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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT01433445

Collaborator

(none)

Enrollment

Locations

Arms

103.7

Actual Duration (Months)

6.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Myelofibrosis Post Essential Thrombocythemia Myelofibrosis Post Polycythemia-Vera Myelofibrosis	Drug: panobinostat Drug: ruxolitinib	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

61 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Nov 1, 2011

Actual Primary Completion Date :

Jun 22, 2020

Actual Study Completion Date :

Jun 22, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 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 Given 3 times a week, every other week in 28-day cycles. Other Names: LBH589 Drug: ruxolitinib Given twice daily in 28-day cycles. Other Names: INC424
Experimental: Cohort 2 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 Given 3 times a week, every other week in 28-day cycles. Other Names: LBH589 Drug: ruxolitinib Given twice daily in 28-day cycles. Other Names: INC424
Experimental: Cohort 3 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 Given 3 times a week, every other week in 28-day cycles. Other Names: LBH589 Drug: ruxolitinib Given twice daily in 28-day cycles. Other Names: INC424
Experimental: Cohort 4 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 Given 3 times a week, every other week in 28-day cycles. Other Names: LBH589 Drug: ruxolitinib Given twice daily in 28-day cycles. Other Names: INC424
Experimental: Cohort 5 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 Given 3 times a week, every other week in 28-day cycles. Other Names: LBH589 Drug: ruxolitinib Given twice daily in 28-day cycles. Other Names: INC424
Experimental: Cohort 6/6+ 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 Given 3 times a week, every other week in 28-day cycles. Other Names: LBH589 Drug: ruxolitinib Given twice daily in 28-day cycles. Other Names: INC424

Outcome Measures

Primary Outcome Measures

Rate of dose limiting toxicities at the different dose levels [Cycle 1 (a cycle = 28 days)]

Secondary Outcome Measures

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 [Ruxolitinib on days 1,2 and 6; Panobinostat on days 2-3 and days 6-7]
Area under the plasma concentration versus time curve
Cmax of ruxolitinib and panobinostat at various dose levels [Ruxolitinib on days 1,2 and 6; Panobinostat on days 2-3 and days 6-7]
Cmax is the Peak Plasma Concentration
Tmax of ruxolitinib and panobinostat at various dose levels [Ruxolitinib on days 1,2 and 6; Panobinostat on days 2-3 and days 6-7]
Tmax: The time of maximum observed concentration sampled during a dosing interval.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Paris		France	75010
2	Novartis Investigative Site	Villejuif Cedex		France	94800
3	Novartis Investigative Site	Magdeburg		Germany	39120
4	Novartis Investigative Site	Mainz		Germany	55131
5	Novartis Investigative Site	Dublin		Ireland	DUBLIN 8
6	Novartis Investigative Site	Galway		Ireland
7	Novartis Investigative Site	Firenze	FI	Italy	50134
8	Novartis Investigative Site	Reggio Calabria	RC	Italy	89124
9	Novartis Investigative Site	Varese	VA	Italy	21100
10	Novartis Investigative Site	London		United Kingdom	SE1 9RT