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A Study to Evaluate Safety and Efficacy of Panobinostat in Participants With Primary Myelofibrosis

Primary Purpose

Primary Myelofibrosis, Post-Polycythemia Vera, Post-Essential Thrombocytopenia

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Panobinostat
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Myelofibrosis focused on measuring Bone marrow, Myelofibrosis, JAK2mutation, Post-Polycythemia Vera, Post-Essential Thrombocytopenia

Eligibility Criteria

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

Inclusion Criteria:

  1. Diagnosis of myelofibrosis, either primary myelofibrosis (PMF), post- polycythemia vera (PV) or post-essential thrombocythemia (ET) myelofibrosis (MF) with international prognostic scoring system (IPSS) score of 2 (intermediate risk) or 3 (high risk) plus at least one of the following:

    Symptomatic spenomegaly (≥10 centimeter [cm] below costal margin [BCM]) Hemoglobin < 10 or red cell transfusion dependent. (The presence of a janus kinase (JAK2) V617F mutation is not required for study entry).

  2. Participants must meet the following laboratory criteria:

    • Participants can be either JAK2 V617F mutated or wild type.
    • Serum potassium, magnesium, phosphorous, sodium, total calcium (corrected for serum albumin) or ionized calcium within normal limits (WNL) for the institution Note: Potassium, magnesium, phosphorous, sodium, and/or calcium supplements maybe given to correct values that are < lower limit of normal (LLN). Post correction values must not be deemed to be a clinically significant abnormality prior to participants being dosed.
    • Creatinine < 1.5 X upper limit of normal (ULN) or calculated creatinine clearance (CrCl) ≥ 50 milliliter per minute (mL/min) (modification of diet in renal diseases [MDRD] formula).
    • Aspartate aminotransferase [AST] and alanine transaminase [ALT] ≤ 2.5 x ULN.
    • Serum total bilirubin ≤ 1.5 x ULN.
  3. Eastern cooperative oncology group (ECOG) performance status of ≤ 2.
  4. Clinically euthyroid. Note: Participants are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.

Exclusion Criteria:

  1. Prior histone deacetylases (HDAC), deacetylase (DAC), heat shock protein 90 (HSP90) inhibitors or valproic acid for the treatment of cancer.
  2. Previous treatment with JAK2 inhibitors.
  3. Any participant who has previously received radiation therapy to ≥ 30% of the bone marrow.
  4. Impaired cardiac function or clinically significant cardiac diseases.
  5. Participant with unresolved diarrhoea ≥ grade 2.
  6. Participants using medications that have a relative risk of prolonging the QT interval or inducing Torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug.
  7. Participants who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of surgery.
  8. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not using an effective method of birth control. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). Women of childbearing potential must have a negative serum pregnancy test at screening and at baseline.
  9. Male participants whose sexual partners are WOCBP not using effective birth control.
  10. Participants with a prior malignancy with in the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix).
  11. Participants with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required.

Other protocol-defined inclusion/exclusion criteria may apply.

Sites / Locations

  • Mayo Clinic - Scottsdale
  • City of Hope National Medical Center
  • Stanford Comprehensive Cancer Center
  • Medical College of Georgia
  • Northwestern University Feinberg School of Medicine
  • Dana Farber Cancer Institute
  • University of Michigan
  • Mayo Clinic - Rochester
  • New York Presbyterian Hospital - Weill Cornell Medical College

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Panobinostat

Arm Description

Participants received panobinostat 40 mg, capsules, orally, with or without food, three times a week on Monday, Wednesday, and Friday for up to 6 treatment cycles (each cycle of 28-days) with dose adjustments possible.

Outcomes

Primary Outcome Measures

Overall Response (OR) Rate Per International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) Criteria
Overall response (OR) = Complete remission (CR) + Partial remission (PR) + Clinical improvement (CI). CR: complete resolution of disease-related symptoms and signs with hemoglobin level 110 grams per deciliter (g/L), platelet count 100 x 10^9/liter (L), and absolute neutrophil count (ANC) 1.0 x 10^9/L, all 3 blood counts < upper normal limit (UNL), normal leukocyte differential, and bone marrow histologic remission. PR= all of the criteria for CR except the requirement for bone marrow histologic remission. CI= minimum 20 g/L increase in hemoglobin for transfusion or becoming transfusion independent or reduction in splenomegaly ≥ 50% or 100% increase in platelet count and absolute platelet count of 50 x 10^9/L and 100% increase in ANC of at least 0.5 x 10^9/L.

