Panobinostat and Ruxolitinib In MyElofibrosis (PRIME Trial)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Mount Sinai School of Medicine
Sponsor:
Information provided by (Responsible Party):
John Mascarenhas, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier:
NCT01693601
First received: September 14, 2012
Last updated: August 13, 2014
Last verified: August 2014
  Purpose

This is a single-center, single arm, dose finding study to assess safety and tolerability of the oral combination of Panobinostat and Ruxolitinib in patients with myelofibrosis (MF) in chronic and accelerated phase.


Condition Intervention Phase
Myelofibrosis
Drug: Panobinostat
Drug: Ruxolitinib
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Panobinostat and Ruxolitinib In MyElofibrosis (PRIME STUDY) - Phase I/II Study of Combination Oral JAK2 Tyrosine Kinase Inhibitor (JAK2-TKI) and Histone Deacetylase Inhibitor (HDACI) Therapy in Patients With Myelofibrosis

Resource links provided by NLM:


Further study details as provided by Mount Sinai School of Medicine:

Primary Outcome Measures:
  • number of patients that experience adverse events [ Time Frame: at least 28 days ] [ Designated as safety issue: Yes ]
    Assess the safety and tolerability of Ruxolitinib in combination with Panobinostat in patients with MF

  • proportion of patients that achieve at least stable disease [ Time Frame: at least 6 months ] [ Designated as safety issue: No ]
    Assess treatment response as defined by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)


Secondary Outcome Measures:
  • Spleen size [ Time Frame: up to 14 months ] [ Designated as safety issue: No ]
    Assess changes in spleen size by palpation and MRI

  • exploratory biomarkers [ Time Frame: up to 14 months ] [ Designated as safety issue: No ]
    o evaluate changes in inflammatory cytokines to therapy

  • symptom response [ Time Frame: at least 6 months ] [ Designated as safety issue: No ]
    Assess symptom response with a validated MPN tool (MPN-SAF)


Estimated Enrollment: 58
Study Start Date: January 2013
Estimated Study Completion Date: August 2018
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Panobinostat and Ruxolitinib
Combination of Panobinostat and Ruxolitinib
Drug: Panobinostat
PO TIW QOW or PO TIW QW
Other Name: LBH589
Drug: Ruxolitinib
PO BID x 28 days
Other Name: INCB424, Jakafi

Detailed Description:

Phase I/II open label, single institution, combination therapy trial of induction Ruxolitinib followed by combination with Panobinostat in dose escalation cohorts with a primary endpoint of determining the safety and tolerability of combination therapy in patients with myelofibrosis (MF) in chronic and accelerated phase. A 3+3standard dose escalation scheme will be employed and the occurrence of dose limiting toxicities (DLTs) will be captured and the occurrence of such events will determine dose cohort escalation by predetermined and established rules. In addition to establishing the DLTs, maximally tolerated dose (MTD), and recommended phase II dose (RPTD) in the phase I portion of this trial, exploratory biomarkers will be evaluated within phase I as well. Pharmacodynamics and exploratory genetic and epigenetic biomarkers will be explored as predictors of response to therapy. The RPTD cohort will be expanded to incorporate a total of 22 patients, including 6 from phase I, in order to assess clinical response as assessed by International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) as a primary endpoint for the phase II portion of this trial.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female patients aged ≥ 18 years old
  • Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
  • Intermediate-2 and higher by IWG-MRT Post PV/ET MF and PMF patients either in

