Clinical trial NCT01433445: Panobinostat and Ruxolitinib in Primary Myelofibrosis, Post-polycythemia Vera-myelofibrosis or Post-essential Thrombocythemia-myelofibrosis
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Idiopathic Myelofibrosis
Post Essential Thrombocythemia Myelofibrosis
Post Polycythemia-Vera Myelofibrosis
Keywords: Myelofibrosis
Panobinostat
LBH589
Ruxolitinib
MF
PMF
PPV
PPV-MF
PET
PET-MF
JAK2
DACi
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2011-09-14
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Rate of dose limiting toxicities at the different dose levels
timeFrame: Cycle 1 (a cycle = 28 days)
Secondary outcomes:
measure: Rate of adverse events, serious adverse events, notable laboratory, vital signs and ECG results by dose level
timeFrame: From screening until safety follow up visit (30 days after last treatment), approx. 8.5 years
measure: AUC of ruxolitinib and panobinostat at various dose levels
timeFrame: Ruxolitinib on days 1,2 and 6; Panobinostat on days 2-3 and days 6-7
measure: Cmax of ruxolitinib and panobinostat at various dose levels
timeFrame: Ruxolitinib on days 1,2 and 6; Panobinostat on days 2-3 and days 6-7
measure: Tmax of ruxolitinib and panobinostat at various dose levels
timeFrame: Ruxolitinib on days 1,2 and 6; Panobinostat on days 2-3 and days 6-7
Other outcomes:
Locations:
city: Paris
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Magdeburg
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Dublin
country: Ireland
facility: Novartis Investigative Site
city: Galway
country: Ireland
facility: Novartis Investigative Site
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Reggio Calabria
country: Italy
facility: Novartis Investigative Site
state: RC
city: Varese
country: Italy
facility: Novartis Investigative Site
state: VA
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: