Text Size

A Phase Ib/IIb, Open-label, Multi-center, Study of Oral Panobinostat Administered With 5-Azacitidine (in Adult Patients With Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML).

This study is currently recruiting participants.
Verified October 2012 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00946647
First received: July 7, 2009
Last updated: October 15, 2012
Last verified: October 2012
History of Changes
  Purpose

The purpose of this randomized, two-arm, open-label expansion phase study is to collect preliminary efficacy data of panobinostat at the recommended phase II dose (RPIID) level in combination with azacytidine (5-Aza) versus an active control arm 5-Aza alone. This randomized phase II part allows also collecting safety data of panobinostat in combination with 5-Aza in comparison to single-agent 5-aza.


Condition Intervention Phase
Myelodysplastic Syndromes
Chronic Myelomonocytic Leukemia
Acute Myeloid Leukemia
 Drug: Panobinostat (LBH589) and 5-Azacytidine
Drug: 5-Azacytidine
 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib/IIb, Open-label, Multi-center, Study of Oral Panobinostat (LBH589) Administered With 5-Azacitidine (in Adult Patients With Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML).

Resource links provided by NLM:

Drug Information available for: Azacitidine
U.S. FDA Resources

Further study details as provided by Novartis:

Primary Outcome Measures:
  • Incidence of dose limiting toxicity (DLT) (Phase l) [ Time Frame: 1 cycle (1 cycle = 28 days) ] [ Designated as safety issue: Yes ]
    D3, D5, D8, D10, D12, D15

  • Composite Complete Response (CR) (CR or CRi or bone marrow CR) (Phase llb) [ Time Frame: 40 weeks ] [ Designated as safety issue: Yes ]
    By assessing preliminary efficacy of treatment with the panobinostat and 5-Aza combination at RPIID relative to treatment with single agent 5-Aza.


Secondary Outcome Measures:
  • Rate of partial and complete response (Phase l) [ Time Frame: After two, four and six LBH589 / Vidaza cycles (1 cycle 28 days) ] [ Designated as safety issue: No ]
  • Clinical response for acute myeloid leukemia (AML) and for myeloid dysplastic syndromes(MDS)/chronic myelomonocytic leukemia (CMML) and Hematologic Improvement (HI) (Phase llb) [ Time Frame: 40 weeks ] [ Designated as safety issue: No ]
    AML, MDS, CMML: partial response (PR)

  • Overall response (Phase llb) [ Time Frame: 40 weeks ] [ Designated as safety issue: No ]
    CR or CRi or bone marrow CR or PR

  • 1-year survival rate (Phase llb) [ Time Frame: 40 weeks ] [ Designated as safety issue: No ]
  • Time to progression (TTP) (Phase llb) [ Time Frame: 40 weeks ] [ Designated as safety issue: No ]
    Based on the Guidelines for Implementation of international working group (IWG) response criteria in AML, MDS and CMML according to Cheson 2003 and 2006 and specified in Post-text supplement 1.

  • Type, duration, frequency and relatedness of Adverse Events (AE) (Phase llb) [ Time Frame: 40 weeks ] [ Designated as safety issue: Yes ]
    AE severity will be assessed according to NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3.0

  • Laboratory (Phase llb) [ Time Frame: 40 weeks ] [ Designated as safety issue: No ]
    biochemistry, hematology

  • Electrocardiogram (ECG) monitoring (Phase llb) [ Time Frame: 40 weeks ] [ Designated as safety issue: No ]
    By central review using eRT


Estimated Enrollment: 111
Study Start Date: December 2009
Estimated Study Completion Date: January 2014
Estimated Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Panobinostat + 5-Azacytidine

In phase I: Panobinostat : Escalating doses starting with 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15.

In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15.

In both phases, dose of 5-Azacytidine will be 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.

 Drug: Panobinostat (LBH589) and 5-Azacytidine

Each dose of panobinostat should be taken with 240 mL of water. Patients should be instructed to swallow the capsules whole and not chew them.

