inactivity (ability to move and walk around), cough, night sweats, itching (pruritus), bone pain (diffuse not joint pain or arthritis), fever, change in appetite/unintentional weight loss (or gain) in past 6 months, overall quality of life (QoL).
Time Frame
48 Weeks
Secondary Outcome Measure Information:
Title
Percentage of Participants With Best Overall Response
Description
Response to treatment and disease progression was assessed by physical examination, specifically assessing changes in spleen size by palpation. Disease response and progression was evaluated using the International Working Group for myelofibrosis Research and Treatment Response Criteria.
Time Frame
week 48
Title
Change From Baseline in Myelofibrosis Symptoms Assessment Form (MF-SAF)
Description
The MF-SAF consists of seven questions about key symptoms and impact of MF. Questions are scored on a scale of 0-10, with higher scores indicating more severe symptoms and greater inactivity. Questions 1-6, which together comprise a Total Symptom Score (TSS), investigate the following symptoms: night sweats, pruritus/itching, abdominal discomfort, pain under the ribs, early satiety and bone/muscle pain. Question 7 asks patients to report levels of inactivity. The TSS reflects the sum of the scores of these symptoms excluding inactivity, with the maximum possible score being 60 (most severe symptom experienced).
Time Frame
Baseline, week 4, week 12, week 24, week 48
Title
Change From Baseline in EQ5D Preference Index (5 Level EuroQol Questionnaire Determining Quality of Life) From Baseline
Description
The EQ-5D is a standardized instrument used for measuring health outcomes in a wide range of health conditions and treatment. It consists of a descriptive system and a visual analogue scale (EQ-VAS). The descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The EQ-VAS records the participant's self-rated health on a vertical, VAS where the endpoints are labeled 'best imaginable health state' and 'worst imaginable health state'. The EQ-5D health state was converted to a single summary index by applying a formula that attaches a weight to each of the levels in each dimension. The final EQ5D preference index scores range from 0 to 1 with higher scores indicating better health.
Time Frame
Baseline, week 4, week 12, week 24, week 48
Title
Number of Hospitalizations
Description
Medical resource utilization (MRU) was assessed according to the number of hospitalizations.
Time Frame
week 12, week 24, week 26, week 48
Title
Duration of Hospitalizations
Description
MRU was assessed according to the mean duration of hospitalization visits.
Time Frame
week 48
Title
Number of Accident & Emergency Visits From Baseline
Description
MRU was assessed according to the number of accidents and emergency room visits.
Time Frame
baseline to week 12, week 12 to week 24, week 24 to week 36, week 36 to week 48
Title
Number of General Practitioner (GP), Specialists' and Urgent Care Visits
Description
MRU was assessed according to the number of GP, specialists', and urgent care visits.
Time Frame
baseline to week 12, week 12 to, week 24, week 24 to week 36, week 36 to week 48
Title
Percentage of Participants With Transfusion Dependency Status
Description
Transfusion dependency status from baseline through the end of study was assessed. New onset of transfusion dependency was defined as the use of 2 or more units of red blood cell products during the 8 weeks prior to a study visit. New onset of transfusion independency was defined as the use of 0 or 1 unit of red blood cell products during the 8 weeks prior to a study visit.
Time Frame
baseline (BL), end of treatment (up to 28 days post last treatment) (EOT)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must not be eligible for another ongoing INC424 clinical trial. Patients must be diagnosed with PMF, PPV MF or PET-MF, according to the 2008 revised World Health Organization criteria irrespective of JAK2 mutation status. Patients with PMF requiring therapy must be classified as high risk (3 prognostic factors) OR intermediate risk level 2 (2 prognostic factors, no more), OR intermediate risk level 1 (1 prognostic factor, no more) with an enlarged spleen. The prognostic factors, defined by the International Working Group are: Age > 65 years; Presence of constitutional symptoms (weight loss, fever, night sweats); marked anemia (Hgb < 10g/dL)*; Leukocytosis (history of WBC > 25 x109/L); Circulating blasts > 1%. • A hemoglobin value < 10 g/dL must be demonstrated during the Screening Visit for patients who are not transfusion dependent. Patients receiving regular transfusions of packed red blood cells will be considered to have hemoglobin < 10 g/dL for the purpose of evaluation of risk factors. Patients with Intermediate-1 disease and splenomegaly must have a palpable spleen measuring 5 cm or greater from the costal margin to the point of greatest splenic protrusion. Patients must have a peripheral blood blast count of < 10%. Patients with adequate liver function defined as direct bilirubin ≤ 2.0 x ULN and ALT ≤ 2.5 x ULN. Patients with adequate renal function defined as serum creatinine ≤ 2 x ULN. Patients with an ECOG performance status of 0, 1, or 2 (Appendix 5). Exclusion criteria: Patients eligible for hematopoietic stem cell transplantation (suitable candidate and a suitable donor is available). Patients with history of malignancy in past 3 years except for treated, early-stage squamous or basal cell carcinoma in situ. Patients undergoing treatment with hematopoietic growth factor receptor agonists (i.e., erythropoietin [Epo], granulocyte colony stimulating factor (GCSF [Neupogen; Neulasta], romiplostim, eltrombopag) at any time within 2 weeks prior to Screening or 4 weeks prior to Baseline. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral INC424 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection). Patients with cardiac disease which in the Investigator's opinion may jeopardize the safety of the patient or the compliance with the protocol. Patients with clinically significant bacterial, fungal, parasitic or viral infection which require therapy. Patients with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed. Patients with known active hepatitis A, B, C or who are HIV-positive. Patients with inadequate bone marrow reserve as demonstrated by: Absolute neutrophil count (ANC) that is ≤ 1000/µL. Platelet count that is < 100,000/µL without the assistance of growth factors, thrombopoietic factors or platelet transfusions. Patients with any history of platelet counts < 50,000/µL or ANC < 500/µL except during treatment for a myeloproliferative disorder or treatment with cytotoxic therapy for any other reason. Patients with coagulation parameters (PT, PTT, INR) ≥ 1.5. Patients with known hypersensitivity to INC424 or other JAK1/2 inhibitors, or to their excipients. Patients under ongoing treatment with another investigational medication or having been treated with an investigational medication within 30 days of screening. Patients with any concurrent condition that, in the Investigator's opinion would jeopardize the safety of the patient or compliance with the protocol. Other protocol-defined inclusion/exclusion criteria may apply.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Cardiff
State/Province
Wales
ZIP/Postal Code
CF14 4XN
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Bournemouth
ZIP/Postal Code
BH7 7DW
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
East Yorkshire
ZIP/Postal Code
HU16 5JQ
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Edinburgh
ZIP/Postal Code
EH4 2XU
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Leicester
ZIP/Postal Code
LE7 5WW
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Liverpool
ZIP/Postal Code
L7 8XP
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
London
ZIP/Postal Code
SE1 9RT
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
London
ZIP/Postal Code
W12 0HS
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Manchester
ZIP/Postal Code
M13 9NT
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Oxford
ZIP/Postal Code
OX3 7LJ
Country
United Kingdom

12. IPD Sharing Statement

Learn more about this trial

Exploratory Phase II Study of INC424 Patients With Primary Myelofibrosis (PMF) or Post Polycythaemia Myelofibrosis (PPV MF) or Post Essential Thrombocythaemia Myelofibrosis (PET-MF)

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