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

NCT ID: NCT01433445

Last Updated: 2021-06-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 61 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-11-01
• Study Completion Date: 2020-06-22

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.

Conditions

Idiopathic Myelofibrosis; Post Essential Thrombocythemia Myelofibrosis; Post Polycythemia-Vera Myelofibrosis

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

panobinostat

Intervention Type: DRUG

Given 3 times a week, every other week in 28-day cycles.

ruxolitinib

Intervention Type: DRUG

Given twice daily in 28-day cycles.

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

Group Type: EXPERIMENTAL

panobinostat

Intervention Type: DRUG

Given 3 times a week, every other week in 28-day cycles.

ruxolitinib

Intervention Type: DRUG

Given twice daily in 28-day cycles.

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

Group Type: EXPERIMENTAL

panobinostat

Intervention Type: DRUG

Given 3 times a week, every other week in 28-day cycles.

ruxolitinib

Intervention Type: DRUG

Given twice daily in 28-day cycles.

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

Group Type: EXPERIMENTAL

panobinostat

Intervention Type: DRUG

Given 3 times a week, every other week in 28-day cycles.

ruxolitinib

Intervention Type: DRUG

Given twice daily in 28-day cycles.

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

Group Type: EXPERIMENTAL

panobinostat

Intervention Type: DRUG

Given 3 times a week, every other week in 28-day cycles.

ruxolitinib

Intervention Type: DRUG

Given twice daily in 28-day cycles.

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

Group Type: EXPERIMENTAL

panobinostat

Intervention Type: DRUG

Given 3 times a week, every other week in 28-day cycles.

ruxolitinib

Intervention Type: DRUG

Given twice daily in 28-day cycles.

Interventions

panobinostat

Given 3 times a week, every other week in 28-day cycles.

Intervention Type: DRUG

ruxolitinib

Given twice daily in 28-day cycles.

Intervention Type: DRUG

Other Intervention Names

LBH589; INC424

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Villejuif, , France

Novartis Investigative Site

Magdeburg, , Germany

Novartis Investigative Site

Mainz, , Germany

Novartis Investigative Site

Dublin, , Ireland

Novartis Investigative Site

Galway, , Ireland

Novartis Investigative Site

Florence, FI, Italy

Novartis Investigative Site

Reggio Calabria, RC, Italy

Novartis Investigative Site

Varese, VA, Italy

Novartis Investigative Site

London, , United Kingdom

Countries

France; Germany; Ireland; Italy; United Kingdom

Related Links

https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=17838

Novartis Clinical Trials results database

Other Identifiers

2011-000861-10

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CLBH589X2106

Identifier Type: -

Identifier Source: org_study_id