If the patient forgets to take his/her dose during the morning on a scheduled treatment day then the missed dose should be taken on that same day within 12 hours. After more than 12 hours, that day's dose should be withheld, and the patient should wait to take panobinostat until the next scheduled treatment day. The patient should then continue treatment with the original dosing schedule.

The days when panobinostat and 5-Aza are scheduled together (Day 3 and Day 5 of a treatment cycle), panobinostat should be administered approximately 30 min prior to 5-Aza.
Active Comparator: 5-Azacytidine
Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.
 Drug: 5-Azacytidine

  Eligibility

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

Inclusion Criteria:

Phase l:

  • Patients with cytopathologically confirmed diagnosis of AML according to WHO criteria, excluding acute promyelocytic leukemia who are eligible for Vidaza treatment
  • ECOG performance status greater less than or equal to 2

Phase ll:

  • Adult patients (age ≥ 18 years) who are candidates for treatment with 5-Aza and present with one of the following:

    • intermediate-2 or high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS). OR
    • AML with multilineage dysplasia and maximum of 30% blasts (former RAEB-T according to FAB) OR
    • chronic myelomonocytic leukemia (CMML)
  • Patients must have the following laboratory values unless elevations are considered due to MDS or leukemia: AST/SGOT and/or ALT/SGPT ≤ 2.5 x ULN; serum creatinine ≤ 1.5 x ULN; serum bilirubin (total and direct) ≤ 2 x ULN; electrolyte panel within normal ranges (WNL) for the institution.

Exclusion Criteria:

Phase l:

  • Prior treatment with deacetylase inhibitors
  • Concurrent therapy with any other investigational agent

Phase ll:

  • Planned hematopoietic stem-cell transplantation (HSCT)
  • Patients with therapy-related MDS
  • Patients with therapy-related AML and/or relapsed/refractory AML

  • Patients with impaired cardiac function including any of the following:

    • Complete left bundle branch block or use of a permanent cardiac pacemaker, congenital long QT syndrome, history or presence of ventricular tachyarrhythmia, clinically significant resting bradycardia (<50 beats per minute), QTcF > 460 ms on screening ECG, or right bundle branch block + left anterior hemiblock (bifascicular block)
    • Presence of unstable atrial fibrillation (ventricular response rate >100 bpm). Patients with stable atrial fibrillation are eligible provided they do not meet the other cardiac exclusion criteria
    • Previous history of angina pectoris or acute MI within 6 months
    • Screening LVEF <45% by echocardiography or MUGA
    • Other clinically significant heart disease (e.g. uncontrolled hypertension or history of poor compliance with an antihypertensive regimen).

  • Any of concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study. For example:

    • Uncontrolled diabetes
    • Active or uncontrolled infection
    • Uncontrolled hypothyroidism
    • Acute or chronic liver or renal disease
  • Patient has evidence of clinically significant mucosal or internal bleeding

Other protocol-defined inclusion/exclusion criteria may apply

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00946647

Contacts
Contact: Novartis Pharmaceuticals +1(800)340-6843

  Show 45 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00946647     History of Changes
Other Study ID Numbers: CLBH589H2101, 2009-010548-32
Study First Received: July 7, 2009
Last Updated: October 15, 2012
Health Authority: United States: Food and Drug Administration
Canada: Health Canada

Keywords provided by Novartis:
Myelodysplastic Syndromes
Chronic Myelomonocytic Leukemia
Acute Myeloid Leukemia
hypomethylating therapy
 deacetylase inhibitor
MDS
CMML
AML

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelomonocytic, Chronic
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Acute
Neoplasms by Histologic Type
Neoplasms
Myelodysplastic-Myeloproliferative Diseases
Bone Marrow Diseases
 Hematologic Diseases
Precancerous Conditions
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on May 16, 2013