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

June 22, 2021 updated by: Novartis Pharmaceuticals

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)

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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

61

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Paris, France, 75010
        • Novartis Investigative Site
      • Villejuif Cedex, France, 94800
        • Novartis Investigative Site
  • Germany
      • Magdeburg, Germany, 39120
        • Novartis Investigative Site
      • Mainz, Germany, 55131
        • Novartis Investigative Site
  • Ireland
      • Dublin, Ireland, DUBLIN 8
        • Novartis Investigative Site
      • Galway, Ireland
        • Novartis Investigative Site
  • Italy
    • FI
      • Firenze, FI, Italy, 50134
        • Novartis Investigative Site
    • RC
      • Reggio Calabria, RC, Italy, 89124
        • Novartis Investigative Site
    • VA
      • Varese, VA, Italy, 21100
        • Novartis Investigative Site
  • United Kingdom
      • London, United Kingdom, SE1 9RT
        • Novartis Investigative Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Rate of dose limiting toxicities at the different dose levels
Time Frame: Cycle 1 (a cycle = 28 days)
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
Time Frame: From screening until safety follow up visit (30 days after last treatment), approx. 8.5 years
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
Time Frame: Ruxolitinib on days 1,2 and 6; Panobinostat on days 2-3 and days 6-7
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
Time Frame: Ruxolitinib on days 1,2 and 6; Panobinostat on days 2-3 and days 6-7
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
Time Frame: 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.
Ruxolitinib on days 1,2 and 6; Panobinostat on days 2-3 and days 6-7

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Novartis Pharmaceuticals

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 1, 2011

Primary Completion (Actual)

June 22, 2020

Study Completion (Actual)

June 22, 2020

Study Registration Dates

First Submitted

June 27, 2011

First Submitted That Met QC Criteria

September 12, 2011

First Posted (Estimate)

September 14, 2011

Study Record Updates

Last Update Posted (Actual)

June 25, 2021

Last Update Submitted That Met QC Criteria

June 22, 2021

Last Verified

June 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CLBH589X2106
  • 2011-000861-10 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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