Clinical trial NCT00931762: 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
Overall status: TERMINATED
Phase: PHASE2
Conditions: Primary Myelofibrosis
Post-Polycythemia Vera
Post-Essential Thrombocytopenia
Keywords: Bone marrow
Myelofibrosis
JAK2mutation
Post-Polycythemia Vera
Post-Essential Thrombocytopenia
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2009-07-02
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Overall Response (OR) Rate Per International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) Criteria
timeFrame: Up to approximately 2 years
Secondary outcomes:
measure: Change From Baseline in Myelofibrosis Symptom Assessment Form (MF-SAF) Scale Scores At Cycle 6
timeFrame: Baseline, Cycle 6 (each cycle was of 28 days)
measure: Change From Baseline in Myelofibrosis Symptom Assessment Form (MF-SAF) Scale Scores
timeFrame: Baseline, Cycles 2, and 4 (each cycle was of 28-days)
measure: Number of Participants With Adverse Events (AEs), and Serious Adverse Events (SAEs)
timeFrame: 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 outcomes:
measure: Monthly Capsule Counts to Assess Compliance to Panobinostat Treatment
timeFrame: Up to approximately 2 years
measure: To Compare the Response to Panobinostat in Patients With the JAK2 V617F Mutation to Those Without the JAK2 V617F Mutation
timeFrame: Up to approximately 2 years
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic - Scottsdale
state: Arizona
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Stanford
country: United States
facility: Stanford Comprehensive Cancer Center
state: California
city: Augusta
country: United States
facility: Medical College of Georgia
state: Georgia
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: New York
country: United States
facility: New York Presbyterian Hospital - Weill Cornell Medical College
state: New York
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
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.