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

Study Overview
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Brief Summary
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: Panobinostat


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panobinostat<br>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. | Drug: Panobinostat<br>* Panobinostat oral capsules<br>* Other names: H-DAC Inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Cycle 6 (each cycle was of 28 days) | 
| 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. | Baseline, Cycles 2, and 4 (each cycle was of 28-days) | 
| 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 | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bone marrow, Myelofibrosis, JAK2mutation, Post-Polycythemia Vera, Post-Essential Thrombocytopenia