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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).

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00946647
Recruitment Status : Active, not recruiting
First Posted : July 27, 2009
Last Update Posted : January 24, 2019
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
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 or disease Intervention/treatment Phase
Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia Acute Myeloid Leukemia Drug: Panobinostat (LBH589) and 5-Azacytidine Drug: 5-Azacytidine Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 112 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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).
Actual Study Start Date : December 2, 2009
Estimated Primary Completion Date : June 13, 2019
Estimated Study Completion Date : June 13, 2019

Arm Intervention/treatment
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

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

  2. Composite Complete Response (CR) (CR or CRi or bone marrow CR) (Phase llb) [ Time Frame: 40 weeks ]
    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 :
  1. Rate of partial and complete response (Phase l) [ Time Frame: After two, four and six LBH589 / Vidaza cycles (1 cycle 28 days) ]
  2. 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 ]
    AML, MDS, CMML: partial response (PR)

  3. Overall response (Phase llb) [ Time Frame: 40 weeks ]
    CR or CRi or bone marrow CR or PR

  4. 1-year survival rate (Phase llb) [ Time Frame: 40 weeks ]
  5. Time to progression (TTP) (Phase llb) [ Time Frame: 40 weeks ]
    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.

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

  7. Laboratory (Phase llb) [ Time Frame: 40 weeks ]
    biochemistry, hematology

  8. Electrocardiogram (ECG) monitoring (Phase llb) [ Time Frame: 40 weeks ]
    By central review using eRT

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00946647

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Sponsors and Collaborators
Novartis Pharmaceuticals
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals Identifier: NCT00946647     History of Changes
Other Study ID Numbers: CLBH589H2101
2009-010548-32 ( EudraCT Number )
First Posted: July 27, 2009    Key Record Dates
Last Update Posted: January 24, 2019
Last Verified: January 2019

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Myelodysplastic Syndromes
Chronic Myelomonocytic Leukemia
Acute Myeloid Leukemia
hypomethylating therapy
deacetylase inhibitor

Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Pathologic Processes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Histone Deacetylase Inhibitors