    1. Chronic Phase (MF-CP)
    2. Accelerated Phase (MF-AP)
  • Patients must meet the following laboratory criteria:

    1. ANC ≥ .750 x 109/L
    2. Platelets ≥ 75 x 109/L
    3. Creatinine ≤ 1.5 x ULN,
    4. AST and ALT ≤ 2.5 x ULN
    5. Serum bilirubin ≤ 1.5 x ULN (unless Gilbert's syndrome and evidence of hemolysis)
    6. Serum potassium ≥ LLN
    7. Total serum calcium [corrected for serum albumin] or ionized calcium ≥LLN,
    8. Serum magnesium ≥ LLN
    9. Serum phosphorus ≥ LLN
    10. Free T4 within normal limits
  • ECOG Performance Status of ≤ 3
  • Any prior therapy with JAK2-TKI, hypomethylating agents, HDACI, mTORi, or iMiDs is allowed as long as it is greater than 3 weeks since last dose of administration and in the case of a JAK2-TKI or HDACI that discontinuation was not due to non-hematologic drug toxicity. An exception to this criteria are patients currently on at least 10mg BID of ruxolitinib for greater than 3 months and who have not shown an optimal response (i.e. without 50% reduction in palpable splenomegaly or 50% reduction in symptom burden). With a reduction of ruxolitinib to 10mg BID these patients may enter onto the study without stopping ruxolitinib

Exclusion Criteria:

  • Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first PANOBINOSTAT treatment.
  • Impaired cardiac function or clinically significant cardiac diseases, including any one of the following:

    1. With permanent cardiac pacemaker
    2. Resting bradycardia defined as <50 beats per minute
    3. QTcF >450 msec on screening ECG
    4. Complete Left bundle branch block, bifascicular block
    5. Any clinically significant ST segment and/or T-wave abnormalities
    6. Presence of unstable atrial fibrillation (ventricular response rate >100 bpm). Patients with stable atrial fibrillation can be enrolled provided they do not meet other cardiac exclusion criteria.
    7. Symptomatic congestive heart failure (NYHA class III-IV)
  • Impairment of GI function or GI disease that may significantly alter the absorption of PANOBINOSTAT or RUXOLITINIB
  • Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol
  • Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug
  • Concomitant use of CYP3A4 inhibitors
  • Patients who have received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is longer) and who have not recovered from side effects of those therapies.
  • Chemotherapy within 3 weeks prior to screening are excluded (other than hydroxyurea at stable doses and will be discontinued 24 hours prior to starting study drug).
  • Patients with an active bleeding tendency or are receiving any treatment with therapeutic doses of sodium warfarin (Coumadin®) or coumadin derivatives. Patients will be allowed to enter study on aspirin at doses of 81mg/d.
  • Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
  • Women who are pregnant or breast-feeding or women of childbearing potential (WOCBP) not using an effective method of birth control. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). Women of childbearing potential must have a negative serum pregnancy test within 24hrs of receiving the first dose of study medication.
  • Male patients whose sexual partners are WOCBP not using effective birth control
  • Patients with a prior malignancy within the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix)
  • Disease associated with secondary MF such as metastatic carcinoma, lymphoma, myelodysplasia, hairy cell leukemia, mast cell disease or acute leukemia (including M7 disease or acute panmyelosis with MF)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01693601

Contacts
Contact: John Mascarenhas, MD 212-241-3417 john.mascarenhas@mssm.edu
Contact: Jill Kleczko, MPA 212-241-0573 jill.kleczko@mssm.edu

Locations
United States, New York
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Principal Investigator: John Mascarenhas, MD         
Sub-Investigator: Ronald Hoffman, MD         
Sub-Investigator: Marina Kremyanskaya, MD         
Sub-Investigator: James Godbold, PhD         
Sponsors and Collaborators
John Mascarenhas
Investigators
Principal Investigator: John Mascarenhas, MD Mount Sinai School of Medicine
  More Information

No publications provided

Responsible Party: John Mascarenhas, Assistant Professor of Medicine, Hematology and Medical Oncology, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier: NCT01693601     History of Changes
Other Study ID Numbers: GCO 12-1225
Study First Received: September 14, 2012
Last Updated: August 13, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Mount Sinai School of Medicine:
Myelofibrosis
Panobinostat
Ruxolitinib

Additional relevant MeSH terms:
Primary Myelofibrosis
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Panobinostat
Histone Deacetylase Inhibitors
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 18, 2014