Panobinostat and Ruxolitinib in Primary Myelofibrosis, Post-polycythemia Vera-myelofibrosis or Post-essential Thrombocythemia-myelofibrosis

Study Overview
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Brief Summary
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This study will assess safety as well as establish a Recommended Phase II dose of the combination of panobinostat and ruxolitinib in patients with or without the JAK2V617F mutation who have been diagnosed with primary myelofibrosis (PMF), Post Essential Thrombocythemia Myelofibrosis (PET MF), or Post-Polycythemia Vera Myelofibrosis (PPV MF).

Detailed Description
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In 2011 the treatment goals for MF focused on symptom-orientated palliation and quality of life. Both ruxolitinib and panobinostat, as single agents, had shown significant improvement in both of those treatment goals and ruxolitinib had also shown greater reductions in splenomegaly compared to the standard of care at that time. To further the benefit seen with ruxolitinib in MF patients, panobinostat was added to the treatment regimen to act synergistically in the blockade of the dysregulated pathway driving this disease. The study was conducted in 2 phases - an escalation phase and an expansion phase. Escalation phase: the study utilised the Bayesian Logistic Regression Model (BLRM), incorporating escalation with overdose control (EWOC), which is a well established method for dose escalation in oncology trials. Following this process, successive cohorts of 3 newly enrolled patients received increasing doses of ruxolitinib and panobinostat until the maximum tolerated dose (MTD) or recommended phase II dose (RPIID) was determined. Once the MTD and/or RPIID were suspected in a minimum of 3 patients, additional patients were enrolled to the same cohort level to reach a minimum of 9 evaluable patients. The process also included safety, PK/PD assessments and estimates of efficacy based on measures of splenic reduction at each dose level. Expansion: following the determination of the MTD and/or RPIID, a dose expansion phase was conducted at that dose to further define the safety and tolerability of the combination. At least 13, and no more than 23, additional patients were to be enrolled into the expansion phase.

Official Title
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A Phase 1b, Open-label, Multi-center, Single Arm, Dose Finding Study to Assess Safety and Pharmacokinetics of the Oral Combination of Panobinostat and Ruxolitinib in Patients With Primary Myelofibrosis (PMF), Post-polycythemia Vera-myelofibrosis (PPV-MF) or Post-essential Thrombocythemia-myelofibrosis (PET-MF)

Conditions
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Idiopathic Myelofibrosis, Post Essential Thrombocythemia Myelofibrosis, Post Polycythemia-Vera Myelofibrosis

Intervention / Treatment
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* Drug: panobinostat
* Drug: ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of myelofibrosis, either PMF, PPV or PET MF Palpable splenomegaly ≥ 5cm May have been previously treated with either panobinostat or ruxolitinib (unless discontinued for clinically relevant toxicities) Acceptable lab ranges for all organ systems Specifically: Platelet count > 100,000 not reached with the aide of transfusions Blast count < 10% at screening ECOG ≤ 2 Must be able to discontinue all drugs being used to treat MF at least 7 days prior to starting study drug Exclusion Criteria: Active malignancy Clinically significant heart disease Splenic irradiation within 12 months of starting study drug Need for ongoing systemic anticoagulation with the exception of Aspirin < 150mg/day or Low Molecular Weight Heparin History of platelet dysfunction or bleeding disorder in the 6 months prior to screening Patient is at risk for spontaneous bleeding Willing and/or eligible for stem-cell transplantation Impairment of gastro-intestinal function that may impact the absorption of study treatment Unwilling to use highly effective methods of contraception during dosing and for 13 weeks (female participants) or for 6 months (male participants and their female partners) after stopping study treatment

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Subjects will be treated with ruxolitinib 5 mg twice daily (BID) and panobinostat 10 mg three times per week (TIW) every other week (QOW) on a 28 day cycle | Drug: panobinostat<br>* Given 3 times a week, every other week in 28-day cycles.<br>* Other names: LBH589;Drug: ruxolitinib<br>* Given twice daily in 28-day cycles.<br>* Other names: INC424;|
| Experimental: Cohort 2<br>Subjects will be treated with ruxolitinib 10 mg twice daily (BID) and panobinostat 10 mg three times per week (TIW) every other week (QOW) on a 28 day cycle | Drug: panobinostat<br>* Given 3 times a week, every other week in 28-day cycles.<br>* Other names: LBH589;Drug: ruxolitinib<br>* Given twice daily in 28-day cycles.<br>* Other names: INC424;|
| Experimental: Cohort 3<br>Subjects will be treated with ruxolitinib 15 mg twice daily (BID) and panobinostat 10 mg three times per week (TIW) every other week (QOW) on a 28 day cycle | Drug: panobinostat<br>* Given 3 times a week, every other week in 28-day cycles.<br>* Other names: LBH589;Drug: ruxolitinib<br>* Given twice daily in 28-day cycles.<br>* Other names: INC424;|
| Experimental: Cohort 4<br>Subjects will be treated with ruxolitinib 15 mg twice daily (BID) and panobinostat 15 mg three times per week (TIW) every other week (QOW) on a 28 day cycle | Drug: panobinostat<br>* Given 3 times a week, every other week in 28-day cycles.<br>* Other names: LBH589;Drug: ruxolitinib<br>* Given twice daily in 28-day cycles.<br>* Other names: INC424;|
| Experimental: Cohort 5<br>Subjects will be treated with ruxolitinib 15 mg twice daily (BID) and panobinostat 20 mg three times per week (TIW) every other week (QOW) on a 28 day cycle | Drug: panobinostat<br>* Given 3 times a week, every other week in 28-day cycles.<br>* Other names: LBH589;Drug: ruxolitinib<br>* Given twice daily in 28-day cycles.<br>* Other names: INC424;|
| Experimental: Cohort 6/6+<br>Subjects will be treated with ruxolitinib 15 mg twice daily (BID) and panobinostat 25 mg three times per week (TIW) every other week (QOW) on a 28 day cycle | Drug: panobinostat<br>* Given 3 times a week, every other week in 28-day cycles.<br>* Other names: LBH589;Drug: ruxolitinib<br>* Given twice daily in 28-day cycles.<br>* Other names: INC424;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of dose limiting toxicities at the different dose levels |  | Cycle 1 (a cycle = 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of adverse events, serious adverse events, notable laboratory, vital signs and ECG results by dose level |  | From screening until safety follow up visit (30 days after last treatment), approx. 8.5 years | 
| AUC of ruxolitinib and panobinostat at various dose levels | Area under the plasma concentration versus time curve | Ruxolitinib on days 1,2 and 6; Panobinostat on days 2-3 and days 6-7 | 
| Cmax of ruxolitinib and panobinostat at various dose levels | Cmax is the Peak Plasma Concentration | Ruxolitinib on days 1,2 and 6; Panobinostat on days 2-3 and days 6-7 | 
| Tmax of ruxolitinib and panobinostat at various dose levels | Tmax: The time of maximum observed concentration sampled during a dosing interval. | Ruxolitinib on days 1,2 and 6; Panobinostat on days 2-3 and days 6-7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelofibrosis, Panobinostat, LBH589, Ruxolitinib, MF, PMF, PPV, PPV-MF, PET, PET-MF, JAK2, DACi