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

Phase 2

Terminated

• Conditions: Post-Polycythemia Vera; Post-Essential Thrombocytopenia; Primary Myelofibrosis
• Interventions: Drug: Panobinostat

• Registration Number: NCT00931762
• Lead Sponsor: Novartis Pharmaceuticals

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2009-07-01
• Study First Submitted QC: 2009-07-01
• Study First Posted: 2009-07-02
• Study Start: 2009-08-31
• Primary Completion: 2011-08-29
• Study Completion: 2011-08-29
• Results First Submitted: 2021-05-17
• Status Verified: 2021-07
• Results First Submitted QC: 2021-07-09
• Last Update Submitted: 2021-07-09
• Results First Posted: 2021-07-30
• Last Update Posted: 2021-07-30

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 35

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Panobinostat	Panobinostat	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.

Primary Outcome Measures

Name	Time	Method
Overall Response (OR) Rate Per International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) Criteria	Up to approximately 2 years	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

Name	Time	Method
Number of Participants With Adverse Events (AEs), and Serious Adverse Events (SAEs)	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)	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
Change From Baseline in Myelofibrosis Symptom Assessment Form (MF-SAF) Scale Scores At Cycle 6	Baseline, Cycle 6 (each cycle was of 28 days)	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	Baseline, Cycles 2, and 4 (each cycle was of 28-days)	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.

Trial Locations

Locations (9)

Medical College of Georgia; 🇺🇸 Augusta, Georgia, United States

Northwestern University Feinberg School of Medicine; 🇺🇸 Chicago, Illinois, United States

Mayo Clinic - Scottsdale; 🇺🇸 Scottsdale, Arizona, United States

City of Hope National Medical Center; 🇺🇸 Duarte, California, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Stanford Comprehensive Cancer Center; 🇺🇸 Stanford, California, United States

Mayo Clinic - Rochester; 🇺🇸 Rochester, Minnesota, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

New York Presbyterian Hospital - Weill Cornell Medical College; 🇺🇸 New York, New York, United States