Secondary Outcome Measures

Change From Baseline in Myelofibrosis Symptom Assessment Form (MF-SAF) Scale Scores At Cycle 6
The MF-SAF consists of seven questions about key symptoms and impact of MF. Questions were scored on a scale of 0-10, with higher scores indicating more severe symptoms and greater inactivity. Questions 1-6 investigate the following symptoms: night sweats, pruritus/itching, abdominal discomfort, pain under the ribs, early satiety and bone/muscle pain. Question 7 asked participants to report levels of inactivity. Negative change from baseline indicates improvement.
Change From Baseline in Myelofibrosis Symptom Assessment Form (MF-SAF) Scale Scores
The MF-SAF consists of seven questions about key symptoms and impact of MF. Questions were scored on a scale of 0-10, with higher scores indicating more severe symptoms and greater inactivity. Questions 1-6 investigate the following symptoms: night sweats, pruritus/itching, abdominal discomfort, pain under the ribs, early satiety and bone/muscle pain. Question 7 asked participants to report levels of inactivity. Negative change from baseline indicates improvement.
Number of Participants With Adverse Events (AEs), and Serious Adverse Events (SAEs)
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. SAEs was an undesirable sign, symptom or medical condition which is: life-threatening, persistent or significant disability/incapacity, congenital anomaly/birth defect, requires hospitalizations or prolongation of hospitalizations, or is medically significant

Full Information

First Posted
July 1, 2009
Last Updated
July 9, 2021
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT00931762
Brief Title
A Study to Evaluate Safety and Efficacy of Panobinostat in Participants With Primary Myelofibrosis
Official Title
Phase II Trial of Oral Panobinostat (LBH589), a Novel Deacetylase Inhibitor (DACi) in Patients With Primary Myelofibrosis (PMF), Post Essential Thrombocythemia (ET) Myelofibrosis and Post- Polycythemia Vera (PV) Myelofibrosis
Study Type
Interventional

2. Study Status

Record Verification Date
July 2021
Overall Recruitment Status
Terminated
Study Start Date
August 31, 2009 (Actual)
Primary Completion Date
August 29, 2011 (Actual)
Study Completion Date
August 29, 2011 (Actual)

3. Sponsor/Collaborators

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This study assessed the safety and efficacy of Panobinostat as a single agent in the treatment of Primary Myelofibrosis, Post-Polycythemia Vera and Post-Essential Thrombocythemia. There were two cohorts - participants with JAK2 mutation and participants without JAK2 mutation.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Myelofibrosis, Post-Polycythemia Vera, Post-Essential Thrombocytopenia
Keywords
Bone marrow, Myelofibrosis, JAK2mutation, Post-Polycythemia Vera, Post-Essential Thrombocytopenia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
35 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Panobinostat
Arm Type
Experimental
Arm Description
Participants received panobinostat 40 mg, capsules, orally, with or without food, three times a week on Monday, Wednesday, and Friday for up to 6 treatment cycles (each cycle of 28-days) with dose adjustments possible.
Intervention Type
Drug
Intervention Name(s)
Panobinostat
Other Intervention Name(s)
LBH589, H-DAC Inhibitor
Intervention Description
Panobinostat oral capsules
Primary Outcome Measure Information:
Title
Overall Response (OR) Rate Per International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) Criteria
Description
Overall response (OR) = Complete remission (CR) + Partial remission (PR) + Clinical improvement (CI). CR: complete resolution of disease-related symptoms and signs with hemoglobin level 110 grams per deciliter (g/L), platelet count 100 x 10^9/liter (L), and absolute neutrophil count (ANC) 1.0 x 10^9/L, all 3 blood counts < upper normal limit (UNL), normal leukocyte differential, and bone marrow histologic remission. PR= all of the criteria for CR except the requirement for bone marrow histologic remission. CI= minimum 20 g/L increase in hemoglobin for transfusion or becoming transfusion independent or reduction in splenomegaly ≥ 50% or 100% increase in platelet count and absolute platelet count of 50 x 10^9/L and 100% increase in ANC of at least 0.5 x 10^9/L.
Time Frame
Up to approximately 2 years
Secondary Outcome Measure Information:
Title
Change From Baseline in Myelofibrosis Symptom Assessment Form (MF-SAF) Scale Scores At Cycle 6
Description
The MF-SAF consists of seven questions about key symptoms and impact of MF. Questions were scored on a scale of 0-10, with higher scores indicating more severe symptoms and greater inactivity. Questions 1-6 investigate the following symptoms: night sweats, pruritus/itching, abdominal discomfort, pain under the ribs, early satiety and bone/muscle pain. Question 7 asked participants to report levels of inactivity. Negative change from baseline indicates improvement.
Time Frame
Baseline, Cycle 6 (each cycle was of 28 days)
Title
Change From Baseline in Myelofibrosis Symptom Assessment Form (MF-SAF) Scale Scores
Description
The MF-SAF consists of seven questions about key symptoms and impact of MF. Questions were scored on a scale of 0-10, with higher scores indicating more severe symptoms and greater inactivity. Questions 1-6 investigate the following symptoms: night sweats, pruritus/itching, abdominal discomfort, pain under the ribs, early satiety and bone/muscle pain. Question 7 asked participants to report levels of inactivity. Negative change from baseline indicates improvement.
Time Frame
Baseline, Cycles 2, and 4 (each cycle was of 28-days)
Title
Number of Participants With Adverse Events (AEs), and Serious Adverse Events (SAEs)
Description
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. SAEs was an undesirable sign, symptom or medical condition which is: life-threatening, persistent or significant disability/incapacity, congenital anomaly/birth defect, requires hospitalizations or prolongation of hospitalizations, or is medically significant
Time Frame
AE: From the start of treatment up to 28 days after last study dose (up to approximately 2 years); SAE: From time of informed consent up to 4 weeks after last study dose (approximately 2 years)
Other Pre-specified Outcome Measures:
Title
Monthly Capsule Counts to Assess Compliance to Panobinostat Treatment
Time Frame
Up to approximately 2 years
Title
To Compare the Response to Panobinostat in Patients With the JAK2 V617F Mutation to Those Without the JAK2 V617F Mutation
Time Frame
Up to approximately 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of myelofibrosis, either primary myelofibrosis (PMF), post- polycythemia vera (PV) or post-essential thrombocythemia (ET) myelofibrosis (MF) with international prognostic scoring system (IPSS) score of 2 (intermediate risk) or 3 (high risk) plus at least one of the following: Symptomatic spenomegaly (≥10 centimeter [cm] below costal margin [BCM]) Hemoglobin < 10 or red cell transfusion dependent. (The presence of a janus kinase (JAK2) V617F mutation is not required for study entry). Participants must meet the following laboratory criteria: Participants can be either JAK2 V617F mutated or wild type. Serum potassium, magnesium, phosphorous, sodium, total calcium (corrected for serum albumin) or ionized calcium within normal limits (WNL) for the institution Note: Potassium, magnesium, phosphorous, sodium, and/or calcium supplements maybe given to correct values that are < lower limit of normal (LLN). Post correction values must not be deemed to be a clinically significant abnormality prior to participants being dosed. Creatinine < 1.5 X upper limit of normal (ULN) or calculated creatinine clearance (CrCl) ≥ 50 milliliter per minute (mL/min) (modification of diet in renal diseases [MDRD] formula). Aspartate aminotransferase [AST] and alanine transaminase [ALT] ≤ 2.5 x ULN. Serum total bilirubin ≤ 1.5 x ULN. Eastern cooperative oncology group (ECOG) performance status of ≤ 2. Clinically euthyroid. Note: Participants are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism. Exclusion Criteria: Prior histone deacetylases (HDAC), deacetylase (DAC), heat shock protein 90 (HSP90) inhibitors or valproic acid for the treatment of cancer. Previous treatment with JAK2 inhibitors. Any participant who has previously received radiation therapy to ≥ 30% of the bone marrow. Impaired cardiac function or clinically significant cardiac diseases. Participant with unresolved diarrhoea ≥ grade 2. Participants using medications that have a relative risk of prolonging the QT interval or inducing Torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug. Participants who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of surgery. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not using an effective method of birth control. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). Women of childbearing potential must have a negative serum pregnancy test at screening and at baseline. Male participants whose sexual partners are WOCBP not using effective birth control. Participants with a prior malignancy with in the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix). Participants with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required. Other protocol-defined inclusion/exclusion criteria may apply.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Mayo Clinic - Scottsdale
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259
Country
United States
Facility Name
City of Hope National Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Facility Name
Stanford Comprehensive Cancer Center
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Medical College of Georgia
City
Augusta
State/Province
Georgia
ZIP/Postal Code
30912
Country
United States
Facility Name
Northwestern University Feinberg School of Medicine
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Mayo Clinic - Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
New York Presbyterian Hospital - Weill Cornell Medical College
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
23701016
Citation
DeAngelo DJ, Mesa RA, Fiskus W, Tefferi A, Paley C, Wadleigh M, Ritchie EK, Snyder DS, Begna K, Ganguly S, Ondovik MS, Rine J, Bhalla KN. Phase II trial of panobinostat, an oral pan-deacetylase inhibitor in patients with primary myelofibrosis, post-essential thrombocythaemia, and post-polycythaemia vera myelofibrosis. Br J Haematol. 2013 Aug;162(3):326-35. doi: 10.1111/bjh.12384. Epub 2013 May 23.
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A Study to Evaluate Safety and Efficacy of Panobinostat in Participants With Primary Myelofibrosis

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