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).

• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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

Study Design

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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

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
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

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Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

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Study Director:	Novartis Pharmaceuticals	Novartis Pharmaceuticals

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Garcia-Manero G, Sekeres MA, Egyed M, Breccia M, Graux C, Cavenagh JD, Salman H, Illes A, Fenaux P, DeAngelo DJ, Stauder R, Yee K, Zhu N, Lee JH, Valcarcel D, MacWhannell A, Borbenyi Z, Gazi L, Acharyya S, Ide S, Marker M, Ottmann OG. A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts. Leukemia. 2017 Dec;31(12):2799-2806. doi: 10.1038/leu.2017.159. Epub 2017 May 26.

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Responsible Party:	Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT00946647 History of Changes
Other Study ID Numbers:	CLBH589H2101; 2009-010548-32 ( EudraCT Number )
First Posted:	July 27, 2009
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; MDS; CMML; AML

Additional relevant MeSH terms:

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Syndrome; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Preleukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Disease; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms	Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Azacitidine; Panobinostat; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Enzyme Inhibitors; Histone Deacetylase Inhibitors